Acinetobacter baumannii as a causative agent of health care associated infections

Acinetobacter baumannii is an opportunistic pathogen that seriously affects sick patients, causing Health Care Associated Infections (HCAI) such as pneumonia associated with mechanical ventilation, urinary tract infections and bacteremia, in recent years this bacterium has become a health problem worldwide, its isolation from infections present in hospitalized patients has been increasing, and it also has various mechanisms of resistance to antibiotics. The present documentary research aims to describe the mechanisms of pathogenicity and resistance to antibiotics used by Acinetobacter baumannii as a causal agent of HCAI. To carry out this work, a literature search was carried out in databases such as: Scielo, PubMed, NCBI, and Elsevier. The pathogenicity mechanisms that allow it to colonize and develop infections in hospitalized patients are: porins, biofilms, pili, lipopolysaccharides, phospholipases, outer membrane vesicles and the production of siderophores. It has enzymatic resistance mechanisms such as betalactamases and non-enzymatic mechanisms such as porin modification, efflux pumps, and modifications in DNA gyrase. There are extrinsic factors that favor the development of HCAI, such as the immunological and health condition of the patient, as well as the association with medical equipment. Studies carried out between the years 2005 to 2018 reveal that A. baumannii is one of the main causative agents of pneumonia associated with mechanical ventilation in patients admitted to the Intensive care unit.


Introduction
Acinetobacter baumannii is an opportunistic pathogen that affects severely ill patients [1]. It is widely distributed in nature, almost 100% of the samples from soil and water develop this bacterium, so any humid hospital environment can serve as an environmental reservoir [2]. Currently A. baumannii belongs to the group of non-fermenting bacilli, with Gram staining, this bacterium is observed in the form of cocci or coccobacilli, it is gram-negative, oxidase negative, strictly aerobic and immobile, in addition, it is one of the most frequent bacteria isolated in clinical laboratories and is characterized by resistance to penicillin [3].
The antibiotic resistance is the ability of some bacteria to survive in the presence of said antibiotic at different concentrations [4]. It is important to mention that antibiotics are one of the main therapeutic tools that the health sector has to face infectious diseases [5]. Likewise, the pathogenicity mechanisms that this bacterium possesses to be one of the main causes of Infections Associated with Health Care HCAI, formerly called nosocomial or hospital infections, are addressed, the World Health Organization (WHO) defines HCAI as "infections contracted by a patient during their treatment in a hospital or other health center and that said patient did not have, nor was it incubating at the time of admission" [6].
In recent years, A. baumannii has become a major health problem worldwide; It is attributed as the cause of various infections such as; bacteremia, urinary tract infections, but above all as a cause of nosocomial pneumonia, especially those associated with mechanical ventilation in patients admitted to the Intensive Care Unit (ICU) [7], being responsible for 2% to 10% of hospital infections caused by gram-negative bacteria [8].
The fact that this bacterium is one of the most frequent causes of outbreaks of hospital infections is due to that it has an enormous capacity for adherence and survival on surfaces such as biomedical equipment, personal protective equipment, curtains, ventilation ducts, and even in the mobile devices of healthcare workers, in addition to being resistant to most intermediate-grade disinfectants [9]. One of the things that stands out the most about A. baumannii is its ability to accumulate various resistance mechanisms [10]. Because A. baumannii is the causative agent of 10% of all infections in hospital patients (2016), this in relation to other gram-negative bacteria that cause them, in addition to being a bacterium with a considerable mortality rate in patients immunosuppressed, we consider it important to carry out a documentary research, which allows us to recognize the pathogenicity mechanisms used by A. baumannii to cause infections associated with health care, the extrinsic factors that favor their development, as well as to identify the mechanisms of resistance to antibiotics possessed by this bacterium in the treatment of the disease.

Material and methods
The present work is a descriptive documentary investigation, for which a literature search related to the bacterium Acinetobacter baumannii was carried out, the collection of information was obtained from four bibliographic databases, Scielo, PubMed, NCBI and Elsevier. In this search, articles published between the years 2000 to 2020, in English and Spanish, were selected, using keywords such as: "Acinetobacter, resistance, pathogenicity", the website of the World Health Organization was also consulted, an article published in the UNAM Digital University Magazine, an annual report issued by the Secretary of Health through the General Directorate of Epidemiology in Mexico and an electronic book "Koneman´s Color Atlas and Textbook of Diagnostic Microbiology".

Results and discussion
Pathogenicity is the ability of an infectious agent to colonize and cause infection in a host [11]. Acinetobacter baumannnii has pathogenicity mechanisms which give it the ability to colonize humans and subsequently develop infections. Currently A. baumannii is one of the pathogens mostly isolated from hospitalized patients and medical staff, being one of the main causes of HCAI [12]. Table 1 shows the pathogenicity mechanisms of A. baumannii.
Acinetobacter baumannii has become a clinically important pathogen worldwide due to its great capacity to develop antimicrobial resistance [13]. The mechanisms used by this bacterium can be enzymatic mechanisms, such as the action of beta-lactamases and non-enzymatic mechanisms such as the loss of porins, and overexpression of expulsion pumps ( Figure 1) [9]. The enzymatic mechanisms are presented in Table 2 and the non-enzymatic ones in Table 3.

Figure 1
Mechanisms of resistance of A. baumannii [10]

Mechanism Function
Porins (OmpA) It is the most abundant membrane protein of A. baumannii, it is known to bind to the epithelial cells and mitochondria of the host, causing edema, mitochondrial dysfunction and finally apoptosis of the cell; it also participates in the evasion of the complement system and in the formation of biofilms.

Biofilms
Populations of A. baumannii that are in skin and soft tissue infections form robust biofilms within the wound, as well as are capable of forming biofilms on abiotic surfaces in equipment associated with health care, which contributes to the development of infections associated with health care. These biofilms give protection to the bacteria.

Pili
They mediate the interaction between the bacteria and its environment. Most strains of A. baumannii encode and produce a pili system called Csu / pili, which are crucial for the formation and maintenance of biofilms on abiotic surfaces.

Lipopolysaccharide (LPS)
It is an immunostimulatory molecule that is important in bacterial resistance to external stress and human serum, it also allows adhesion to human epithelial cells.

Phospholipases
Acinetobacter baumannii possesses phospholipases C and D which allow the lysis of human cells by cleaving the phospholipids present in the cell membrane.
Outer membrane vesicles (OMV) Allowing pathogens to interact with the host without close contact between the bacteria and the host, A. baumannii OMVs contain LPS, OmpA, proteases, and phospholipases.

Siderophores
Some strains produce siderophores because they synthesize outer membrane proteins that are dependent on iron, which allow it to live inside the human body. [13,8,12,14,15,16]

Betalactamases
The mechanism of action of these enzymes consists of the breakdown of the amide bridge of the beta-lactam ring, which prevents these antibiotics from being able to bind to penicillin-binding proteins (PBPs) and thus allow the formation of the bacterial wall to continue. Through this mechanism, acid derivatives are produced which do not have bactericidal properties. Resistance to carbapenems.

Cephalosporinase • AmpC (ADC)
When ADC is expressed at a low level it confers resistance to penicillin. When ADC is expressed at a high level it provides resistance to cephalothin, piperacillin, cefotaxime, ceftazidime and aztreonam.

Mutations in DNA gyrase
Resistance to fluoroquinolones is also mediated by mutations in the gyrA gene and the parC gene, the combination of both mutations is reflected in the resistance that A. baumannii presents to these antibiotics. [20,15,13,21,19]

Extrinsic factors that favor the development of HCAI
There are extrinsic factors that favor the development of HCAI caused by A. baumannii, studies reveal that people infected by this bacterium are commonly patients with prolonged hospitalization and those with great immunosuppression. These infections usually occur in debilitated patients, the majority are patients admitted to the ICU, as well as those who need mechanical ventilation, these being the highest risk groups. Other factors related to colonization and infection are patients with recent surgeries, vascular catheterization, tracheostomy, enteral feeding, and those receiving antimicrobial therapy with third-generation cephalosporins, fluoroquinolones, and carbapenems [22,23].
Due to the fact that A. baumannii has been shown to be one of the pathogens that causes HCAI, mostly isolated together with other gram-negative bacteria, in the last 20 years there have been studies that seek to demonstrate the frequency with which this bacterium occurs in hospitalized patients. In Chile, between 2000 and 2003, a study was carried out by the national epidemiological surveillance system of the Ministry of Health (MINSAL), which indicated that A. baumannii was the leading cause of pneumonia associated with mechanical ventilators in adults, with 38.2% of the total also mentioned that it represented the third etiology in bloodstream infections in adults with 8.7% and the seventh cause in urinary tract infection (UTI) associated with a urinary catheter with 4.4% as can be seen in table 4 [24]. In 2017, the Secretary of Health [25] presented a report made in Mexico through the Red Hospitalaria de Vigilancia Epidemiológica (RHOVE), which is in charge of the epidemiological surveillance of HCAI in Mexico, this report showed that from 2009 to 2015 Acinetobacter baumannii together with bacteria such as Escherichia coli and Klebsiella pneumoniae showed an upward trend as etiological agents of HCAI, in that year A. baumannii occupied 6.6% of the total etiological agents of HCAI, it was also one of the microorganisms with the highest frequency in the Intensive Care Units for Adults. Table 5 shows the resistance profile of A. baumannii and the rest of the isolated gram-negative bacteria.  figure 2, this is the most isolated microorganism in samples of respiratory origin. The resistance profile of the same was also carried out, which is represented in table 6. And regarding the frequency of microorganisms isolated in urine samples from AICU, A. baumannii ranked third with 14%, only below Klebsiella pneumoniae with 18%, and Escherichia coli with 15%.  In 2018 Ortega et al [28] conducted a study that included 30 patients with a diagnosis of severe sepsis (SS) admitted to the ICU of the Pedro Kourí Tropical Medicine Institute hospital, the results showed that more than 60% of the cases revealed infections by gram-negative pathogens, where the most frequent microorganisms were Pseudomonas aeruginosa (34.8%), Acinetobacter baumannii (26.1%) and Staphylococcus aureus (13.1%), in addition the sensitivity of the microorganisms to the different antimicrobials showed an increase in resistance to carbapenems and colistin.

Conclusion
Acinetobacter baumannii is commonly the causative agent of pneumonia, urinary tract infections, and is frequently isolated in patients admitted to the Intensive Care Unit. Its pathogenicity mechanisms are porins, biofilms, pili, lipopolysaccharides, phospholipases, outer membrane vesicles and siderophores. These mechanisms together with extrinsic factors such as the immunological and health condition of the patient, and the association with a medical team favor the development of HCAI by A. baumannii. The antibiotic resistance mechanisms employed by A. baumannii can be enzymatic, such as the action of beta-lactamases, and non-enzymatic mechanisms, such as the modification of porins, the presence of efflux pumps, and mutations in DNA gyrase.