Abstract
The increase of multidrug-resistant bacteria - including Acinetobacter baumannii (A. baumannii) - has been reported globally. The aim of this systematic review was to determine the risk factors of A. baumannii infection, its resistance profile, reservoirs and mortality rates in Brazil. Data from over 3,000 patients were included. Results suggested that A. baumannii is widely transmitted in Brazil and the endemic clones ST1, ST15, ST 25, ST79, ST162 and ST730 were the most reported; also, blaOXA23, blaOXA51 and blaOXA143 were common resistant genes. The risk factors for A. baumannii infection included the procedure of using invasive devices, previous antibiotic therapy, hemodialysis, comorbidities and higher scores on the Sequential Organ Failure Assessment (SOFA). Two out of five studies identified multidrug resistant A. baumannii to polymyxin. Mortality rates varied between 43.7% to 81%, except for the ST25 strain in which there was a 100% mortality rate. Mortality was associated with sepsis, respiratory infection, septic shock, old age (>60 years) and administration of norepinephrine. Nonetheless, this review highlights the need for more data on A. baumannii infection across Brazil to support public policies aiming to control and prevent the dissemination of this bacteria.
Keywords: A. baumannii, multidrug-resistant, resistant profile, antibiotic resistant, Brazil
Introduction
Reports of increasing outbreaks of multidrug-resistant microorganisms have been growing significantly around the world. The resistance of microorganisms stems from mutations, transposable genetic materials (plasmid, transposon, and integron), and inadequate use of antimicrobials in humans, animals, and environments, thus representing a global threat that requires effective interventions [1]. In 2008, Rice grouped six emerging bacteria capable of rapidly developing antimicrobial resistance mechanisms (“ESKAPE bugs”), including Acinetobacter baumannii (A. baumannii) [2]. Of the 31 species of the genus Acinetobacter, the one that stands out for its opportunism, and which causes numerous global outbreaks, is A. baumannii. Outbreaks associated with A. baumannii have been described in hospitals globally [3] A. baumannii causes severe infections in hospitalized and critically ill patients, mostly in those with severe underlying diseases and undergoing invasive procedures [4].
A. Baumannii acquired resistance phenotypes to multiple drugs [5]. Carbapenem is considered effective against A. baumannii infection, although resistance to this antibiotic is increasing because A. baumannii produces a variety of 0-lactamase enzymes, such as carbapenemases and oxacillinase (OXA).
The Centers for Disease Control and Prevention (CDC) reported 8,500 cases of A. baumannii infection in 2017 and 700 deaths in the United States [6]. In Brazil, data about transmission, incidence, and the resistant profile of A. baumannii infection are scarce; such information might better assist in the decision-making involving clinical interventions and could likewise provide a precise understanding of the burden in the country. Indeed, to the best of our knowledge, there are no systematic reviews on the prevalence of A. baumannii and its resistance profile in the country.
Therefore, the aim of this systematic review was to determine the risk factors of A. baumannii infection, its resistance profile and mortality rates in Brazil. Beyond its immediate application for Brazilian health institutions, the study might aid in the management of A. baumannii infection in other regions, particularly in developing countries.
Methods
Study setting
A systematic review of the literature was performed covering Brazilian national and international databases. The focus of this systematic review was on studies conducted in Brazil that reported on incidence, resistance profiles, mortality and risk factors associated with A. baumannii infection. The investigation had been registered at the International Prospective Register of Systematic Reviews (PROSPERO; record: CRD42021249563) and was conducted following the PRISMA guidelines [6-9].
Search strategy
A search for previous systematic review was carried out in the Cochrane Library using “Acinetobacter”, “Brasil” and “Brazil” as descriptors and records were identified. Subsequently, the following string was used to locate potential studies: “Acinetobacter baumannii” OR ““A. baumannii” AND “intensive care” OR “critical care” AND “resistant” AND “Brasil” OR “Brazil”. Searches were conducted between April and May 2021 in two databases: PubMed and the Virtual Health Library (Biblioteca Virtual em Saude - BVS). BVS covers the most relevant literature on health sciences in Brazil.
Inclusion and exclusion criteria
Studies that provided data on the incidence of Baumannii infection in Brazil (analytical, prospective, retrospective, experimental, randomized trials, cohort and case-control) were considered eligible. Moreover, studies were included when information on resistance profile was available. Only reports written in Portuguese, Spanish and English from the last five years were included. As such, research published more than five years ago, conducted in other countries, literature reviews, editorials, letters, comments, conference abstracts, and case reports were excluded. Studies without a clear focus on A. baumannii, unpublished, or published in the gray literature were excluded.
Data extraction and risk of bias assessment
Data were collected by two investigators (MCBS and HMBW), blindly and independently. Researchers used a standardized sheet form designed according to the inclusion and exclusion criteria. The evaluation was carried out in two stages. Firstly, titles and abstracts were evaluated. Secondly, full texts were read and evaluated. After these selection stages, manual searches were conducted in the articles’ references. Any disagreements between the two investigators while selecting the eligible studies were solved consulting a third investigator (DV). The results obtained were then summarized in a table containing the following characteristics: study name, region of the study, database and journal name, study design and participants, methods, objectives, results, and conclusions.
The assessment of the risk of bias was performed using the New Castle Ottawa Scale. Specific questionnaires according to different study types were used [8-10].
Results
Characteristics of the studies
The identification phase returned 19 and 15 results from PubMed and BVS, respectively (Figure 1). From these, 19 studies were removed (13 due to duplication; 6 for other reasons). In addition, 10 other studies were excluded, mainly because of inappropriate study type (n=5), descriptive studies (n=4) or for not having identified A. baumannii (n=1). Finally, 5 articles [11-15] were included in the final review: four from PubMed [12-15] and one from BVS [11]. A manual search was performed in the references of the included articles and resulted in no further studies to be included.
Figure 1. Flowchart of literature search according to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA).
The characteristics of the studies are summarized in Table 1 and the results of the risk of bias assessment are reported in Table 2. Overall, there was both good quality and low risk of bias in the reports reviewed (Table 2). From these, four were carried out in central Brazil (Goiás (n=1), Minas Gerais (n=1), Mato Grosso (n=1), and Southern Mato Grosso (n=1)) and one was conducted in the South of the country (Paraná; n=1). Four studies were conducted in ICUs [12-15] and one reported data at a hospital level [11].
Table 1. Characteristics of the studies and the main findings.
| Reference | Study location | Study design | Setting and study time | Results |
|---|---|---|---|---|
| Neves et al. (2016) [11] | Minas Gerais | Cohort study | In 500-bed tertiary teaching hospital Prospective data collection of patients over 18 years old colonized with carbapenem-resistant Acinetobacter baumannii (CRAB). |
|
| 12 months (December 2009 to December 2010) |
|
|||
| Castilho et al. (2017) [12] | Goiás | Cohort study | In five ICUs with 10 beds Healthcare-associated infections of A. baumannii. Those infected less than 48 hours of admission was excluded. |
|
| 6 months (June to December 2010) |
|
|||
| da Silva et al. (2018) [13] | Mato Grosso do Sul | Case-control | Two adult ICUs. Case: patients with confirmed OXA-23 enzyme-producing A. baumannii. Control: patients with negative isolates for A. baumannii in the first 48 hours after admission. |
|
| 19 months (September 2013 to April 2015) |
|
|||
| Azevedo et al. (2019) [14] | Mato Grosso | Cohort study | Clinical data were obtained from the patients’ records. |
|
| 43 months (June and December 2010) |
|
|||
| Talizin et al. (2020) [15] | Paraná | Cohort study | A historical cohort of patients who received polymyxin in the treatment of ventilator-associated pneumonia in the ICUs |
|
| 12 months (January 2017 to January 2018) |
|
CRAB: carbapenem-resistant Acinetobacter baumannii; ISA: insertion sequence Acinetobacter; MDR: multi-resistant; SOFA: sequential organ failure assessment
Table 2: Risk of bias assessment results.
| Case-control study | Adequate case definition | Representation | Selection of controls | Definition of controls | Control for important factor or additional factor | Verification of exposure | Same method for cases and controls | Non-response rate | Total (0-9) |
|---|---|---|---|---|---|---|---|---|---|
| Da Silva et al. (2018) [13] | * | * | * | * | ** | * | * | * | 9 |
| Cohort study | Adequate representation of the exposed cohort | Selection of the non-exposed cohort | Confidence in measuring the exposure | The outcome of interest is not present at baseline | Control for an important or additional factor | Adequate outcome measurement | Long follow-up Enough for event development | Adequate cohort follow up | Total (0-9) |
| Castilho et al. (2017) [12] | * | * | * | * | * | * | * | * | 8 |
| Azevedo et al. (2019) [14] | * | * | * | * | ** | * | * | * | 9 |
| Talizin et al. (2020) [15] | * | * | * | * | ** | * | * | * | 9 |
| Neves et al. (2016) [11] | * | * | * | * | * | * | * | * | 8 |
Genetic and antimicrobial resistance profile of A. baumannii in Brazil
Four studies identified carbapenemase-producing A. baumannii and the blaOXA-23 gene was identified in all samples [11-14]. Two studies identified blaOXA-143 while the blaOXA-24 was the most prevalent resistant gene [11, 14] A positive association was identified between the presence of blaOXA-51 and blaOXA-23 in all strains [13]. Resistance to polymyxin and tigecycline was also reported [11, 14].
In 2 studies, predominant genotypes of A. baumannii were ST1, ST15, ST25, ST79 [13], ST162, and ST730 [11]. One investigation reported the ST79 as the most widespread genotype [13]. ST30 was associated with higher mortality rate while ST162 appeared to be linked to higher survival rates [14]. Also, 2 studies found endemic features for the ST1 genotype [11,13].
Risk factors and mortality rates of A. baumannii infection in Brazil
Risk factors of A. baumannii infection were assessed in 3 studies [12,14,15]. Moreover, the use of invasive devices, previous antibiotic therapy, use of nasogastric tube, and hemodialysis increased the risks of infection [15]. Biofilm formation was described in 1 study, in which most isolates (76.8%) presented with this feature [12]
A. baumannii- associated mortality rates were reported in 3 studies, ranging from 43.7%to 81% [11,14,15]. One study identified an association of A. baumannii infection with poor prognosis [11] and another study indicated higher mortality of patients with A. baumannii-associated sepsis and septic shock that received polymyxin [15]. Respiratory infection, age (>60 years), and noradrenaline administration constituted the main risk factors for mortality in those with A. baumannii infection [11]. Notably, patients infected or colonized by the ST25 strain that harbored blaOXA-23 had a 100% mortality rate [13]. Previous use of cephalosporins and carbapenems associated with a six-fold increase in the risk of carbapenem-resistant A. baumannii infection; comorbidities and higher scores on the Sequential Organ Failure Assessment (SOFA) significantly predicted patients mortality [15].
Discussion
Based on the review of studies published between 2016 and 2020, nosocomial infections caused by A. baumannii seem to represent a significant risk to the health of hospitalized patients, particularly in the ICU and, indisputably, when resistance to carbapenems occurs. This risk is explained by the patients’ vulnerability, particularly those with severe comorbidities and receiving invasive procedures. Therefore, ICUs seem to be a main source of acquired infections of A. baumannii [3].
In Brazil, there is the evidence that A. baumannii produced carbapenemases, in particular OXA. The most responsible phenotypes associated with nosocomial outbreaks were A. baumannii producing OXA-23-, OXA-40/24, and OXA-58-like enzymes; among carbapenem-resistant A. baumannii, the most detected was blaOXA-23 [12]. The first outbreak of blaOXA-23-producing A. baumannii was described in 1999 in the city of Curitiba, State of Paraná, Brazil, 14 years after the first identification of the enzyme in Scotland. Since then, several studies have identified this pathogen with a similar resistance profile in several Brazilian states [16]. Results from these investigations revealed that A. baumannii harbored a high prevalence of blaOXA-23, followed by blaOXA-51; blaOXA-143 was found in A. baumannii isolates in Brazil and other Latin American countries [12, 15, 17, 18].
Biofilms are communities of bacteria organized within an envelope of substances. They are produced by the bacteria and protect chemical agents and antibiotics used to fight infections. Wet surfaces are more prone to biofilm formation; moreover, the greater the degree of adhesion, the harder it is to remove biofilms. The penetration of antimicrobials and the selective pressure exerted by them contribute in developing resistance mechanisms by bacteria [19,20].
Our study suggests that the risk factors associated with A. baumannii infection that may influence both the rates of resistance and spread in the ICU includes: having comorbidities, undergoing invasive procedures, prolonged hospitalization, previous exposure to many classes of antimicrobials and old age [12, 21]. A study carried out in several countries also linked these risk factors to a higher prevalence of infections and colonization of A. baumannii in the ICUs; moreover, seasonality was cited as a considerable risk factor in warmer seasons [22].
There is a consensus that colonized or infected patients represent reservoirs for horizontal transmission and dissemination of multidrug resistance bacteria, especially in ICUs. Transfers of patients between units and health teams working in different institutions within the same city are facilitators for the occurrence of this transmission in Brazil [12].
The most frequent clonal variants in Brazil were ST15, ST79, and ST51 and these are also the most frequent ones found in South America. Therefore, these endemic variants represent major risks in ICUs. Importantly, sequencing of strains across regions are needed to better understand the trajectories of these clones [23].
Overall, there was a low risk of bias in the studies reviewed here. This is partially explained by the strict inclusion and exclusion criteria of our protocol. All reports employed the National
Health Surveillance Agency criteria to define hospital-acquired infections. However, the lack of experiments and the poor national representation might encourage and support future investigations.
In summary, this systematic review included recent data from more than 3,000 hospitalized patients and reviewed the resistance profile of A. baumannii, the potential reservoirs, risk factors associated with the infection and mortality rates in Brazil. However, the external validity of the results might be limited due to the non-uniform distribution of the studied regions since 80% of data came from central regions.
Conclusion
This systematic review demonstrates the relevance of hospital-acquired infections caused by multidrug-resistant A. baumannii, especially strains resistant to carbapenems and polymyxin. It characterized A. baumannii as both a threat and a challenge to patients’ health and safety in Brazil due limited treatment options, coupled with the occurrence of biofilm formation. Information provided in this review points to a need for robust studies while highlighting the need for data from different regions of the country to determine genetic variety and resistance factors for A. baumannii infection. Such data might guide protocols to control transmission and could optimize national public policies for detecting and controlling A. baumannii.
Acknowledgments
We are deeply grateful for the support of all of those who contributed in this investigation.
Ethics approval
Not required.
Conflict of interest
The authors declare that they have no competing interests.
Funding
This article has not received any specific grant from funding agencies in the public, commercial or non-profit sectors.
Underlying data
All data underlying the results are available as part of the article and no additional source data are required.
How to cite
Silva MCB, Werlang HMB, Vandresen D, et al. Genetic, antimicrobial resistance profile and mortality rates of Acinetobacter baumannii infection in Brazil: A systematic review. Narra J 2022; 2(1): e68 - https://doi.org/10.52225/narra.v2i1.68.
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Associated Data
This section collects any data citations, data availability statements, or supplementary materials included in this article.
Data Availability Statement
All data underlying the results are available as part of the article and no additional source data are required.