Acinetobacter baumannii in the critically ill: complex infections get complicated

Abstract

Acinetobacter baumannii is increasingly associated with various epidemics, representing a serious concern due to the broad level of antimicrobial resistance and clinical manifestations. During the last decades, A. baumannii has emerged as a major pathogen in vulnerable and critically ill patients. Bacteremia, pneumonia, urinary tract, and skin and soft tissue infections are the most common presentations of A. baumannii, with attributable mortality rates approaching 35%. Carbapenems have been considered the first choice to treat A. baumannii infections. However, due to the widespread prevalence of carbapenem-resistant A. baumannii (CRAB), colistin represents the main therapeutic option, while the role of the new siderophore cephalosporin cefiderocol still needs to be ascertained. Furthermore, high clinical failure rates have been reported for colistin monotherapy when used to treat CRAB infections. Thus, the most effective antibiotic combination remains disputed. In addition to its ability to develop antibiotic resistance, A. baumannii is also known to form biofilm on medical devices, including central venous catheters or endotracheal tubes. Thus, the worrisome spread of biofilm-producing strains in multidrug-resistant populations of A. baumannii poses a significant treatment challenge. This review provides an updated account of antimicrobial resistance patterns and biofilm-mediated tolerance in A. baumannii infections with a special focus on fragile and critically ill patients.

Keywords: Acinetobacter baumannii; biofilm; cancer; carbapenem; cefiderocol; colistin; crab; skin and soft-tissue infections.

Figure 1

The main antibiotics resistance mechanisms of Acinetobacter baumannii. The resistance mechanisms are divided into six categories. (A) The permeability defects are due to porins modification, such as the carbapenem-associated outer membrane protein (CarO) and the OMP family. (B) The one-step or two-step drug extrusion from the cytosol to the outer membrane via the efflux pumps family. Among them, the resistance-nodulation-division superfamily (RND-superfamily) takes over the drug from the cytoplasm or the periplasm by its AdeABC, AdeIJK, or AdeFGH efflux pumps system. The major facilitator superfamily (MFS; e.g., TetA, TetB, CmlA, CraA, AmvA, AbaF), the multidrug and toxic compound extrusion (MATE) transporter family (e.g., AbeM), and the small multidrug resistance (SMR) transporter (e.g., AbeS) are H+ and Na+ coupled multidrug efflux pumps at the inner membrane. (C) The hydrolysis of β-lactam antibiotics by β-lactamases. Acinetobacter baumannii β-lactamases are classified into four molecular classes: class A (e.g., TEM, GES, PER, CTX-M, SCO, VEB, KPC, CRAB enzyme family), class B (e.g., IMP, VIM, NDM, SIM enzyme family), class C (e.g., Amp family) and class D (e.g., OXA subgroups enzyme family). (D) The complete loss of LPS by inactivating the lipid A biosynthesis genes (lpxA, lpxC, and lpxD) results in colistin resistance. (E) The aminoglycoside-modifying enzymes classified in three class acetyltransferases [e.g., AAC3, AAC(6′)], adenyltransferases [e.g., ANT(2″), ANT(3″)], and phosphotransferases [e.g., APH(3″), APH(3′)]. (F) The alteration of targeted sites of TetM confers ribosomal protection against tetracycline, and GyrA subunit modification of DNA gyrase confers resistance to quinolone.

Figure 2

Model for activation of the polymyxin resistance PmrA/PmrB two-component system in Acinetobacter baumannii. Resistance to polymyxins can be induced in response to various stress conditions, such as low Mg2+ and Ca2+ concentrations, acidic pH, and high Fe3+ concentrations, which activate the two-component system PmrA/PmrB. Once activated, PmrA/PmrB upregulates pmrC gene expression, which encodes lipid A phosphoethanolamine (PEtN) transferase that promotes the addition of PEtN to lipid A. PmrC upregulates naxD, which codes for an N-acetylhexosamine deacetylase involved in the deacetylation of the β-galactosamine and Lipid A modification. Alternatively, overexpression of the eptA gene, homolog to PmrC, promotes the addition of the cationic pEtN moiety to the lipid A of LPS. Lastly, the plasmid-mediated mobile colistin resistance (mcr) genes encode a phosphoethanolamine transferase that adds PEtN to lipid A residues lowering the binding affinity of colistin to its target site.