Drug resistance of Acinetobacter ssp. in patients with pneumonia in a Brazilian Pre-Amazon region during the pre-pandemic and pandemic periods of COVID-19Abstract
Antimicrobial resistance is a global public health threat that has been impacted by the COVID-19 pandemic. The aim of this study was to evaluate the resistance of Acinetobacter spp. isolated from patients with pneumonia in a Brazilian Pre-Amazon region during the pre-pandemic and pandemic periods of COVID-19. Bacterial strains were obtained from tracheal aspiration, sputum and bronchoalveolar lavage for diagnosis and phenotypic characterization. MALD-TOF was used to identify strains. The automated Phoenix and VITEK® 2 Compact system and the disc diffusion method were performed to determine the antimicrobial susceptibility profile. Were analyzed a total of 41,590 samples from patients admitted to hospitals of a Brazilian Pre-Amazon region, from January 2019 to December 2021. Of these, 162 isolates of Acinetobacter spp. were from the pre-pandemic period and 308 from the pandemic COVID-19. A. baumannii was the most prevalent species. Among the samples, 52% were male patients, aged over 60 years, hospitalized in intensive care units. Acinetobacter spp. showed higher rates of resistance to cefepime (79.1%), levofloxacin (77.8%), and ceftazidime (77%) in the pre-pandemic period and during the pandemic to piperacillin (72.4%), imipenem (71.6%) and ciprofloxacin (71.8%). Taken together, the data showed that A. baumannii was the most prevalent species among Acinetobacter spp., being more frequent among elderly patients admitted to the ICU. The strains presented high resistance to most antibiotics tested, mainly carbapenems. In addition, there was an increase in resistance to polymyxin B, which raises an alert since this is a therapeutic choice to treat infections caused by Acinetobacter spp. multidrug resistant.
Keywords: Acinetobacter spp.; COVID-19; pandemic; bacterial resistance
Resumo
A resistência antimicrobiana é uma ameaça global à saúde pública e tem sido impactada pela pandemia da COVID-19. O objetivo deste estudo foi avaliar a resistência de Acinetobacter spp. isolados de pacientes com pneumonia em uma região Pré-amazônica do Brasil, durante o período pré-pandêmico e pandêmico da COVID-19. Amostras bacterianas foram obtidas de aspiração traqueal, escarro e lavado bronco-alveolar para diagnóstico e caracterização fenotípica. O MALD-TOF foi usado para identificação das amostras. Os sistemas automatizados Phoenix e VITEK-2, bem como o método de difusão em disco foram utilizados para determinar o perfil de suscetibilidade aos antimicrobianos. Foram analisadas um total de 41.590 amostras de pacientes internados em hospitais de uma região da Pré-Amazônia do Brasil, no período de janeiro de 2019 a dezembro de 2021. Destes, 162 isolados de Acinetobacter spp. foram isolados no período pré-pandêmico e 308 durante a pandemia de COVID-19. A. baumannii foi a espécie mais prevalente. Das amostras, 52% eram oriundas de pacientes do sexo masculino, com idade superior a 60 anos, internados em unidades de terapia intensiva. Acinetobacter spp. apresentaram maiores taxas de resistência à cefepime (79,1%), levofloxacina (77,8%) e ceftazidime (77%) no período pré-pandêmico, e durante a pandemia à piperacilina (72,4%), imipenem (71,6%) e ciprofloxacina (71,8%). Os dados em conjunto mostraram que A. baumannii foi a espécie mais prevalente entre os isolados de Acinetobacter spp., sendo mais frequente entre pacientes idosos internados em UTI. As cepas apresentaram alta resistência à maioria dos antibióticos testados, principalmente aos carbapenêmicos. Além disso, houve um aumento da resistência à polimixina B, o que levanta um alerta, uma vez que esta é uma opção terapêutica para tratar infecções causadas por Acinetobacter spp. resistentes a múltiplas drogas.
Palavras-chave: Acinetobacter spp.; COVID-19; pandemia; resistência bacteriana
1. Introduction
COVID-19, caused by SARS-CoV-2, emerged in the city of Wuham, China, in December 2019 and quickly spread around the world (Bogoch et al., 2020; Du Toit, 2020). More than 7 million official deaths attributed to COVID-19 have been reported by the Institute for Health Metrics and Evaluation; however, the actual number to date is estimated to be 17.7 million (IHME, 2022).
Currently, after the dissemination of preventive measures and, more recently, the availability of vaccines, clinical manifestations are milder or even asymptomatic (Ssentongo et al., 2022). Despite that, patients affected by SARS-CoV-2 may develop severe respiratory failure, requiring the use of mechanical ventilation, more intensive treatments, and are subject to other disorders, such as coinfections (Grieco et al., 2020; Rangel et al., 2021).
Studies indicate that coinfections are associated with increased mortality among patients hospitalized with COVID-19 (Mirzaei et al., 2020; Garcia-Vidal et al., 2021). The predisposition to coinfections is related to hospitalization due to SARS-CoV-2, mainly in Intensive Care Units (ICU), where one usually finds opportunistic nosocomial pathogens such as Acinetobacter spp. (Shinohara et al., 2022).
Acinetobacter spp. are cocci-bacilli, Gram-negative, non-fermenting glucose, catalase-positive and oxidase-negative (Wong et al., 2017). This microorganism is known to be an opportunistic pathogen that benefits from failures in the host's anatomical defenses and changes in the normal microbiota (Lee et al., 2017). Thus, the use of mechanical ventilation, catheterization (venous or urinary), surgeries, invasive procedures and prolonged broad-spectrum antibiotic therapy, especially in patients who are in the ICU, are determining factors to be considered regarding infection by Acinetobacter spp. (Zhou et al., 2019; Kaye and Pogue, 2015).
Of all the species of the genus Acinetobacter, A. baumannii is the pathogen of greatest clinical importance because it is related to Healthcare-associated infections (HAIs) (Harding et al., 2018). A. baumannii isolates demonstrate increasing resistance to antimicrobials, restricting therapeutic options, contributing to a high mortality rate and increased length of hospital stay, thus resulting in high health costs (Ibrahim et al., 2021). For these reasons, it is on the list of priority pathogens of the World Health Organization as a critical microorganism, priority 1 for research and development of new antibiotics (Taconelli et al., 2018).
The pandemic caused by SARS-Cov-2 was responsible for redirecting public health resources and health systems to minimize damage. Consequently, other health issues have been readjusted and, given the emergency of the situation, received less attention (Nieuwlaat et al., 2021). The impact of bacterial resistance in this scenario, especially at the local level, is still unknown, although the prescription of antibiotics played a prominent role in the treatment initially available for COVID-19, as direct therapy for SARS-Cov-2, or even as a prophylactic measure (Segala et al., 2021; Langford et al., 2020).
Thus, considering this context, one of the ways to assess the impact of the COVID-19 pandemic on antimicrobial resistance is to investigate the susceptibility profile of Acinetobacter spp. isolated in the periods leading up to the pandemic and during the pandemic.
2. Material and Methods
2.1. General aspects
This is a descriptive, retrospective and cross-sectional study, carried out from the survey of positive results of cultures for Acinetobacter spp. obtained from test reports of patients hospitalized in public and private hospitals in São Luis, a Brazilian Pre-Amazon region, from January 2019 to December 2021. The samples were obtained for convenience directly from the microbiological sector of a local laboratory. The results of cultures of tracheal secretion, sputum and bronchoalveolar lavage from patients with pneumonia were included in the study. In addition, antimicrobial susceptibility tests were evaluated.
2.2. Microbiological analysis
The positive culture isolation was performed using MacConkey, chromogenic medium, and blood agar plates. Subsequently, the isolates were identified by MALDI-TOF (Matrix Assisted Laser-Desorption Ionization-Time of Flight Mass Spectrometry MS). The mass spectra acquired for each bacterial strain were compared to those contained in the database using Biotyper 3.0 software (Bruker, Billerica, MA). All strains were kept in LB broth supplemented with 15% glycerol at -80 °C.
For antimicrobial susceptibility testing, the Kirby Bauer plate diffusion technique was used, in addition to the automated Phoenix and VITEK® 2 Compact system (Biomerieux L’etoile, France), according to the Brazilian Committee on Antimicrobial Susceptibility Testing (BrCAST, 2018, 2019, 2020, 2021).
2.3. Data analysis
Variables such as gender, age, hospitalization unit, type of clinical sample, isolated species, identification method and antimicrobial susceptibility profile were analyzed. For this study, the pre-pandemic period was defined between January 2019 and March 2020, when the first case of COVID-19 was confirmed in São Luís, Brazil. Therefore, we defined the pandemic period as April 2020 to December 2021.
To assess the distribution, Acinetobacter spp. occurrences in the hospitalization units, the total number of cases was computed, regardless of the species. Then, the relationship in percentage of isolates was verified according to the number of each sector.
As for susceptibility, we tested the antimicrobials most commonly prescribed in the treatment of Acinetobacter spp. infections: amikacin, gentamicin, imipenem, meropenem, ceftazidime, cefepime, piperacillin/tazobactam, ampicillin/sulbactam, polymyxin B, ciprofloxacin, minocycline, tigecycline, sulfamethoxazole/trimethoprim. Then, we classified them into sensitive, intermediate and resistant.
The microorganisms were also evaluated for resistance to carbapenems. To evaluate MIC changes, the carbapenem class was selected using the increased resistance of Acinetobacter spp. to this class of antimicrobials as criterion.
The data were organized and stored in a spreadsheet designed for this purpose using Microsoft Excel® (2020) graphs were generated with Graph Pad Prism® software, version 7.
The results were expressed as the mean and submitted to the Chi-square Test (Fischer’s method) using the Graph Pad Prism software, version 7. The 95% confidence interval (p<0.05) was used to compare the sensitivity profile of isolated samples by age, sex, sectors, and hospital networks.
2.4. Ethical aspects
Following Resolution No. 466/2012 of the National Health Council (CNS), this research was approved by the Research Ethics Committee of the CEUMA University (Process nº 2.221.431/2017).
3. Results
The results are presented in graphs and tables, based on the analysis of 41,590 samples from patients hospitalized between January 2019 and December 2021. Of these, a total of 23,587 were obtained from fourteen hospitals during the pre-pandemic period (January 2019 to March 2020) and 18,003 from eleven hospitals in the pandemic period (April 2020 to December 2021). Were obtained 162 isolates of Acinetobacter spp. in the pre-pandemic and 308 during the pandemic from samples of tracheal secretion, bronchoalveolar lavage and sputum obtained from patients with pneumonia. From those, A. baumannii and A. nosocomialis were the most prevalent species, respectively, in both periods (Table 1).
Biological samples and microorganisms isolated from patients treated at public and private hospitals in São Luís, Brazil (2019-2021).
Regarding gender, there was a predominance of males in cases of pneumonia, and considering age group, the elderly (>60 years) were the most affected (Table 2).
Profile of patients with pneumonia treated at hospitals in São Luís, Brazil, in the pre-pandemic and pandemic periods (2019-2021).
Among the hospitalization units analyzed, the ICUs had more cases of infection by this microorganism, totaling 113 cases (69.8%) in the pre-pandemic period and 178 (57.8%) during the pandemic. The pediatric ICU, nursery and medical clinic were accommodations where the occurrence of Acinetobacter spp. increased during the pandemic, as shown in Figure 1.
Distribution of Acinetobacter spp. in the inpatient units of hospitals in São Luís, Brazil, in the pre-pandemic and pandemic periods (2019-2021).
Regarding the antimicrobial resistance profile (Table 3) in the pre-pandemic period, cefepime (79.1%), levofloxacin (77.8%), and ceftazidime (77%) were the antibiotics against which Acinetobacter spp. showed higher rates of resistance. During the pandemic, piperacillin (72.4%), imipenem (71.6%), and ciprofloxacin (71.8%) were the least effective against the pathogen.
Susceptibility profile of Acinetobacter spp. to the main antimicrobials tested in the clinic.
Among carbapenems, more than half of the samples showed resistance in the pre-pandemic period, with resistance being observed in 69.4% of cases for imipenem and 68.3% for meropenem. During the pandemic, the rate of resistance to the class of antimicrobials increased, reaching 70.8% in the evaluated samples.
Minocycline and polymyxin B were the antibiotics with the highest rate of effectiveness in both periods (>90%), followed by sulfamethoxazole/trimethoprim, tigecycline and gentamicin.
Considering the MIC variation in the carbapenem group, the predominant values were between > 8 and ≤ 16 mg/mL for imipenem and ≥ 32 for meropenem, in both periods. We observed an increase in the rate of cases of resistance during the pandemic (Figure 2).
Variation of the Minimum Inhibitory Concentration of carbapenems (imipenem and meropenem) in the pre-pandemic and pandemic periods (2019-2021).
4. Discussion
The ability to acquire mechanisms of resistance to several classes of antimicrobials and the ability to survive and adapt to adverse situations makes Acinetobacter spp. an important nosocomial pathogen, being declared in 2017 by the World Health Organization as one of the species that poses the greatest risk to human health due to its multidrug resistance capacity (Taconelli et al., 2018).
In the present study, A. baumannii was the most prevalent species, with an occurrence of 82.1% in the pre-pandemic period and 79.9% during the pandemic, a result similar to that found by Ribeiro et al. (2019). When evaluating the occurrence and bacterial profile of cultures collected from patients admitted to the ICU of a tertiary hospital, it was observed that the species with the highest occurrence in samples of tracheal secretion was also A. baumannii, representing 27% of the isolates. These results also corroborate the findings of Souza et al. (2021b), who evaluated the prevalence of microorganisms involved in infections in an infectious disease hospital. Among Gram-negatives, A. baumannii was the third most prevalent pathogen, present in 25% of the study samples.
A. baumannii is known to cause various HAIs, including bacteremia, sepsis, urinary tract infections, wound and soft tissue infections, and meningitis; however, the predominant role of this microorganism is as an agent of nosocomial pneumonia (Sarshar et al., 2021). In addition, other species such as A. nosocomialis, A. seifertii and A. lactucae are considered disseminated nosocomial pathogens and are occasionally involved in nosocomial infections (Rangel et al., 2021).
In our study, the second most prevalent species in both periods was A. nosocomialis, including 10 isolates resistant to carbapenems, with one case being reported in the pre-pandemic period and nine during the pandemic. Corroborating our findings, Singkham-in and Chatsuwan (2018), when evaluating the mechanisms of resistance to carbapenems in isolates of Acinetobacter spp., found 19 isolates of A. nosocomialis in 346 samples, with 26.3% being resistant to carbapenems. The authors concluded that a possible explanation for the increased resistance of the species is related to the transfer of carbapenemase genes between A. baumannii and A. nosocomialis. Lasarte-Monterrubio et al. (2022) explained that the production of β-lactamases of the D-carbapenem hydrolyzing class, such as OXA-24/40, makes the use of carbapenems difficult not only for multidrug-resistant A. baumannii infections, but also for those caused by other species of Acinetobacter spp.
Cerezales et al. (2018) identified strains of A. seifertii in samples initially identified as Acinetobacter spp. Although this species is clinically less relevant compared to others, its incidence in studies associated with infections has increased. In our study, four strains of A. seifertii were associated with infection during the pandemic, one of which was resistant to carbapenems. This suggests that some isolates may acquire resistance genes, hindering the effectiveness of antibiotic therapy.
When comparing the most frequent gender among the bacterial isolates, there was a predominance of Acinetobacter spp. from male patients; however, this did not result in a significant variation between genders, since males represented 52% of the pre-pandemic patients and 55% during the pandemic. Diverging from our results, an epidemiological survey of A. baumannii carried out in an oncological hospital in Belém, in the northern region of Brazil, pointed out a predominance in female patients, with 54.8% of the samples (Souza et al., 2021a).
Similar to our results, in the study by Ciginskiene et al. (2019), no difference was observed between genders in tracheal aspirate samples obtained from patients admitted to the ICU of a hospital with A. baumannii infection, with 51.7% of the isolates coming from male patients.
Patients aged over 60 years are the most affected by infections caused by Acinetobacter spp. Our research showed a prevalence of this group in both pre- and pandemic periods, but with a significant increase in the number of pandemic patients aged 18 to 40 and the presence of infected children and adolescents aged 0 to 17 years. Corroborating our study, Garcia et al. (2013), when carrying out the epidemiological profile of nosocomial infections by multidrug-resistant bacteria in a hospital in Minas Gerais, southeastern Brazil, also observed the predominance of patients affected by infections by Acinetobacter spp. in the age group of 60 to 69 years (29.5%). Thus, susceptibility to infections caused by opportunistic microorganisms, such as Acinetobacter spp., seems to be related to the vulnerability of older patients (Weiskopf et al., 2009).
However, the increased prevalence among young adults infected during the pandemic indicates that in addition to compromised immunity, as seen in children and the elderly, colonization pressure, selection due to exposure to broad-spectrum antibiotics, and barrier disruptions, anatomical features are also important predictors of infection by Acinetobacter spp. (Wong et al., 2017).
Our study also showed that 69.8% of infected patients were in the ICU before and 57.8% during the pandemic, which corroborates a study by Lopes et al. (2022) in hospitals in the city of Natal, northeastern Brazil, showing that 58.2% of Acinetobacter spp. occurred in patients admitted to the ICU.
The prevalence in the ICU is related to the invasive procedures that are constantly performed there, such as the use of catheters, probes and mechanical ventilation equipment. Thus, patients who are in the ICU are more likely to develop HAIs, in addition to being an important reservoir for the horizontal transmission and dissemination of Acinetobacter spp. in a hospital environment (Oliveira and Damasceno, 2010; Silva et al., 2018).
Among the species of Acinetobacter spp., A. baumannii is the most frequent in nosocomial infections worldwide (Lin and Lan, 2014). Virulence mechanisms, such as outer membrane porins, phospholipases, proteases, lipopolysaccharides, capsular polysaccharides, protein secretion system and iron chelating systems, plus the ability to quickly develop resistance to antimicrobials, make infections caused by this pathogen a therapeutic problem (Lee et al., 2017). In our study, a low sensitivity profile was found for the tested antibiotics, pointing to resistance to several classes of antimicrobials, including cephalosporins (cefepime and ceftazidime), fluoroquinolones (levofloxacin) in the pre-pandemic period, and penicillins (piperacillin/tazobactam), carbapenems (imipenem) and quinolones (ciprofloxacin) during the pandemic.
The impact of the pandemic on bacterial resistance within the ICU was somewhat expected since the empirical prescription of broad-spectrum antibiotics was included as part of the recommended therapy for all critically ill patients with COVID-19 admitted to the ICU (Phua et al., 2020; Sieswerda et al., 2021).
In our study, A. baumannii resistance to both meropenem and amikacin was greater than 58% between samples in both periods, different from what was demonstrated by Zuniga-Moya et al. (2020). Julio and colleagues, when carrying out the study in a tertiary hospital in Honduras, found that meropenem and amikacin were the antibiotics to which the isolates showed the highest sensitivity (>60%). On the other hand, Bastos et al. (2020), when evaluating the bacterial profile of biological samples from the clinic of a university hospital in the hinterland of Pernambuco, northeastern Brazil, found high rates of resistance, with 100% of A. baumannii isolates resistant to meropenem, imipenem and piperacillin/tazobactam, corroborating our results, which also showed high rates of resistance between penicillins and carbapenems.
During the pandemic, some cases of carbapenem-resistant A. baumannii outbreaks were reported in hospitals dedicated to COVID, such as the one reported by Nebreda-Mayoral et al. (2022). Among superinfections, A. baumannii was the most frequent pathogen in samples isolated from 712 patients with COVID-19. Despite this, the authors drew attention to the low rate of coinfection in the study (5%), which would not justify the high number of broad-spectrum antibiotics empirically used at hospital admission.
Shinohara et al. (2022) isolated samples of carbapenem-resistant A. baumannii from 14 patients admitted to a COVID ICU. Of these, 10 had ventilator-associated pneumonia or bacteremia, and 7 died. All isolates demonstrated resistance to penicillins, cephalosporins, aminoglycosides, fluoroquinolones and carbapenems. These results suggest that bacterial resistance associated with coinfections with carbapenem-resistant A. baumannii in patients with COVID-19 contributes to the negative outcome.
When conducting a retrospective study, Li et al. (2020) observed that 6.8% of patients acquired secondary infections, and almost half of them (49.0%) died during hospitalization. In this study, A. baumannii was the third most isolated Gram-negative bacteria. As in our study, there were high rates of resistance to several classes of antibiotics, except for minocycline and tigecycline, the isolates showed resistance greater than 80%.
The high rates of resistance occur mainly due to the vertical transfer of genes encoding β-lactamases that have the ability to hydrolyze carbapenems. This mechanism promotes both the increased resistance of Acinetobacter spp. to carbapenems as well as to cephalosporins, limiting the use of these important antimicrobials in the treatment of patients (Higgins et al., 2010). In this scenario, as a last choice, the use of polymyxins is recommended; however, the prolonged use of this antimicrobial is associated with neurotoxicity and nephrotoxicity (Piperaki et al., 2019; Garnacho-Montero and Timsit, 2019).
Polymyxin B was the second most effective antibiotic in both periods (> 90%); however, there was an increase in the percentage of resistance from 3.2% before the pandemic to 5.5% during the pandemic. This result draws attention since antibiotics are used for the treatment of infections caused by Acinetobacter spp. are limited, with antimicrobials from the polymyxin group being the last available choice (Kyriakidis et al., 2021). As well as our results, Carrasco et al. (2021) demonstrated the emergence of resistance to polymyxins to A. baumannii isolated from hospitalized patients during an outbreak in a university hospital in Brazil. A total of 6 isolates out of 16 showed resistance to polymyxin B and colistin, representing 37.5% of incidence. The authors concluded that polymyxin resistance in this outbreak was due to chromosomal mutations in the A. baumannii isolates.
Analyzing the Acinetobacter spp. from our study, we observed a high MIC in both periods for carbapenems. The imipinem cutoff for resistance is a MIC ≥ 4mg/mL, however, more than half of the samples had MIC values greater than 8 mg/mL. The same occurred with meropenem, which had a MIC ≥ 32mg/mL, despite the classification as resistant being >8 mg/mL. Thus, these values suggest an increase in resistance to carbapenems during the study period.
Antibiotic resistance can occur through three mechanisms. First, reduced membrane permeability or increased efflux prevents access to the target. Second, through genetic mutations and lastly, antibiotics can be directly inactivated by hydrolysis or modification (Blair et al., 2015). Intrinsically, bacteria of the genus Acinetobacter spp. have mechanisms of resistance to several groups of antimicrobials and have a capacity to acquire resistance. The production of β-lactamases, aminoglycoside-modifying enzymes, efflux pumps, permeability defects and target site modifications are mechanisms that have gradually reduced the number of classes of antibiotics to clinically treat infections caused by A. baumannii (Lee et al., 2017).
5. Conclusions
Taken together, our data show that A. baumannii was the most prevalent species among Acinetobacter spp. isolates, being more frequent among elderly patients admitted to the ICU.
It is noticeable a high resistance to most antibiotics tested, mainly carbapenems, with a high MIC among the isolates. Regarding sensitivity, minocycline and polymyxin B were the antibiotics with the highest effectiveness rate, followed by sulfamethoxazole/trimethoprim, tigecycline and gentamicin. Despite this, there was an increase in resistance to polymyxin B, which raises an alert since this is considered a therapeutic choice to treat infections caused by Acinetobacter spp.
Thus, the establishment of targeted strategies for detection, prevention and reduction of bacterial resistance in health services are fundamental to controlling the dissemination of multidrug-resistant pathogens, such as Acinetobacter spp. Therefore, to control the long-term impact of COVID-19 on AMR, prospective studies, monitoring measures, and the integration of antimicrobial stewardship activities into the pandemic response are needed.
Acknowledgements
The authors thank the Ceuma University for technical and financial support, and Cedro Laboratory, São Luís, Brazil, for providing the strains. This study was supported by the Fundação de Amparo à Pesquisa e ao Desenvolvimento Científico e Tecnológico do Maranhão (FAPEMA), São Luís, Brazil, grant numbers: Universal No. 00919/19 and BEPP No. 01822/21.
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Publication Dates
-
Publication in this collection
25 Nov 2024 -
Date of issue
2024
History
-
Received
19 Oct 2023 -
Accepted
12 July 2024
