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3 June 2025

33 Pages

Global Epidemiology and Antimicrobial Resistance of Metallo-β-Lactamase (MBL)-Producing Acinetobacter Clinical Isolates: A Systematic Review

,
,
,
and
1
Alfa Institute of Biomedical Sciences (AIBS), 9 Neapoleos Street, 151 23 Marousi, Athens, Greece
2
School of Medicine, European University Cyprus, 2404 Nicosia, Cyprus
3
Department of Medicine, Tufts University School of Medicine, Boston, MA 02111, USA
4
Department of Laboratory Medicine and Pathology, University of Washington School of Medicine, Seattle, WA 98195, USA
Pathogens2025, 14(6), 557;https://doi.org/10.3390/pathogens14060557
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Abstract

This systematic review assessed the global epidemiology of metallo-β-lactamase (MBL)-producing Acinetobacter clinical isolates and the associated antimicrobial resistance. A total of 475 relevant articles from the Cochrane Library, Google Scholar, PubMed, Scopus, and Web of Science were identified and screened as potentially eligible articles. Data from 85 articles were extracted for the analysis. Most reports on MBL-producing Acinetobacter clinical isolates originated from Asia [68/85 (80%) studies] and Africa [14/85 (16.5%) studies]. There were also scarce reports from Europe and America. The blaVIM (in 31 studies), blaIMP (in 29 studies), and blaNDM (in 21 studies) genes were the most commonly identified genes. In 22 out of 28 (78.6%) studies with comparable data, the proportions of MBL-producing pathogens detected using phenotypic methods were numerically higher than those using genotypic methods. MBL-producing Acinetobacter isolates showed high resistance (up to 100%) to several antibiotic classes, including carbapenems, cephalosporins, fluoroquinolones, and monobactams. However, they showed low resistance to colistin [ranging from 0% (in six studies) to 14.3% (in one study)] and to tigecycline [0% (in three studies)]. No risk of bias assessment was conducted. The findings emphasize the global spread of MBL-producing Acinetobacter and the need for enhanced antimicrobial stewardship, infection control measures, and surveillance.

1. Introduction

Pathogens resistant to antimicrobial agents are increasing worldwide and pose a threat to public health because they cause significant mortality, morbidity, and increased healthcare costs [1]. Many of the most frequently encountered resistant isolates belong to the so-called ‘ESKAPE’ pathogens (Enterococcus faecium, Staphylococcus aureus, Klebsiella pneumoniae, Acinetobacter baumannii, Pseudomonas aeruginosa, and Enterobacterales), for which the treatment options are limited [2,3].
Among these, Acinetobacter baumannii infections are particularly associated with advanced antimicrobial resistance [4]. Such infections are usually healthcare associated, but may also be community acquired [5]. Moreover, patients with Acinetobacter baumannii infections experience high mortality [6], especially when caused by carbapenem-resistant strains [7].
The World Health Organization (WHO) has designated carbapenem-resistant Acinetobacter baumannii as a critical priority pathogen and has called for the development of new therapeutic options to treat these infections [8]. Furthermore, the resistance of Acinetobacter clinical isolates to carbapenems is increasing worldwide, driven by various mechanisms, including the production of β-lactamases [9].
Beta-lactamases inactivate β-lactam antibiotics by hydrolyzing the β-lactam ring. According to the Ambler classification, β-lactamases are divided into four molecular classes: A, B, C, and D [10,11]. Classes A, C, and D have an active serine site, whereas class B [also called metallo-β-lactamases (MBLs)] uses zinc as a cofactor [12,13]. Metal ion chelators like ethylene-diamine-tetra-acetic acid (EDTA) inhibit MBL activity [12], a property utilized in phenotypic tests to detect MBL production [14]. MBLs can hydrolyze almost all β-lactam antibiotics, including carbapenems, with the notable exception of monobactams [15,16].
Previous studies are limited in scope: some examined the regional prevalence of carbapenemase-producing Acinetobacter [17,18,19,20], while others focused specifically on Acinetobacter isolates carrying the blaNDM gene [21]. However, a gap remains in understanding the global epidemiology of MBL-producing Acinetobacter. The therapeutic options for such infections are limited, as these pathogens are often resistant to most antibiotics. Potential therapeutic options include carbapenems (imipenem and meropenem), polymyxins (colistin and polymyxin B), tigecycline, and new β-lactamase inhibitor combinations (sulbactam–durlobactam and aztreonam–avibactam) [22,23,24,25]. Also, there are antibiotics in the pipeline for treating patients with these infections that could potentially be used as alternatives to the available agents, but currently they are under development in clinical trials [26]. Thus, as it is useful to evaluate the global epidemiology of MBL-producing Acinetobacter, this systematic review aims to address the knowledge gap by assessing the data on this clinically important issue.

2. Methods

2.1. Objectives

The objective of this review was to assess the global epidemiology of MBL-producing Acinetobacter clinical isolates and their resistance profiles in regard to various antimicrobial agents.

2.2. Eligibility Criteria

We included all the research articles reporting on Acinetobacter clinical isolates, with no restrictions in terms of the language, publication date, journal, region, patient demographics (adult or pediatric), or setting (inpatient or outpatient). We excluded gray literature (e.g., conference abstracts and industry reports) and any studies analyzing fewer than 5 Acinetobacter isolates.
We included studies that detected MBLs using genotypic methods [polymerase chain reaction (PCR)] and/or phenotypic methods [combined disk test (CDT), double-disk synergy test (DDST), or E-test]. Both CDT and DDST methods use imipenem plus EDTA disks in different settings to test for MBL production, as EDTA inhibits the action of MBLs. Thus, imipenem can act against the growth of MBL-producing strains [27,28]. For the CDT, a zone of inhibition more than 7 mm around the EDTA–imipenem-containing disk is considered a positive result for the production of MBL [27,29]. For the DDST, inhibition between the imipenem and EDTA disks, placed at a 10 mm distance, is a positive result [28,29]. For the E-test, a strip containing imipenem and EDTA is used [30]. We extracted antimicrobial susceptibility data from the studies that used antibiotic diffusion or microdilution methods for antimicrobial susceptibility testing.

2.3. Search Strategy

We searched five databases on 5 February 2025 (the Cochrane Library, Google Scholar, PubMed, Scopus, and Web of Science), using specific search strings (see Supplementary Table S1). Additionally, we screened the reference lists of the included studies for any further relevant articles.

2.4. Selection of Articles

Two investigators (DSK and MZ) conducted the searches. In Google Scholar, only the first 1000 results were accessible, and no bulk export option is available; therefore, we screened the Google Scholar results by title/abstract manually, before deduplication. All the citations from the Cochrane Library, PubMed, Scopus, and Web of Science were exported into Zotero version 7.0.11 (citation management software). These, combined with the Google Scholar selections, were deduplicated using the SR Accelerator tool. Two reviewers (DSK and MZ) independently screened the articles first based on the title and/or abstract and then by reviewing the full text. Any disagreements were resolved by consensus, during scientific meetings with a senior author (MEF).

2.5. Data Extraction

Two investigators (DSK and MZ) independently extracted and tabulated the key data from each study, including first author and publication year; study location (continent and country); patient population characteristics (e.g., age group, inpatient vs. outpatient); hospital/department setting; specimen type from which Acinetobacter isolates were obtained; identified Acinetobacter species; and the MBL genes tested. The main text was translated, using a web software program, if the studies were in a language other than English. For each study, we evaluated the proportion of Acinetobacter isolates that were MBL producers, as determined by genotypic and/or phenotypic methods. The studies were grouped based on the continent and country where the isolates were detected. If multiple data points were provided in a study regarding the isolation of MBL-producing Acinetobacter isolates, they were all extracted and presented separately (e.g., per isolation period). We also noted the proportion of MBL-producing isolates that were non-susceptible to various antibiotics, when such antimicrobial susceptibility data were available.

2.6. Adherence to the PRISMA Guidelines

This systematic review complies with the most recent “Preferred Reporting Items for Systematic Reviews and Meta-Analyses” (PRISMA) guidelines, and any omission is explicitly reported in the discussion section of this study. The study research protocol was not registered in a database. The PRISMA checklists for the abstract and full-text review are provided in Supplementary Tables S2 and S3, respectively.

3. Results

Identification of Relevant Articles

Figure 1 presents a PRISMA flow diagram on the identification, selection, and inclusion of articles included in this systematic review. In total, our searches yielded 73 articles from Google Scholar and 622 from the other sources. After removing duplicates, 475 articles remained for screening. Ultimately, 85 studies met the inclusion criteria and were included in our analysis, and nine articles were excluded after a full-text evaluation (Figure 1). Three studies did not present data specifically for MBL production in Acinetobacter isolates, three studies reported the isolation of less than five Acinetobacter pathogens, one study reported the isolation of pathogens from surfaces and healthcare workers, one study was a dissertation, and one study was a conference abstract. Sixty-eight of the included studies originated from Asia [31,32,33,34,35,36,37,38,39,40,41,42,43,44,45,46,47,48,49,50,51,52,53,54,55,56,57,58,59,60,61,62,63,64,65,66,67,68,69,70,71,72,73,74,75,76,77,78,79,80,81,82,83,84,85,86,87,88,89,90,91,92,93,94,95,96,97,98], fourteen from Africa [99,100,101,102,103,104,105,106,107,108,109,110,111,112], two from America [113,114], and one from Europe [115].
Figure 1. “Preferred Reporting Items for Systematic Reviews and Meta-Analyses” (PRISMA) flow diagram for identification, screening, and inclusion of articles. i Even though 16,300 results were retrieved with the Google Scholar search, only the first 1000 results could be accessed. Source: Page MJ, et al. BMJ 2021;372:n71. doi: 10.1136/bmj.n71 [116]. This work is licensed under CC BY 4.0. To view a copy of this license, visit https://creativecommons.org/licenses/by/4.0/ (accessed on 6 February 2025).
Table 1 presents the proportions of MBL-producing Acinetobacter isolates identified using genotypic and phenotypic methods, sorted by continent and country. In summary, 68 studies reported clinical Acinetobacter strains isolated from patients in countries in Asia (26 in India, 14 in Iran, 9 in Nepal, 5 in Iraq, 5 in Pakistan, 2 in Japan, 1 in Bangladesh, China, Lebanon, Malaysia, Saudi Arabia, South Korea, Taiwan), 14 in Africa (7 in Egypt, 1 in Algeria, Ghana, Libya, Morocco, South Africa, Sudan, Uganda), 2 in America (1 in Canada and the USA, 1 in Colombia), and 1 in Europe (1 in Romania). Seventy-eight studies included clinical isolates from hospitalized patients, six from both hospitalized patients and outpatients, and only one from outpatients [76]. The isolates were obtained from a variety of clinical specimens, most frequently respiratory sources (e.g., sputum and other respiratory secretions) [in 64 of 76 (84.2%) studies with available relevant data], blood [in 56/76 (73.7%)], and urine [in 50/76 (65.8%)]. Wound swabs were the next most common [in 34/76 (44.7%)], followed by cerebrospinal fluid [in 18/76 (23.7%)], pleural fluid [in 9/76 (11.8%)], burn wound samples [in 3/76 (3.9%)], and other sources.
Table 1. Proportion of phenotypic and genotypic detection of MBLs in various Acinetobacter species.
In the 85 included studies, the most commonly identified Acinetobacter species were Acinetobacter baumannii [in 63/85 (74.1%)], followed by Acinetobacter baumannii–calcoaceticus complex [in 6/85 (7.1%)], and Acinetobacter hemolyticus [in 5/85 (5.9%)]. Other Acinetobacter species were also reported in 12 studies. However, 18/85 (21.2%) studies did not specify the isolated Acinetobacter species.
Forty-seven of the 85 studies included in our analysis (55.3%) employed genotypic methods (PCR) to detect MBL genes. In total, blaVIM was tested in 31 studies, blaIMP in 29, blaNDM in 21, blaSPM in 7, blaGIM in 7, blaSIM in 5, and blaDIM in 1 study. In Africa, 10/13 (76.9%) studies tested for blaNDM, 6/13 (46.2%) for blaVIM, and 5/13 (38.5%) for blaIMP. However, in Asia, 23/31 (74.2%) studies tested for blaIMP, 22/31 (71%) for blaVIM, and 11/31 (35.5%) for blaNDM. In America, two studies tested for blaVIM, and 1/2 (50%) studies tested for blaNDM, blaVIM, and blaIMP. In Europe, the one relevant study tested for blaVIM. Only 8 of the 85 studies (9%) included in our analysis reported data on clones of Acinetobacter baumannii isolates.
Seventy of the 85 studies (82.4%) employed phenotypic tests (CDT, DDST, and/or E-test) for MBL detection. Notably, six studies used modified versions of these tests [52,77,79,80,109,117]. Thirty-two studies (37.6%) used both genotypic and phenotypic methods. In four of those thirty-two studies [55,59,79,112], the data were not directly comparable because the number of isolates tested using each method differed. Thus, 28 studies had directly comparable results between genotypic and phenotypic detection and were analyzed for concordance.
In 22 of the 28 studies (78.6%), phenotypic methods detected a higher proportion of MBL-producing Acinetobacter isolates than genotypic methods. Of those twenty-two studies, eight relied solely on the CDT for phenotypic testing [50,62,65,72,73,102,103,107], six used only the E-test [63,67,68,98,111,117], and three used only the DDST [53,57,64] method. One study used all the CDT, DDST, and E-test methods [100], and two studies used both CDT and E-test methods [51,61]. In one of the last studies, the E-test method had a lower proportion of phenotypic MBL-production detection [117/172 (68.0%)] than the genotypic method [139/172 (80.8%)] in contrast to the CDT method [144/172 (83.7%)] [51]. Also, one study used a modified CDT method, with an increase of more than 10 mm in the zone of inhibition for a positive result [80], and one used the EDTA-modified carbapenem inactivation method [117].
In 4/28 (14.3%) studies, the proportion of MBL-producing Acinetobacter detected was higher using genotypic than phenotypic methods. Among these four studies, two used only the DDST method [39,94], one used only the CDT method [101], and one used both CDT and DDST methods [69]. Finally, in 2/28 (7.1%) studies, the proportion of MBL-producing Acinetobacter detected was equal using the genotypic and phenotypic methods. One study used the CDT [31] and one used the DDST phenotypic method [99].
Table 2 presents data on the antimicrobial resistance of the studied clinical isolates. Among the 33 studies that reported antimicrobial susceptibility data for MBL-producing Acinetobacter, the resistance rates were as high as 100% in regard to most of the tested antibiotics, including carbapenems, cephalosporins, and fluoroquinolones. In five studies, MBL-producing pathogens showed resistance to monobactams too. Notably, in six of seven studies (85.7%) that evaluated colistin (six using antibiotic diffusion methods [34,36,55,66,71,84] and one using the agar dilution method [101]), no colistin resistance was detected among the MBL-producing isolates [34,36,55,66,71,84]. In the remaining study, colistin resistance was 14.3% (6 of 42 MBL-producing isolates) [101]. In addition, in all three studies that evaluated tigecycline, no tigecycline resistance was detected [34,44,87].
Table 2. Proportion of the studied resistant MBL-producing Acinetobacter clinical isolates to various antimicrobial agents.

4. Discussion

The objective of this study was the assessment of the global epidemiology of MBL-producing Acinetobacter isolates and their resistance to various antimicrobial agents. Our main finding confirms that these isolates have now spread worldwide, with most reported cases coming from Asia and Africa. In most studies, MBL-producing Acinetobacter isolates were 100% resistant to most of the tested antibiotics, including all carbapenems. Interestingly, although MBLs do not hydrolyze monobactams, the studies that tested for aztreonam susceptibility showed high resistance to this agent. This finding implies that these isolates were co-producing other types of lactamases (such as extended-spectrum β-lactamases), thus making them resistant to aztreonam, a monobactam antibiotic.
Colistin was the only agent that retained activity against the majority of these isolates (as most studies reported 0% resistance to colistin). However, all six studies that reported 0% resistance to colistin used disk diffusion methods for antimicrobial susceptibility testing. According to the joint Clinical and Laboratory Standards Institute (CLSI)/European Committee on Antimicrobial Susceptibility Testing (EUCAST) guidelines on colistin susceptibility testing, broth and agar microdilution methods are recommended over diffusion methods [118]. Thus, colistin resistance could be underestimated in these studies, with more false-susceptible pathogens reported, and the 0% percentage of resistance to colistin could have been higher if microdilution methods had been used.
In most studies with comparable data (78.6%), MBL-producing Acinetobacter was more frequently detected using phenotypic methods, specifically the CDT, followed by the DDST and E-test methods. This finding indicates that the genes encoding MBLs in the isolates from these studies possibly differed from those included in the PCR assay. The fact that the CDT detected more MBL-producing isolates compared to the other phenotypic methods is in keeping with results from previous studies demonstrating that this method is more sensitive than the DDST or E-test in regard to identifying MBL-producing pathogens [119,120,121]. Moreover, in Africa, most studies tested for the presence of the blaNDM, whereas in Asia most studies tested for blaIMP and blaVIM, highlighting the different prevalence of MBL genes between these geographical regions. Only a small proportion of studies reported data on the clones of Acinetobacter baumannii isolates.
Data from the included studies were heterogeneous, as patients were in different settings (ICU, other clinical departments, or outpatients) and had various infections. Also, the sources of isolation varied from study to study. These limitations made the analyses and synthesis of the data in the subgroups challenging and, thus, only a descriptive evaluation was conducted.
Antimicrobial resistance (AMR) is a growing global threat in regard to the treatment of infectious diseases. In response to rising AMR, standardized definitions for multidrug-resistant (MDR), extensively drug-resistant (XDR), and pandrug-resistant (PDR) bacteria have been adopted [122]. Briefly, MDR organisms are non-susceptible to ≥1 agent in at least three antibiotic categories, XDR organisms are resistant to all but one or two available categories, and PDR organisms are resistant to all categories [122].
Gram-negative bacteria have emerged as the most problematic causes of MDR/XDR/PDR infections from a public health perspective. In particular, Acinetobacter baumannii, once dismissed as a harmless colonizer, is now understood to cause severe infections. Numerous studies have demonstrated that Acinetobacter baumannii infections lead to considerable morbidity, prolonged hospital stays, higher healthcare costs, and attributable mortality [6,123]. Today, the need for immediate interventions and targeted research initiatives related to Acinetobacter baumannii infections is more urgent than ever. There is an urgent need for immediate interventions and targeted research to address Acinetobacter baumannii infections. Developing new antimicrobials, implementing personalized therapeutic approaches, and strengthening infection prevention and control programs are all crucial strategies to stem this crisis.
The global spread of MDR, XDR, and PDR Acinetobacter baumannii infections, including those caused by MBL-producing isolates, is not solely a consequence of antibiotic misuse and overuse, due to a lack of adherence to antimicrobial stewardship policies. Multiple factors, including inadequate infection control in hospitals and transmission via contaminated medical devices, also drive the spread [124]. Additionally, the genetic flexibility of Acinetobacter baumannii enables it to acquire and maintain resistance genes, complicating efforts to eradicate the bacteria [125]. The increasing use of invasive medical procedures, exposure to disinfectants, and heavy metals, further promote the persistence of resistant strains. Particularly concerning is the spread of MBL-producing strains, facilitated by horizontal gene transfer, plasmids, and resistance islands [125].
Extensive antibiotic resistance dramatically limits treatment options, making the management of patients with MDR Acinetobacter infections extremely challenging. The remaining therapeutic choices, such as polymyxins, tigecycline, and sulbactam, come with significant drawbacks, including nephrotoxicity, gastrointestinal disturbances, and limited effectiveness in certain cases [124,126,127,128]. Also, there are limited data on the clinical use of new antibiotics (cefiderocol and sulbactam–durlobactam) that may have activity against MDR Acinetobacter isolates. Cefiderocol was demonstrated to have considerable antimicrobial activity against Gram-negative bacterial isolates, including Acinetobacter baumannii [129]. Although higher mortality was observed in patients who received cefiderocol in a randomized controlled clinical trial for Acinetobacter baumannii infection, subsequent observational studies suggested better clinical outcomes in patients with Acinetobacter baumannii infection treated with this new siderophore, cephalosporin [130,131,132]. In addition, a non-inferiority randomized controlled trial comparing sulbactam–durlobactam with colistin (both combined with imipenem–cilastatin) in patients with carbapenem-resistant Acinetobacter baumannii infection showed promising results for this new combination of two β-lactamase inhibitors [133,134]. Notably, sulbactam may have activity against Acinetobacter baumannii isolates and has been used in high doses for patients with such infections [135]. This underscores the complexity of managing such infections, highlighting the urgent need for stricter surveillance, enhanced infection control programs, and the development of new therapeutic strategies [126].
Our analysis has several limitations. First, most of the included studies were from single hospitals or limited geographic areas rather than broad multicenter surveillance efforts, which may limit the generalizability of their findings. Second, there was inconsistency in the phenotypic MBL detection methods used among the studies, some used modified tests with different zone diameter cut-offs, which complicates direct comparisons of the MBL rates. Third, our analysis did not include data on some of the newest antimicrobials (e.g., recently developed β-lactam/β-lactamase inhibitor combinations), since most of the included studies were published before those agents became available. In addition, we did not perform a formal quality assessment of the included studies, sensitivity analyses, statistical methods to assess the heterogeneity of the studies, and publication bias (e.g., a tendency to report outbreaks or unusually resistant cases), which might have influenced the literature available. These factors should be kept in mind when interpreting our results.

5. Conclusions

The assessed data show that MBL-producing Acinetobacter strains that cause infections have spread globally. These isolates are associated with advanced antimicrobial resistance and pose a critical therapeutic challenge, with important consequences for global public health. These findings underscore the urgent need for a multifaceted approach, including enhanced antimicrobial stewardship, strengthened infection control measures, and sustained global surveillance, to mitigate the spread of MBL-producing Acinetobacter isolates.

Supplementary Materials

The following supporting information can be downloaded at: https://www.mdpi.com/article/10.3390/pathogens14060557/s1, Table S1: Search strings for each resource; Table S2: “Preferred Reporting Items for Systematic Reviews and Meta-Analyses” (PRISMA) checklist for the abstract; Table S3: “Preferred Reporting Items for Systematic Reviews and Meta-Analyses” (PRISMA) checklist for the full-text review.

Author Contributions

M.E.F. had the idea for the article. All authors contributed to the methodology used in the article. D.S.K. and M.Z. conducted the literature search, data extraction, and tabulation. M.E.F., D.S.K. and M.Z. contributed to the first version of the manuscript. C.F. and G.S.T. revised the manuscript. All authors have read and agreed to the published version of the manuscript.

Funding

This research received no external funding.

Institutional Review Board Statement

Not applicable.

Data Availability Statement

The data used in the conduction of this study are available upon request.

Conflicts of Interest

The authors declare that there are no conflicts of interest.

Abbreviations

AMRAntimicrobial resistance
CDTCombined disk test
CLSIClinical and Laboratory Standards Institute
DDSTDouble-disk synergy test
EDTAEthylene-diamine-tetra-acetic acid
EUCASTEuropean Committee on Antimicrobial Susceptibility Testing
MBLMetallo-β-lactamase
MDRMultidrug resistant
PCRPolymerase chain reaction
PDRPandrug resistant
PRISMAPreferred Reporting Items for Systematic Reviews and Meta-Analyses
WHOWorld Health Organization
XDRExtensively drug resistant

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