Multi-resistant Acinetobacter baumannii emergence associated with healthcare infections : Meta-analysis Emergência de Acinetobacter baumannii multirresistente associado a infecções relacionadas à assistência à saúde : Metanálise Aparición de Acinetobacter baumannii multi-resistente asociada con infecciones relacionadas

The high resistance to antimicrobials has made hospitals a potentially dangerous environment for the development of HAIs, especially when associated with multi-resistant bacteria such as A. baumannii. The work aimed to evaluate the incidence of multidrug-resistant Acinetobacter baumannii described in the literature through a meta-analysis. A meta-analysis of a qualitative and quantitative nature was carried out in which original articles and review articles that presented data on the occurrence and existence of multidrug resistance in Acinetobacter baumannii were evaluated. The Scientific Electronic Library on Line (SciELO) and Medical Literature Analysis and Retrieval System Online (Pubmed / MEDLINE) databases were consulted using the descriptors "Acinetobacter baumannii," "multi-resistance," "IRAS," "incidence." Most studies were carried out in 2018. In general, most studies were crosssectional 85.00% (n = 17) and cohort 15.00% (n = 3). In the selected studies, 5877 cases were reported, of which 3544 corresponded to multi-resistant species of Acinetobacter. The cumulative prevalence ratio corresponded to 0.603 with a 95% confidence interval [0.590 to 0.615]. The analysis of the temporal trend of the Ratio of the prevalence of multidrugresistant Acinetobacter baumanni according to the year of the selected studies indicated that the PR suffered a decline in 2009 and 2013 and a new tendency to increase from 2015 and suffered small fluctuations until 2019, the trend did not show significant (R = 0.0772). Therefore, the MDR profile is worrying, given the currently available therapeutic alternatives.


Introduction
Health Care Related Infections (IRCH) are defined as infections acquired after the patient's admission to the hospital environment. Usually 72 hours after admission, which may occur during hospitalization or after discharge, related to hospital procedures and to the period of hospitalization itself. In the case of the presence of infection since admission, IRAS is considered when there is a worsening or isolation of another pathogen in the same topography (ANVISA, 2017a).
The development of IRCH often results in several losses, such as more extended hospitalization, the economic impact on the public health sector, higher mortality, and advancement in bacterial resistance (Leoncio et al., 2019). Among the losses cited, bacterial resistance has gained much prominence, and its most frequent pathogens are associated with IRAS were grouped in an acronym and called "ESKAPE" (Enterococcus faecium, Staphylococcus aureus, Klebsiella pneumoniae, Acinetobacter baumannii, Pseudomonas aeruginosa, and Enterobacter spp) (Araújo & Pereira, 2018). The high resistance to antimicrobials has made hospitals a potentially dangerous environment for IRCH development, significantly when associated with multi-resistant bacteria such as A. baumannii (Dalmasio, 2018). Several mechanisms of resistance to different antimicrobials have been described for the genus Acinetobacter, among them the enzymatic mechanism (β-lactamases), which degrade antibiotics by the action of enzymes such as cephalosporinases (class A of Ambler Ex: AmpC and ESBL-β-lactamases Extended Spectrum) (Ranjbar, et al., 2018). Also, the metalo-β-lactamases (class B of Ambler) and Research, Society and Development, v. 9, n. 10, e1889108270, 2020 (CC BY 4.0) | ISSN 2525-3409 | DOI: http://dx.doi.org/10.33448/rsd-v9i10.8270 5 oxacillinases (class D of Ambler) that have activity against carbapenem antibiotics (Chagas, 2015).
Other resistance mechanisms include multidrug efflux pumps that decrease the concentration of antibiotics in the periplasmic space (Vashist et al., 2011). In addition to changes in affinity for penicillin-binding proteins (PBPs) and decreased permeability of external membranes (Pagano, et al., 2016). Individuals admitted to the intensive care unit (ICU), carriers of HIV/AIDS, presence of invasive devices, and excessive use of antimicrobials are near related to the emergence of bacterial resistance (Roberts, et al. , 2009). Even in the face of the evolution of research for the development of several antimicrobials classes, these have been presenting failures in the combat due to the constant mutations of bacterial strains and increase of resistance mechanisms (Gomes, et al, 2014).
Given this, the early detection, control, and prevention of IRCH are fundamental measures for reducing outbreaks of A. baumannii. (Paula, et al. , 2017). Considering the high rates of IRAS associated with this species in recent years, the work aimed to evaluate the incidence of multi-resistant A. baumannii described in the literature through a meta-analysis.

Methodology
For this study, a meta-analysis of a quali-quantitative nature was carried out in which original articles and review articles presenting data on the occurrence and existence of multi-resistance in A. baumannii were evaluated. According to the scientific research elaboration manual proposed by Pereira et al. (2018), the data were collected by simple random sampling. The Scientific Electronic Library on Line (SciELO) and Medical Literature Analysis and Retrieval System Online (Pubmed/MEDLINE) databases were Research, Society and Development, v. 9, n. 10, e1889108270, 2020 (CC BY 4.0) | ISSN 2525-3409 | DOI: http://dx.doi.org/10.33448/rsd-v9i10.8270 6 consulted using the descriptors "Acinetobacter baumannii," "multi-resistance," " IRCH," "incidence." As inclusion criteria, national and international articles were selected, available in full, published in Portuguese or English, between 2003 and 2019. The exclusion criterion was duplicity, non-availability in full, and articles that, despite presenting the selected descriptors, the scope did not present a direct relation to the proposed theme and the absence of absolute data necessary for meta-analysis. Finally, considering these aspects, 33 articles were selected for analysis.
Considering the likely heterogeneity among observational studies, an effects model was applied to calculate 95% confidence intervals (CIs). The Confidence Interval Calculator prepared by Herbert (2013) was used to calculate the CI and Prevalence Ratio (RP) of multi-resistance. When the prevalence was reported for several years that extended for more than one year, the study was included in the period that captured the most updated data. Only studies that reported the year the study was conducted were included in the meta-analysis. To demonstrate the distribution of multi-resistance among A. baumannii, a

Results
A total of 987 records were identified in the databases, of which 20 studies were included for analysis (Table 1). Most of the excluded works were research articles, followed by short reports, only abstract for annals, and letter to the editor. We selected data published in Latin America, Europe, and the Middle East, with works predominantly published in Brazil (85%).
Most studies in Table 1 were conducted in 2018, and the duration of the studies varied from 1 to 10 years. There were variations in susceptibility testing methods, including automated methods, such as VITEK, and other tests, including E-test, diffusion disk, and broth microdilution. In general, most studies were 85.00% (n = 17) transversal and 15.00% (n = 3) cohort.

Discussion
Multidrug-resistant (MDR) is considered that microorganism resistant to at least one agent in three or more classes of antimicrobial agents (Oliveira & Damasceno, 2010 Development, v. 9, n. 10, e1889108270, 2020 (CC BY 4.0) | ISSN 2525-3409 | DOI: http://dx.doi.org/10.33448/rsd-v9i10.8270 9 more than two classes of antibacterial in 68% of cases. Besides the abusive use of antimicrobials, the resistance to these agents is related to indifferent prescriptions to the current evidence-based methods, and the lack of global epidemiological surveillance (Gurgel & Carvalho, 2008).
Class D carbapenemases or oxacillinase (OXA) can hydrolyze the beta-lactam ring of carbapenems (Chen et al., 2014). The high resistance to carbapenems found in this study exemplifies the increasing loss of sensitivity of A. baumannii to these drugs, which is mostly due to the presence of oxacillininses (OXA) and which are identified by molecular baumannii were identified. (Higgins, et al., 2013).
The study by Genteluci (2016) was relevant in identifying high rates of OXA isolates, in which all samples 100% (n=92) had the blaOXA-51 gene and 92.3% (n=85) had the blaOXA-23 gene.
Currently, polymyxins have been considered the only option for treating severe infections caused by A. baumannii MDR, which generates concern due to the scarcity of therapeutic alternatives (Pogue, 2015). The generalized reintroduction of this antibiotic and its non-rational use may trigger adverse reactions such as nephrotoxicity and neurotoxicity, which led to its abandonment (Arroyo, et al., 2009). Although currently considered the only therapeutic option, the intensive use of polymyxins has already shown the emergence of resistant A. baumannii samples, with resistance rates of 40.7% in Spain and 30.6% in South Korea (Ko, et al., 2007).
In studies by Gomes and Genteluci et al. (2016), both conducted from samples collected from patients treated in the public health network of Rio de Janeiro, in different institutions, through the performance of antibiogram identified resistance to polymyxins in most samples 75 (n=92) and 41 (n=60) respectively. The absence of susceptibility to the antibiotic was identified in polymyxin concentrations below 4 μg/mL, and CIM (minimum inhibitory concentration) ≥ 4 μg/mL. According to the National Health Surveillance Agency, resistance to polymyxins must be monitored continuously, and its detection reported to health authorities according to the National Plan for the Prevention and Control of Microbial Resistance in Health Services (ANVISA, 2017a).
baumannii developed septic shock. Moreover, about 50% of the patients had a median survival for up to two days after diagnosing infection by this microorganism. It is noted that the direct consequences of bacterial resistance are the high costs generated by hospitalization (bed, drugs, etc.), polyantibiotic therapy resulting in greater chances of drug interactions, and immeasurable disorders (suffering, death, pain) (Ballot, et al. , 2012).
The clinical microbiology laboratory plays a guiding role in the correct prescription of antimicrobials because it isolates, identifies, and determines the sensitivity profile to antimicrobials of pathogens causing infections (ANVISA, 2017b). Moreover, the pharmacy sector's participation is essential for the fulfillment of the stages of pharmaceutical assistance, which aims to ensure the population's access to quality drugs, contributing to rational use (Ministry of Health, 2007). The pharmacy sector also participates in the triage (review) of medical prescriptions, which reduces possible errors of dose or therapeutic indication (Silva, 2012). Besides, the clinical pharmacy assists in therapeutic monitoring (dose adjustment based on plasma concentration), optimization of dosage according to the clinical characteristics of the patient (weight, renal function), the etiological agent, and the pharmacokinetic and pharmacodynamic characteristics of the drug (Santos, et al. , 2019).
Some articles selected here stand out for the dissemination of strategies in the confrontation and reduction of IRAS by A. baumannii as Modesto and Brito (2019), which claim to be an effective measure to promote the decolonization of empirical therapy, i.e., opting for therapy with the use of reduced spectrum antimicrobials, even when treatment with broad-spectrum antibiotics has begun, and they show positive results. Viana (2013) emphasizes the fundamental role of measures such as hygiene of the hands, minimizing the risks of infection associated with the use of procedures, equipment, medical devices, and standard precautions.
Veloso, Campelo e Sá (2017) ratify that for the rational use of antimicrobials, it is essential to adopt educational and restrictive measures, such as continued education of prescribers, the requirement to fill out a form for the supply of restricted antimicrobials, and actions that limit the interference of the pharmaceutical industry. Therefore, in front of the limited therapeutic alternatives for the treatment of IRAS by A. baumanni MDR, we conclude that it shows the necessary development of new drugs. Research, Society and Development, v. 9, n. 10, e1889108270, 2020 (CC BY 4.0) | ISSN 2525-3409 | DOI: http://dx.doi.org/10.33448/rsd-v9i10.8270

Conclusion and Suggestions
It is possible to conclude that Acinetobacter baumannii multi-resistant presents a substantial incidence, which represents a worrying public health problem since it contributes to an increase in mortality and costs. Among the study's limitations, we mentioned the small number of randomly selected articles, which may or may not have underestimated or overestimated the data.
Among the suggestions for the reduction of the incidence of multi-resistant species of A. bauumannii, we recommend the implantation of a program of management of the use of antimicrobials in health services, which involves a set of actions destined to its control, which include the excellent practices of dilution, conservation and administration, besides the audit and monitoring of prescriptions, education of professionals and patients, assuring optimal therapeutic results with minimum potential risk.
As a tool, the Brazilian Ministry of Health instituted the National Program for Prevention and Control of Health-related Infections as a tool to guide professionals. The document has produced guides for several actions, such as surveillance and monitoring of microbial resistance, early identification, patient management flows, biosafety standards for professionals and patients, guidelines for collecting and forwarding samples to Central Public Health Laboratories (LACEN).
This study indicates that the characteristics of MDR are similar in the multiple published studies; however, new work must be carried out to expand scientific knowledge on the subject.