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Antimicrobial Resistance in Acinetobacter baumannii
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This entry is adapted from the peer-reviewed paper 10.3390/ijms23126582

Acinetobacter baumannii is a Gram-negative bacillus that causes multiple infections that can become severe, mainly in hospitalized patients. Its high ability to persist on abiotic surfaces and to resist stressors, together with its high genomic plasticity, make it a remarkable pathogen. The isolation of strains with high antimicrobial resistance profiles has gained relevance, which complicates patient treatment and prognosis. This resistance capacity is generated by various mechanisms, including the modification of the target site where antimicrobial action is directed. This mechanism is mainly generated by genetic mutations and contributes to resistance against a wide variety of antimicrobials, such as β-lactams, macrolides, fluoroquinolones, aminoglycosides, among others, including polymyxin resistance, which includes colistin, a rescue antimicrobial used in the treatment of multidrug-resistant strains of A. baumannii and other Gram-negative bacteria.

Acinetobacter baumannii antimicrobial resistance mechanisms of antimicrobial resistance

1. Introduction

Antimicrobial resistance is a worrying and growing problem [1][2]. In the USA, it is estimated that antibiotic-resistant microorganisms cause more than one million infections each year, which is linked to at least 23,000 deaths. It is estimated that by the year 2050, the number of deaths will increase tenfold [3]. In recent years, the World Health Organization (WHO) has recommended global action to reduce the presence of antibiotic resistant isolates in all countries; carbapenem-resistant Acinetobacter baumannii is a microorganism that is a priority for research and development of new treatments [4]. Currently, there are more than 50 designated species of Acinetobacter, of which the vast majority are considered non-pathogenic. The most clinically important species of the genus Acinetobacter are within the Acinetobacter calcoaceticus-baumannii (Acb) complex [5]. The Acinetobacter complex is composed of five pathogenic species (A. baumannii, Acinetobacter nosocomialis, Acinetobacter pittii, Acinetobacter seifertii, and Acinetobacter dijkshoorniae) and a non-pathogenic member (Acinetobacter calcoaceticus) [5][6]. A. baumanni is the most relevant and most studied species; it is considered an opportunistic human pathogen. A total of 2% of HCAIs (healthcare-associated infections) are caused by this microorganism [6]. It is estimated that 45% of isolates worldwide are multidrug-resistant (MDR), reaching percentages of up to 70% in Latin America and the Middle East [7]. This bacterium can cause several HCAIs [8]. One of the most frequent with the highest mortality rates is ventilator-associated pneumonia and bacteremia; these infections are directly related to patients with comorbidities or in critical condition. Infections caused by this pathogenic carrier have been observed in patients with prolonged periods of hospitalization [9][10]. As mentioned above, A. baumannii has been detected in sputum cultures and tracheal aspirates from COVID-19 mechanically ventilated patients. This opportunistic pathogen is responsible for approximately 47% of the cases of monomicrobial ventilator-associated pneumonia (VAP) infections in the ICU (intensive care unit); however, other bacterial species are also related to this infection, such as Pseudomonas aeruginosa, Staphylococcus aureus, and some members of the Enterobacterales group; even co-infections between the aforementioned microorganisms have been reported. Patients with impaired COVID-19 present the main risk factors for developing VAP caused by A. baumannii, which are hypertension, chronic obstructive pulmonary disease, chronic renal failure, and prolonged stay in the ICU [11][12][13][14][15][16][17]. Many reports have shown that A. baumannii rapidly develops antimicrobial resistance [18]. Several mechanisms of resistance have been reported in this microorganism, such as the enzyme-mediated degradation of antibiotics, modifications of target sites, efflux pumps, and changes in membrane permeability [19].

2. Current Status of Antimicrobial Resistance in A. baumannii

Currently in the clinic, the isolation of A. baumannii is of relevance and has become a serious problem, mainly due to the ability of this bacterium to acquire and regulate various resistance determinants, which has made it one of the most successful pathogens in colonization and infection [20]. This success is also due to its ability to resist the action of different antimicrobials, as described below.
In the literature, there are several reports on the resistance of this bacterium to different families of antimicrobials, such as β-lactams, which mainly occur by the presence of β-lactamases. It has been described that A. baumannii presents the four types of these enzymes proposed by Ambler (classes A, B, C, and D). Strains that present class A enzymes show resistance to all penicillins and cephalosporins, except cephamycins. Within the above, reports stand out where it is mentioned that this bacterium presents KPC enzymes (KPC-2, KPC-3, and KPC-5) [21][22][23]. For strains that present class B enzymes, known as MBLs, they have resistance to all β-lactams, including carbapenem [24]; this highlights the presence of NDM-1 enzymes reported in various parts of the world, such as Iran, China, Tunisia, Saudi Arabia, and Lebanon [23].
Class C enzymes, known as acinetobacter-derived cephalosporinases (ADCs), which are intrinsic to all A. baumannii, confer resistance to cefoxitin, cefotenan, cephalosporins, and penicillin. In the case of class D enzymes or oxacilinases (OXAs), it is known that, in A. baumannii, they confer resistance to carbapenem; these are mainly found encoded in plasmids [19][24][25]. Currently, it is known that, in A. baumannii, apart from the resistance to β-lactams presented by these enzymes, there may be non-enzymatic mechanisms that confer resistance against this type of antimicrobials, such as changes in the porins of their membranes, such as CarO, which is associated with resistance to imipenem and meropenem [26]. Not only are porins related to this resistance, but also efflux pumps that generate resistance against several β-lactams, aminoglycosides, erythromycin, chloramphenicol, fluoroquilones, tetracyclines, and trimethoprim [27].
Regarding antimicrobials that do not belong to the β-lactam family, it is known that this bacterium can present resistance to tetracyclines and glycylcyclines for the first case involving efflux pumps where RND pumps participate [28]. There are reports where there are strains with resistance to tigecycline, related to efflux pumps [29].
A. baumannii also presents resistance to fluroquinolones. The mutations in the gyrA gene are related to resistance to fluoroquinolones; however, there are other mechanisms of resistance to these antibiotics, such as efflux pumps, which do not have a broad spectrum on all particular antibiotics of the fluoroquinolone group; this spectrum is reduced only to ciprofloxacin and norfloxacin [30].
There is evidence of resistance to aminoglycosides in this bacterium, mainly given by the participation of enzymes with the activity of acetyltransferases, adenyltransferases, and phosphotransferases, which causes resistance to amikacin. Likewise, there are changes in ribosomal target sites where the action of these antimicrobials is directed, which can provide resistance to gentamicin, trobamycin, and amikacin [31], as well as the involvement of efflux pumps, where the action of gentamicin is affected [32].
Regarding macrolides, there are reports of resistance to azithromycin, erythromycin, and chloramphenicol, although some strains of A. baumannii show variable resistance to azithromycin [33].
In terms of polymyxin resistance, colistin resistance stands out, as it is a rescue antimicrobial, which, in recent years, has considerably increased [34].

Intrinsic Resistance in A. baumannii

Intrinsic resistance is that which is innate in bacteria, which is not acquired, but occurs naturally due to the characteristics of the bacteria themselves. This type of resistance is reflected in all or most wild-type strains [19][35].
Knowing this type of resistance is relevant in the clinic to avoid ineffective treatments as well as performing susceptibility testing that will be unnecessary [35][36].
A clear example of intrinsic resistance in A. baumannii is towards β-lactams due to different causes, for example, in the chromosome of this bacterium there are blaOXA, blaADC, and blaAmpC genes encoding for β-lactamases. In addition, naturally, there are alterations in PBPs, there is also the presence of efflux pumps naturally found in the bacterium, such as the RND family, and finally, it is known that there are changes in the membrane permeability of this bacterium that lead to resistance [19][25][37][38][39][40].
One study showed that intrinsic resistance in A. baumannii can be affected when there are mutations leading to a deficit in the production of capsular polysaccharides [41].
The US Clinical and Laboratory Standard Institute (CLSI) reports that this bacterium is intrinsically resistant to ampicillin, amoxicillin, amoxicillin with clavulanate, aztreonam, ertapenem, trimethoprim, chloramphenicol, and fosfomycin (Table 1) [36].
Table 1. Antimicrobial resistance described in A. baumannii.
Table
Antimicrobial Family Antimicrobials
β-lactams Penicillins Ampicillin a
Amoxicillin-clavulanate a
Ticarcillin
Mezlocillin
Piperacillin
Piperacillin-tazobactam
Cephalosporins Cefoxitin
Cefotetan
Cefepime
Ceftazidime
Cephalothin
Ceftriaxone
Cefotaxime
Monobactams Aztreonam a
Carbapenems Ertapenem a
Imipenem
Meropenem
Amphenicols Chloramphenicol a
Phosphonates Fosfomycin a
Sulfonamides and diaminopyrimidines Trimetroprim a
Trimethoprim/sulfamethoxasol
Aminoglycosides Amikacin
Gentamicin
Trobamycin
Macrolides Erythromycin
Azithromycin
Tetracyclines Glycylcyclines
Tigecycline
Doxycycline
Minocycline
Fluoroquinolones Ciprofloxacin
Norfloxacin
Levofloxacin
Moxifloxacin
Gatifloxacin
Nitrofurans Nitrofurantoin
Polymyxins Polymyxin B
Colistin
a Intrinsic resistance in A. baumannii [36]. Modified from the literature [23][26][33][37][38][39][40][41][42][43][44].

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Arturo Martínez-Trejo
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Juan Manuel Ruiz-Ruiz
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Luis Uriel Gonzalez-Avila
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Andrés Saldaña-Padilla
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Cecilia Hernández-Cortez
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Miguel Angel Loyola-Cruz
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Juan Manuel Bello-López
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Graciela Castro-Escarpulli
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Update Date: 27 Jun 2022
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