Acinetobacter baumannii Infections in Times of COVID-19 Pandemic

The COVID-19 pandemic has generated an overuse of antimicrobials in critically ill patients. Acinetobacter baumannii frequently causes nosocomial infections, particularly in intensive care units (ICUs), where the incidence has increased over time. Since the WHO declared the COVID-19 pandemic on 12 March 2020, the disease has spread rapidly, and many of the patients infected with SARS-CoV-2 needed to be admitted to the ICU. Bacterial co-pathogens are commonly identified in viral respiratory infections and are important causes of morbidity and mortality. However, we cannot neglect the increased incidence of antimicrobial resistance, which may be attributed to the excess use of antimicrobial agents during the COVID-19 pandemic. Patients with COVID-19 could be vulnerable to other infections owing to multiple comorbidities with severe COVID-19, prolonged hospitalization, and SARS-CoV-2-associated immune dysfunction. These patients have acquired secondary bacterial infections or superinfections, mainly bacteremia and urinary tract infections. This review will summarize the prevalence of A. baumannii coinfection and secondary infection in patients with COVID-19.


Introduction
After its recognition in Wuhan, China, in December 2019, coronavirus disease 2019 , caused by the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), quickly spread across the globe. It became a global health threat [1][2][3]. As of 2 July 2021, SARS-CoV-2 had infected exceeding 180 million people and caused almost 4 million deaths around the world, according to the COVID-19 Weekly Epidemiological Update for that date [4]. Commonly, the clinical manifestations of COVID-19 are less severe, such as a mild upper respiratory tract disease or even asymptomatic infection [5,6]. However, SARS-CoV-2 infection can lead to severe and critical respiratory failure requiring mechanical ventilation, septic shock, or other organ dysfunction or loss that requires intensive care treatment [7]. Moreover, evidence suggests that coinfections and secondary infections can play an essential role in higher mortality risk during COVID-19 among a significant number of hospitalized patients [3,8,9].
Previous experiences with other coronaviruses and other respiratory pathogens have indicated this possibility of coinfection and secondary infections, especially by bacteria [10][11][12][13][14]. For example, Streptococcus pneumoniae, Haemophilus influenzae, and Staphylococcus aureus are the most commonly reported bacteria associated with co/secondary influenza infections [15,16]. In COVID-19 cases, while the prevalence of coinfections varied, the prevalence of secondary infections could be as high as 50% among non-surviving patients [2]. like, OXA-143-like, and OXA-235-like groups, and the intrinsic chromosomal OXA-51-like group [90]. Acquired resistance to aminoglycosides (plasmid-borne aminoglycosidesmodifying enzymes and 16S rRNA methylases) and fluoroquinolones (mutations in gyrA and/or parC) have been described in carbapenemase-producing A. baumannii strains [91]. Because of the increasing carbapenem resistance, second-line agents such as polymyxins and tigecycline have been considered for treating carbapenem-resistant A. baumannii infections [77]. However, resistance to polymyxins emerged and has been reported [92,93].
Antibiotic resistance mechanisms can be classified into three groups [94]: (1) Restriction or impediment of target access by reducing membrane permeability or increasing antibiotic efflux. (2) Direct antibiotic inactivation by a genetic mutation, post-translational modification, or enzymatic hydrolysis. (3) Access restriction through a structural change of membrane components or number of transmembrane segments.
The antibiotic resistance mechanisms of A. baumannii based on this classification are summarized in Figure 1.
Antibiotic resistance mechanisms can be classified into three groups [94]: (1) Restriction or impediment of target access by reducing membrane permeability or increasing antibiotic efflux. (2) Direct antibiotic inactivation by a genetic mutation, post-translational modification, or enzymatic hydrolysis. (3) Access restriction through a structural change of membrane components or number of transmembrane segments.
The antibiotic resistance mechanisms of A. baumannii based on this classification are summarized in Figure 1.

Carbapenem-Resistant A. baumannii in Hospitals
Carbapenem-resistant Acinetobacter baumannii (CRAb), an opportunistic pathogen primarily associated with hospital-acquired infections, is an urgent public health threat [95]. CRAb readily contaminates the hospital environment and health care providers' hands, can survive for prolonged periods on dry surfaces, and can be spread by asymp-

Carbapenem-Resistant A. baumannii in Hospitals
Carbapenem-resistant Acinetobacter baumannii (CRAb), an opportunistic pathogen primarily associated with hospital-acquired infections, is an urgent public health threat [95]. CRAb readily contaminates the hospital environment and health care providers' hands, can survive for prolonged periods on dry surfaces, and can be spread by asymptomatic colonization; these factors make CRAb outbreaks in acute care hospitals challenging to control [34,[96][97][98]. It is resistant to common disinfectants, leading to outbreaks that are hard to contain and affect the most vulnerable and critically ill patients [34].
CRAb is the leading cause of morbi-mortality from infection in several European countries, with Italy being one of the top affected countries [99]. Compared to the pre-COVID-19 period, some authors observed a decreased antibiotic susceptibility in local pathogens during the first wave [100]. Others reported an increased risk of carbapenemresistant infections in patients hospitalized with COVID-19 [18,99]. In both ICU and  [104].
A recent study from a Mexican ICU with COVID-19 patients identified and characterized ESKAPE bacterias, detecting their possible clonal spread on medical devices, inert surfaces, medical personnel, and patients. A. baumannii was the most predominant ESKAPE member (52%) with all strains showing multidrug resistance (MDR). Moreover, the analysis of intergenic regions revealed a critical clonal distribution of A. baumannii (AdeABCRS+) in the ICU [105].
The outbreak of A. baumannii was described as one of the main determinants of severity and mortality of ICU patients in [106]. A New Jersey hospital experienced a large multidrugresistant OXA-23 CRAb outbreak, primarily involving ICU patients, which extended across multiple units during a surge in COVID-19 cases [98]. A Japanese tertiary hospital reported an OXA-23-producing A. baumannii outbreak in 5 of 10 ICU beds, and all isolates had similar antibiotic susceptibility patterns with resistance to all β-lactams, including imipenem [107]. Of interest, an outbreak of A. baumannii was a determining factor in the increases of the incidence of infection and the morbi-mortality of ICU patients, with all strains multidrug resistant and only sensitive to colistin [108]. Gottesman et al. described a monoclonal outbreak of CRAb in two wards of a dedicated hospital to treat COVID-19 patients. All clinical (five cases) and environmental specimens (n = 24) belonged to international clonal lineage 2 (bla OXA-66 allele) and harbored the bla OXA-24-like carbapenemase [109]. Shinohara et al. also report a monoclonal outbreak of an endemic strain of CRAb (14 cases) in a new COVID-19 ICU of a tertiary teaching hospital in southern Brazil [18]. Interestingly, CRAb outbreaks in COVID-19 patients seem to be effectively treated with a pre-optimized two-phage cocktail [110].

COVID-19 and A. baumannii Coinfections
The COVID-19 pandemic caused many immunocompromised individuals to be hospitalized, and some reports indicated that some COVID-19 patients were diagnosed with coinfections and secondary infections [93,94,111,112]. The incidence, prevalence, and characteristics of bacterial infection in these patients were not well understood and were raised as an important knowledge gap [113,114]. The specific nature and source of these infections have not yet been fully investigated; however, evidence indicates that multidrug-resistant bacteria are among the microbes responsible for developing these infections. The prevalence of coinfection was variable among COVID-19 patients in different studies. However, it could be up to 50% among non-survivors [2]. A systematic review and meta-analysis of bacterial coinfection and secondary infection in patients with COVID-19 reported 3.5% and 14.3% for coinfection and secondary infection, respectively. However, in general, bacterial infection was 6.9%, varying slightly in the patient population, ranging from 5.9% in hospitalized patients to 8.1% in critically ill patients [115]. Similarly, another study concluded that only 7% of hospitalized patients presented a bacterial coinfection with a high degree of heterogeneity, although this increased to 14% in studies that only included ICU patients [116,117].
Coinfection with A. baumannii secondary to SARS-CoV-2 infections has been reported multiple times in literature during the COVID-19 pandemic including Wuhan (China), France, Spain, Iran, Egypt, New York (USA), Italy, and Brazil ( Table 1). The incidence of secondary infections (mostly lower respiratory tract infections) due to A. baumannii was said to be as high as 1% of hospitalized COVID-19 patients in an Italian hospital [118]. A descriptive study reported the exact incidence (1%) among hospitalized patients from Wuhan, China [119]. A simultaneous survey from Wuhan reported coinfection with A. baumannii in 1 out of 69 hospitalized patients (1.4%) with COVID-19 [120]. In addition, a recent study from a French ICU reported a 28% rate of bacterial coinfection with A. baumannii at 1 out of 92 (1.1%) in severe SARS-CoV-2 pneumonia patients [121]. A study conducted by Siyuan et al. (2021) investigated the frequency and characteristics of respiratory coinfections in COVID-19 patients in the ICU; they detected that A. baumannii and S. aureus were more frequently identified during late ICU admission [122].
Within the first few days of SARS-CoV-2 infection, critically ill patients with COVID-19 often develop pulmonary dysbiosis or respiratory tract distortion, which can progress further to a secondary bacterial or fungal infection a few weeks later [123][124][125]. A retrospective cohort study in a secondary care setting in Cambridge, UK, reported that a high percentage of patients with COVID-19 (9 out of 14) in the ICUs had confirmed secondary ventilator-associated pneumonia (VAP) [126]. Lescure et al. (2020) identified A. baumannii as the responsible agent in a COVID-19 patient of VAP [127]. A retrospective observational study of all patients admitted for COVID-19 in a University Hospital in Spain showed that 16% presented with fungal or bacterial coinfection/superinfection, and multidrugresistant A. baumannii was the leading agent in respiratory infections and bacteremia with an outbreak contributing to this result [106]. Chen et al. (2020) also reported that bacterial and fungal coinfections in COVID-19 patients, including one patient that presented with an A. baumannii infection that was highly resistant to antibiotics, cause difficulties with anti-infective treatment, leading to the higher possibility of developing septic shock [119]. In a cohort study, the authors evaluated data from 212 severely ill COVID-19 patients admitted in a public tertiary hospital exclusively dedicated to attending COVID-19 patients during the pandemic and analyzed the association between fungal/bacterial coinfections and the mortality of these patients. Acinetobacter spp. was the second most isolated of the patients with positive bacterial cultures and was responsible for the third-highest mortality rate of COVID-19 patients suffering from these coinfections [108].
A study in an Iranian ICU reported coinfection with MDR A. baumannii in 17 out of 19 COVID-19 patients with high-level resistance to all antimicrobials tested, except colistin, which showed a resistance rate of 52%, although none of the patients survived [19]. Among 1495 COVID-19 patients hospitalized in Wuhan, 102 (6.8%) patients had acquired secondary bacterial infections, mainly due to A. baumannii (35.8%) with high resistance rates (91.2%), and almost half of them (49.0%, 50/102) died during hospitalization [8]. An Italian retrospective analysis of 32 COVID-19 ICU patients showed that 50% of patients developed an MDR infection during ICU stay. Overall, >80% of MDR bacteria isolated were Gramnegative bacilli, and the second most common pathogen isolated was carbapenem-resistant A. baumannii (CRAb). Four patients were coinfected with an extensively drug-resistant A. baumannii phenotype (12.5%) [128]. A. baumannii was detected in 20% of samples acquired from COVID-19 patients in an ICU in Beijing, China, during late ICU admission [122]. The highest incidence of MDR A. baumannii coinfection was documented in an Egyptian study (2.7%; 7 out of 260 patients hospitalized with COVID-19, susceptible only to tigecycline and fluoroquinolones, having resistance genes NDM-1, TEM, and CTX-M) [129]. Another study in hospitalized COVID-19 patients from Spain showed that coinfection with A. baumannii was apparent in 2.4% of hospitalized patients (17 out of 712; 16 of these 17 patients in ICU); it was the strongest determinant of mortality [106]. Cultrera et al. (2021) compared coinfections in critically ill patients with or without COVID-19, and A. baumannii was the most frequently isolated bacterium found in the three ICUs. In addition, CRAb infections in COVID-19-positive patients admitted to the ICU were more frequent compared to those that were COVID-19 negative [130]. The rapid expansion of the ICU to manage SARS-CoV-2 can potentially increase nosocomial infection rates in the hospital environment. As a result, there is great concern with bacterial coinfections in patients with COVID-19 as they significantly increase the morbidity and mortality of these patients. Thus, the early identification of bacterial infections will help to identify high-risk patients and determine the correct interventions to reduce mortality.

Conclusions
The worldwide outbreak of COVID-19 emerged in late 2019, and caused severe public health crises with considerably more significant morbidities and mortality rates, particularly in individuals with severe medical comorbidities and elderly populations. COVID-19 disease symptoms are diverse and may have varied manifestations among patients. In extreme cases, patients may develop pneumonia, acute respiratory distress syndrome, and multi-organ dysfunction. The screening and understanding of the proportion of COVID-19 patients with acute respiratory bacterial coinfection, especially VAP, is crucial for treating patients with COVID-19 and assisting in the responsible use of antibiotics, minimizing damaging consequences of overuse, and ensuring a better clinical outcome. In addition, this knowledge could have a significant impact on refining empirical antibiotic management guidelines for patients with COVID-19. The coinfection of SARS-CoV-2 and secondary infections with other microorganisms, such as A. baumannii, is an essential factor in COVID-19, and it can aggravate the progression and prognosis, especially in hospitalized patients. However, there are few reports about secondary infections and SARS-CoV-2 coinfections with bacteria; it is necessary to understand and strengthen the investigation of them. While there are many guidelines for diagnosing COVID-19 patients, bacterial coinfections and secondary infections have gaps and require further study.
This summarized review was designed to offer insight into A. baumannii coinfections and secondary infection in patients with COVID-19 using the most recent information available. In hospital settings, COVID-19 patients may face another health threat: antimicrobialresistant bacteria such as A. baumannii and its carbapenem resistance pattern, which poses a considerable challenge to the health system. The isolation and the recognition of A. baumannii from COVID-19 patients highlights the importance of appropriate prevention and control practices. This microorganism potentially has important and severe implications for the clinical outcomes of these COVID-19 patients. Further studies are necessary to investigate the incidence, prevalence, and characteristics of COVID-19 coinfection and microbiological (especially A. baumannii) distribution.