Integrative review on Acinetobacter baumannii as a multidrug-resistant pathogen: resistance mechanisms and therapeutic perspectives in the context of nosocomial infections

TL;DR

This paper reviews Acinetobacter baumannii's resistance mechanisms and new treatments for hospital-acquired infections.

Contribution

The paper provides an updated overview of resistance mechanisms and emerging therapies for MDR A. baumannii.

Findings

MDR in A. baumannii is driven by efflux pumps, enzyme production, and structural modifications.

New drugs like cefiderocol and combinations with colistin show promise against MDR A. baumannii.

Current treatment options remain limited, highlighting the need for novel therapeutic strategies.

Abstract

Acinetobacter baumannii is a gram-negative opportunistic pathogen associated with high morbidity and mortality in nosocomial infections, particularly in intensive care units. Multidrug resistance (MDR) is mediated by efflux pumps, lipopolysaccharide modifications, aminoglycoside adenylyltransferases, FosA, structural alterations, and production of enzymes that inactivate antibiotics, such as carbapenemases. These factors limit the therapeutic options and increase clinical challenges, as there are currently few drugs or combinations with therapeutic success against A. baumannii infections. Some strategies and new drugs, such as cefiderocol, eravacycline, sulbactam-darlobactam, tigecycline, and their combinations with colistin, are being tested and have shown apparent advances. This integrative review discusses the current resistance mechanisms and emerging therapeutic strategies aimed at overcoming the growing threat posed by MDR A. baumannii.

Full text

INTRODUCTION

Acinetobacter baumannii (A. baumannii) is a bacterium of great clinical relevance today due to its spread in the hospital environment and, consequently, its relationship with opportunistic nosocomial infections and is one of the major concerns regarding current infections due to its high fatality rate1. In many cases, this bacterium is related to pneumonia, especially in association with mechanical ventilation; urinary infection, typically associated with bladder catheters placed for a long time; and meningitis, especially in patients after neurosurgery2^,^3.

The current major concern is the widespread resistance of A. baumannii to various classes of antibiotics used in the clinical management of its infections, which reduces the chances of therapeutic success and increases the likelihood of death3. The World Health Organization (WHO) has listed carbapenem-resistant A. baumannii (CRAB) as one of the world's critical priority bacteria4 and ratified this warning in 2024, with permanence within this category on the new list5.

Understanding the mechanisms involved in this resistance is essential for establishing new treatment alternatives and developing drugs that avoid these mechanisms to achieve greater success in containing these infections.

This review aimed to provide a comprehensive overview of the epidemiology, resistance mechanisms, and current therapeutic strategies targeting MDR A. baumannii in the context of increasing nosocomial infections.

METHODS

This integrative review was conducted by searching PubMed/MEDLINE, Embase, Web of Science, Scopus, and the Cochrane Library to identify articles that could answer the guiding question: “what are the resistance mechanisms and therapeutic strategies currently available for multidrug-resistant Acinetobacter baumannii in nosocomial infections?”. The following search string was applied: ("Acinetobacter baumannii" OR "A. baumannii" OR "MDR A. baumannii" OR "CRAB") AND ("resistance" OR "resistance mechanisms" OR "antimicrobial resistance" OR "multidrug resistance" OR "carbapenemase" OR "efflux pumps" OR "lipopolysaccharide modification" OR "genetic mutations") AND ("nosocomial infection" OR "healthcare-associated infection" OR "hospital infection" OR "intensive care unit" OR "ICU") AND ("treatment" OR "therapeutics" OR "antibiotic therapy" OR "combination therapy"). Original studies and relevant reviews were included without initial language restrictions, but articles published in English were prioritized. We conducted a qualitative synthesis of the findings, highlighting the methodological limitations and knowledge gaps.

RESISTANCE EPIDEMIOLOGY

Infection records in intensive care units (ICUs) indicate the frequency of A. baumannii outbreaks in several continents, mainly in Europe and North and South America6. These outbreaks were mainly caused by three MDR clones, although new strains are now common in some parts of the world, with reported cases in the United States, Canada, South America, Europe, Africa, the Middle East, Southeast Asia, and Australia7.

In a global assessment of the activity of antimicrobials against MDR gram-negative pathogens, A. baumannii accounted for 2-10% of all infections, with resistance rates increasing in 2017, showing a global increase of >40% in resistance between 2004 and 2014. When analyzed by continental region, the overall MDR among A. baumannii was the lowest in North America (31%), whereas >50% of A. baumannii isolates collected in Africa, the Middle East, and Latin America were MDR. In addition, the highest overall rates of MDR were observed among A. baumannii isolates, 44% of which were MDR8.

According to the Study for Monitoring Antimicrobial Resistance Trends (SMART), conducted with strains isolated from 48 countries between 2011 and 2014, A. baumannii had lower MDR rates in North America (47%) and higher rates in Europe and the Middle East (>93%), with higher rates in ICUs. Antimicrobial susceptibility profiles varied by region, with no tested antimicrobial agent able to inhibit >70% of those infected with A. baumannii9. Recent studies, in line with data presented in the SMART report, have indicated the prevalence of Acinetobacter MDR infections in the Gulf Cooperation Council, Middle East, and North Africa (MENA) regions10. For example, alarming levels of resistance to Acinetobacter MDR bacteria have been reported in ICUs in Saudi Arabia, Qatar, Kuwait, and the United Arab Emirates11^-^13.

Studies carried out by the SENTRY Antimicrobial Surveillance Program based on Acinetobacter spp. showed the percentages of susceptibility to meropenem in some regions of the globe, including Asia/Pacific (21.0%), Europe (22.2%), Latin America (13.7%), and North America (54.4%). Among the Acinetobacter spp. samples collected by Seifert et al.14 between 2016 and 2018, the percentages of susceptibility to meropenem were as follows: Africa/Middle East (17.2%), Asia/South Pacific (31.4%), Europe (33.8%), Latin America (19.6%), North America (63.6%), and globally (32.9%).

In South Korea, only 22.4% of the samples isolated during the prepandemic period (2015-2020) were susceptible to carbapenems15. In a Chinese hospital study conducted during the COVID-19 pandemic, 60% of the collected pathogen samples were resistant to carbapenems16. Another important factor during this period was the increase in nosocomial infections caused by carbapenem-resistant A. baumannii in ICU patients, especially in Italy and the USA17^-^19.

Tests have identified colistin-resistant strains in several countries, such as Spain, where a study revealed 19.1% resistance20, and a recent multicenter study carried out in southern Europe revealed that resistance was as high as 47.7%21. In South Korea, surveys have reported a resistance rate of 30.6 %22.

RESISTANCE MECHANISMS

The main resistance mechanisms of A. baumannii and their descriptions are summarized in a table (Table 1).

TABLE 1:Main resistance mechanisms of A. baumannii.RESISTANCE MECHANISMSDESCRIPTIONRELATED GENE, PROTEIN, OR ENZYMEEfflux pumpsTransport antibiotics from the intracellular to the extracellular environmentFive different transporter protein families: SMR, DMT, ABC, RND, and MATECarbapenemasesEnzymes capable of hydrolyzing and therefore inactivating beta-lactam antibioticsMainly OXA β-lactamases, encoded by genes as bla _ OXA-23-like _ , bla _ OXA24/40-like _ and bla _ OXA-51-like _ . But other enzymes such as New Delhi metallo-β-lactamase-1 encoded by the bla _ NDM-1 _ gene can also be foundChange in the structure of LPSProduction of cationic groups that bind to lipid A in order to reduce its electronegative character; complete loss of LPS; addition of pEtN to the structure of lipid A by a phosphoethanolamiOverexpression of the pmrCAB chromosomal operon; mutations in the lpxA, lpxC, or lpxD genes; plasmid gene mcr-1Fluoroquinolones resistenceAlteration in the structure of type II topoisomerases and protection of binding siteMutations in gyrA and parC (e.g. Ser83Leu, Ser80Leu), qnr proteins, AAC(6')-IbAntifolate resistanceResistance via alternative enzyme variants and effluxsulI, sulII, dfrA1, dfrA12, dfrA14; efflux pumps such as OqxABFosfomycin resistanceInactivation of drug, efflux, and changes in membrane permeabilityfosA, abaF, abpr genesAminoglycosides heteroresistanceGene amplification and enzymatic modification of aminoglycosidesaadB(ant2")Ia, aph(3')-Via, AphA1 (Tn6020), RecAAmphenicols resistanceDrug efflux and enzymatic acetylationcatA1, catA2, catB11, catB3, catB8; cmlA5, craA, abrpTetracyclines resistanceEfflux pumps and enzymatic inactivation (TetX variants)tet(A), tet(X3), tet(X4), tet(X6); adeABC, adeIJK, adeFGH

EFFLUX PUMPS (GENERAL OVERVIEW)

Some strains of A. baumannii possess many of these transporters,23 which “expel” antibiotics and reduce their intracellular concentrations ​24. Efflux pumps are of particular concern because of their role in resistance to various biocides, including chlorhexidine. Acinetobacter chlorhexidine efflux protein, found in A. baumannii, expels the biocide antiseptic and survives in hostile environments25^,^26.

Efflux pumps are associated with resistance to antibiotics such as macrolides, tetracyclines, and quinolones27. Different mechanisms are associated with efflux pumps, which are divided into different families24^,^28.

SMALL MDR (SMR) - EFFLUX PUMPS

SMR are a family of four functional subdivisions that transport the small, charged metabolite guanidinium, bulky hydrophobic drugs, antiseptics, polyamines, and glycolipids29. Guanidinium exporters are the most common microorganisms30.

MAJOR FACILITATOR SUPERFAMILY (MFS) - EFFLUX PUMPS

MFS promotes substrate translocation by exploiting the free energy stored in the ion or solute gradients generated by primary transporters30. The MFS proteins transport various substrates31. In A. baumannii there are three MFS transporters are important for MDR: CraA, which provides resistance to chloramphenicol; AmvA, which provides resistance to erythromycin; and AbaQ, which transports quinolones32^,^33.

RESISTANCE-NODULATION DIVISION FAMILY (RND) - EFFLUX PUMPS

RND in A. baumannii can expel most antibiotics among other substrates34. Some of its proteins that confer resistance are AdeABC, which contributes to resistance to aminoglycosides, trimethoprim, chloramphenicol, fluoroquinolones, and tetracyclines; AdeFGH, which confers resistance to trimethoprim, tetracycline, clindamycin, and fluoroquinolones; AdeIJK, which acts on β-lactams, chloramphenicol, tetracycline, erythromycin, lincosamides, fluoroquinolones, fusidic acid, novobiocin, rifampin, and trimethoprim; AbeD, which confers protection against ceftriaxone, gentamicin, rifampin, tobramycin, and benzalkonium chloride; and ArpAB, which ensures resistance to amikacin and tobramycin32^,^35.

CARBAPENEMASES AS A ROUTE OF RESISTANCE TO CARBAPENEMS

Carbapenemases are enzymes capable of hydrolyzing and inactivating antibiotics of β-lactam antibiotics. β-lactamases are classified according to the classification scheme based on amino acid sequences, with class D being the most evident in MDR A. baumannii strains, whereas class B is seen less frequently36^,^37. This predominance of class D is probably related to their ability to integrate efficiently into the genome of local strains, their dissemination by plasmids, and their stability, which facilitates their maintenance and propagation. The lower prevalence of class B genes may be related to their even more restricted dissemination and regional factors affecting the circulation of resistance genes38.

Oxacillinase (OXA) β-lactamases are enzymes belonging to class D and are encoded by groups of genes, such as bla _ OXA-23-like _ , bla _ OXA24/40-like _ and bla _ OXA-51-like _39. One study showed that increased expression of OXA-23, the first carbapenemase identified in A. baumannii and encoded by bla OXA-2339^,^40, increased the minimum inhibitory concentration (MICs) of imipenem by 128 times41. The ability of this enzyme to change its conformation, as proven in recent studies42, suggests that this mechanism is intrinsically related to the broad spectrum of β-lactams with compromised therapeutic action. OXA-24/40-like is originated from the bla _ OXA24/40-like _ gene group and strains containing this gene showed higher MIC values than those with bla _ OXA-23-like _ , even though the number of OXA-24/40 β-lactamases is more restricted than the OXA-23 group39^,^40^,^43.

New Delhi metallo-β-lactamase-1 (NDM-1) is a class B β-lactamase synthesized from the bla _ NDM-1 _ of A. baumannii strains in infections in the city of New Delhi44. It can successfully hydrolyze all members of the β-lactam family, except monobactams, is not affected by β-lactamase inhibitors, and provides resistance to other antibiotics outside this class owing to its alternative mechanisms of action44^-^46.

CHANGES IN THE STRUCTURE OF LIPOPOLYSACCHARIDE

A. baumannii already has resistance mechanisms to polymyxins based on alterations in the structure of the lipopolysaccharide or the complete loss of this molecule from its outer membrane47^-^49. Several factors are involved in this resistance, such as genetic mutations, reduced production of cofactors for LPS production, and lack of stabilizing proteins50^,^51.

Overexpression of the pmrCAB chromosomal operon is one of the main factors involved in the resistance of A. baumannii to colistin, once the influence of the pmrA and pmrB genes on the structure of LPS has been discovered52^,^53. Their mechanism involves inducing the production of cationic groups attached to lipid A to reduce its affinity for polymyxins52^,^54. The PmrB protein phosphorylates and activates PmrA, which in turn induces the expression of pmrC, which encodes the phosphoethanolamine transferase PmrC, to add the phosphoethanolamine (pEtN) group to lipid A55^-^57.

Mutations in lpxA, lpxC, or lpxD genes prevent lipid A synthesis. The loss of one of the main sites of action of polymyxins increases the MIC, making their use for the treatment of this type of strain unfeasible58. However, one study indicated that A. baumannii with this mutation is more susceptible to immune system defenses promoted by neutrophils59.

As for plasmid interference, mrc-1, despite recent evidence of its possible relevance to polymyxin resistance in A. baumannii54, is a gene capable of encoding a phosphoethanolamine transferase that adds pEtN to the structure of lipid A56.

RESISTANCE TO FLUOROQUINOLONES

Changes in the amino acid sequence, and consequently, changes in the interaction of type II topoisomerases with fluoroquinolones, are generally characterized as recurring mechanisms in bacteria for resistance to these antibiotics60. The most recurrent mutations occur in the A subunit of DNA gyrase and the C subunit of topoisomerase, which are expressed by gyrA and parC, respectively. Studies have shown that alterations in serine amino acids are the most significant and recurrent for resistance, such as the Ser83Leu mutations in the gyrA genes and Ser80Leu in parC61^,^62. Unlike other bacteria, A. baumannii shows high resistance, even to a single double mutation involving at least one change in each of the subunits mentioned61.

Proteins that protect the sites of type II topoisomerase enzymes and DNA are synthesized by the qrn plasmid gene family63. These proteins destabilize the quinolone-binding site with the enzyme through new interactions, enabling regions to form again during distension and maintaining the activity of type II topoisomerases64^-^66.

The expression of efflux pumps that resist the action of fluoroquinolones in A. baumannii is mainly related to the QepA and OqxAB pumps67^,^68. However, other studies have reported discrepant results, with little influence or expression of these pumps on A. baumannii resistance69^,^70.

RESISTANCE TO ANTIFOLATE ANTIBIOTICS

Different mechanisms are involved in the resistance of these classes; however, as they are easily transferable, they are commonly related to each other71. The sul I and sul II genes encode dihydropteroate synthase enzymes with structural alterations that decrease their affinity for sulfonamides, but maintain their interaction with p-aminobenzoic acid, a precursor substrate for folic acid in this metabolic pathway72. The sul I gene is generally associated with transposons, which delimit resistance to other microbes72^,^73.

Genes from the dfr family, such as dfrA1, are responsible for producing dihydrofolate reductase with a structure altered enough to maintain interaction with the substrate dihydrofolate, but drastically lose interaction with trimethoprim, which increases the MIC in strains carrying these genes74.

The expression of efflux pumps may also be related to the mechanism of antifolate resistance in A. baumannii, as OqxAB has been shown to confer resistance to various classes of antibiotics, including trimethropine75.

FOSFOMYCIN RESISTANCE

FosA is a glutathione S-transferase synthesized by a gene of the fosA family that inactivates fosfomycin by altering its MurA-binding structural portion, which is the site of action of this drug, and is widespread in A. baumannii76^,^77.

The AbaF efflux pump, encoded by the abaF gene, is associated with loss of susceptibility to fosfomycin, as its nonexpression resulted in an eight-fold increase in the therapeutic efficiency of this drug in A. baumannii strains78. These pumps appear to confer additional resistance and virulence traits, as the expression of other efflux proteins did not show the same results, whereas AbaF, in addition to reducing susceptibility, favored the formation of biofilms78.

The abpr gene has been shown to reduce susceptibility to fosfomycin and other classes of antibiotics, owing to changes in the selection characteristics of cell membrane permeability, and consequently, the therapeutic efficiency of the drugs79.

AMINOGLYCOSIDES HETERORESISTENCE

As observed via hybridization, 82.7% of the bacterial strains of A. baumannii that show resistance to aminoglycosides have the aph(3')-Via gene, however, this resistance is multifactorial, and is related to more than one gene or mechanism80.

The basis of heteroresistance to aminoglycosides is the amplification of the aadB(ant2″)Ia gene, which encodes an aminoglycoside adenylyltransferase, capable of adding adenosine monophosphate to other molecules, making the strain capable of inactivating tobramycin and gentamicin. This gene is highly amplified in a RecA-dependent manner and is responsible for genetic recombination, gene expression regulation, and DNA repair81. This amplification occurred stochastically, even without antibiotic pressure, in approximately 1 in 200 cells​82.

Another gene related to aminoglycoside resistance is aphA1, which encodes an enzyme called phosphotransferase that modifies aminoglycosides by adding a phosphate group to them24. However, when the number of gene copies is very high (>40), the bacterial response is modified and loses its ability, which suggests that a high number of copies overload the cell83.

AMPHENICOLS RESISTANCE

The genes that confer resistance to amphenicols are redundant, more than one for the same antibiotic, which increases resistance, one of which is the catB8 gene that allows the expression of CatB8, which has a greater capacity to process and neutralize the effect of the antibiotic because this protein can bind to up to four molecules of chloramphenicol84^,^85.

Some strains of A. baumannii harbored the abrp gene, which, when deleted from the bacterial gene, showed reduced susceptibility to chloramphenicol (>8-fold)86. Other genes, such as craA and cmlA5 have been identified as responsible for resistance to chloramphenicol and other antibiotics in different strains of bacteria. In addition, impermeability of the outer membrane contributes to amphenicol resistance in A. baumannii85.

Another gene of significant importance in chloramphenicol resistance is ABUW_0982, which, when deleted via mutations in the transposon, increases bacterial susceptibility to this antibiotic87.

TETRACYCLINE RESISTANCE

The first antimicrobial drug efflux pumps to be recognized were the Tet(A) pumps, which belong to the MFS, that remove the drug from the cytoplasm to the periplasm in A. baumannii and; subsequently, the RND-type transporters AdeABC and AdeIJK extrude tigecycline through the outer membrane88^-^92. The tet(X3) and tet(X4) genes found in some strains of A. baumannii significantly increase the minimum therapeutic dose of tetracyclines together with the superexpression of RND efflux pumps, which are the main resistance mechanisms to tigecycline93^,^94. TetX modifies first- and second-generation tetracyclines, with tigecycline as one of its substrates95.

The main mechanisms of resistance to tetracyclines involve efflux pumps, most commonly AdeABC and AdeFGH, and in some cases, AdeIJK96. Among these, the most studied efflux pump is AdeABC, whose activity is regulated by a set of genes called AdeRS. Mutations in these genes can cause deregulation and overexpression of the AdeABC efflux pump, thereby reducing the susceptibility of the pathogen to tetracyclines97^,^98.

CLINICAL MANAGEMENT

The main therapeutic and clinical management strategies are summarized in Table 2.

TABLE 2:Therapeutic alternatives in clinical management.DRUGS/COMBINATIONSCLASSACTIONS MECHANISMSOBSERVATIONSSulbactam-durlobactamβ-lactamase inhibitorsThey compete with and irreversibly inhibit β-lactamase, lowering the minimum inhibitory concentration Durlobactam is a state-of-the-art inhibitor with broad action against β-lactamases of Ambler classes A, C and D that is being developed with sulbactam for the treatment of MDR A. baumanniiAmpicillin-sulbactam with meropenem and polymyxin BAmpicillin and meropenem: β-lactam Polymyxin B: polymyxinAmpicillin and meropenem prevent transpeptidation of the cell wall; polymyxin B is a cationic detergent of the outer membraneThis association demonstrated quick elimination of A. baumannii, but isolated therapies or the combination of only two resulted in bacterial regrowthColistinPolymyxinCationic detergent that deactivates the bacterial outer membraneAssociations with other drugs have shown a higher success rate, such as use with meropenem or a tetracycline plus ampicillin-sulbactam.EravacyclineTetracyclineExerts its antibacterial action by binding reversibly to the bacterial 30S ribosomal subunitIt is a new antibiotic introduced on the market that has shown high synergy with β-lactams to treat A. baumannii, especially when used together with ceftazidime.CefiderocolSiderophore cephalosporinInhibits cell wall synthesis by binding to PBPs and β-lactamases; enters via active iron transportersEffective against CRAB and MBL strains; recommended for combination therapyTigecyclineGlycylcyclineBinds to 30S ribosomal subunit with high affinity, blocking protein synthesisResistance may occur via efflux pumps; synergy with β-lactams and polymyxins

SULBACTAM-DURLOBACTAM

Sulbactam is a competitive inhibitor of serine β-lactamase, which binds to penicillin-binding proteins. Research has shown that sulbactam alone has direct antibacterial activity against clinical isolates of A. baumannii99. Several studies have suggested that high-dose sulbactam is advantageous for the treatment of MDR A. baumanni100^,^101; however, combination therapy is the most effective treatment regimen for these infections102^,^103. Durlobactam is a state-of-the-art β-lactamase inhibitor, with broad action against β-lactamases classes A, C and D. Durlobactam recovers the in vitro efficacy of sulbactam against strains of the A. baumannii-A. calcoaceticus (ABC) complex, for which sulbactam has low effectiveness. Durlobactam reduced sulbactam's minimum inhibitory concentration by 16-64 times104, so this combination is being developed for the treatment of infections caused by the ABC complex105 and for the treatment of infections caused by CRAB106.

A randomized clinical trial evaluated the efficacy and safety of sulbactam-durlobactam compared with colistin, each combined with imipenem-cilastatin. The final study population consisted of 125 patients with confirmed CRAB infection. The 28-day fatality rate was lower in the sulbactam-durlobactam group than in the colistin group (19.0% vs. 32.3%), and the incidence of nephrotoxicity was lower (13% vs. 38%; P<0.001)107.

AMPICILLIN-SULBACTAM WITH MEROPENEM AND POLYMYXIN B

In studies using the hollow fiber infection model, the administration of ampicillin-sulbactam at high doses (8/4 g every 8 h) combined with meropenem (2 g every 8 h) and polymyxin B (1.43 mg/kg body weight every 12 h with an initial loading dose) led to the rapid elimination of A. baumannii in 96 h, whereas isolated therapies and combinations of the two drugs resulted in bacterial regrowth108^,^109.

ASSOCIATIONS WITH COLISTIN

A Greek study110 analyzed the treatment of patients with ventilator-associated pneumonia caused by A. baumannii. The patients were then treated with intravenous colistin, tigecycline, and ampicillin/sulbactam. Inhaled colistin was administered simultaneously. The result was 90% patient survival, which demonstrates the promising efficacy of the combination.

A Korean study111 found that patients with A. baumannii bacteremia who were treated with colistin and meropenem tended to have a higher clinical success rate than those treated with colistin monotherapy (61.3% vs. 40.0%).

ERAVACYCLINE

Eravacycline and omadacycline, two new antibiotics, have shown promising results for the treatment of gram-negative infections112^,^113. Combination therapy, which is widely used in clinical practice114, has also proven to be effective with antibiotics already in use.

Eravacycline belongs to the tetracycline class of antibiotics owing to its similar chemical structure and mechanisms of action115^,^116. After in vitro tests based on the MICs, eravacycline was found to be highly effective against MDR strains117.

One study evaluated the activity of eravacycline combined with colistin against ten CRAB isolates and showed 10% synergy and no antagonism118. Tests that showed The most active combination against A. baumannii was eravacycline-ceftazidime and eravacycline-imipenem, which showed synergy against >50% of the isolates119. More recent studies have shown that the eravacycline-ceftazidime combination was the most potent against A. baumannii with 80% synergism120.

CEFIDEROCOL

Cefiderocol was designed for the treatment of carbapenem-resistant gram-negative pathogens, particularly nonfermenting species, such as A. baumannii121. The drug penetrates bacterial cells via active iron transporters, overcoming drug resistance caused by mutations in porin channels and overexpression of efflux pumps. It also has intrinsic stability against hydrolysis by carbapenemases such as KPC, OXA-23, OXA-48-like, OXA-51-like, and OXA-58122^-^124.

The clinical use of cefiderocol has been linked to higher fatality rates in certain groups of patients than the best available therapy125. Other studies have reported a high success rate for this molecule, especially in critically ill patients126^,^127. Thus, cefiderocol should be used with caution, particularly in individuals with complex clinical profiles, such as those with renal dysfunction or septic shock128.

TIGECYCLINE

Compared to tetracyclines, tigecycline shows greater antibacterial potency owing to its higher binding affinity for the 70S ribosome, or more specifically, with helices 31 and 34 of the 16S rRNA at the head of the 30S subunit129^,^130.

The treatment of choice for A. baumannii is based on clinical experience and in vitro susceptibility test131 s. A retrospective study of infections involving tigecycline treatment was conducted in the UK, isolating the cases of thirty-four patients and 68% of the isolates were susceptible to tigecycline. All patients were treated with a standard dosage regimen of 100 mg loading dose, followed by 50 mg of intravenous tigecycline every 12 h132. In a study conducted in Shandong, China, clinical isolates of A. baumannii were collected from patients in three hospitals. Overall, 1,026 strains of A. baumannii strains were identified. The rate of resistance to tigecycline was 13.4%, which was associated with the overexpression of efflux systems133.

Emphasizing the effects of combinations, tigecycline have been reported in many studies and demonstrate that combination with β-lactams or polymyxin B can lead to high synergistic activity against MDR A. baumannii118^,^134^,^135.

PRACTICAL RECOMMENDATIONS BASED ON THE REVIEWED DATA

Strengthen infection control measures in hospitals, particularly strict hand hygiene, isolation of colonized/infected patients, and environmental cleaning, to prevent A. baumannii dissemination.

Implementation of routine surveillance of antimicrobial resistance patterns in A. baumannii isolates to guide empirical therapy.

Prefer combination therapy (e.g., high-dose sulbactam with durlobactam, ampicillin-sulbactam plus meropenem, and/or polymyxin B) for MDR A. baumannii infections instead of monotherapy when supported by susceptibility data.

New agents (cefiderocol, eravacycline, and tigecycline) in critically ill patients when standard regimens fail or resistance is documented.

Reserve polymyxins and other last-line agents for documented infections to slow the development of resistance.

Encourage research on antibiotic to restore antimicrobial activity.

The development and application of hospital stewardship programs have focused on rational antibiotic use to reduce selective pressure.

CONCLUDING REMARKS

Acinetobacter baumannii is a pathogen that is difficult to treat clinically because of its seemingly endless potential to acquire resistance to antibiotics and the wide dissemination of MDR strains. The main mechanisms of resistance in current clinical management include efflux pumps, the production of carbapenemases, and changes in LPS. In addition, it displays mutations in topoisomerases and expresses genes that inactivate antifolates, aminoglycosides, and fosfomycin. Presumably, effective treatment depends on combined therapeutic strategies because single therapies often fail or show limited results, making antibiotic combinations promising options.

Therefore, measures are required to prevent and control A. baumannii infections and elucidate their mechanisms of resistance. This includes the rational use of antibiotics, continuous monitoring of antimicrobial resistance, strict hospital hygiene measures, proper hand hygiene, and isolation of patients colonized or infected with MDR A. baumannii. Encouraging research into new therapies and combinations to develop new antibiotics that avoid the resistance mechanisms discussed and develop innovative therapeutic strategies is essential in this context and may offer hope. However, only judicious use of current treatments will slow the continued increase in resistance to this emerging pathogen.