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Review Article
17 (
3
); 235-246
doi:
10.25259/JLP_31_2025

Escalating threat of Acinetobacter baumannii: Resistance mechanisms and mitigation strategies a perspective

, , ,
1Department of Microbiology, Assam Down Town University, Guwahati, Assam, India.
2Department of Microbiology and Immunology, Purbanchal Educational Welfare Society College of Paramedical Sciences, Guwahati, Assam, India.

*Corresponding author: Laishram Shantikumar Singh, Department of Microbiology, Assam Down Town University, Guwahati, Assam, India. sk1laishram@gmail.com

Received: , Accepted: ,
© 2025 Published by Indian Association of Laboratory Physicians
Licence
This is an open-access article distributed under the terms of the Creative Commons Attribution-Non Commercial-Share Alike 4.0 License, which allows others to remix, transform, and build upon the work non-commercially, as long as the author is credited and the new creations are licensed under the identical terms.

How to cite this article: Baruah J, Shantikumar Singh L, Salvia T, Bhowmik D. Escalating threat of Acinetobacter baumannii: Resistance mechanisms and mitigation strategies a perspective. J Lab Physicians. 2025;17:235-46. doi: 10.25259/JLP_31_2025

Abstract

Acinetobacter baumannii has emerged as a notorious multidrug-resistant pathogen, particularly prevalent in healthcare-associated infections. Its ability to cause outbreaks in intensive care units and other critical care settings is attributed to various virulence factors, including biofilm formation, adhesion properties, and the production of virulence-associated proteins. This review aims to indicate the current understanding of the resistance mechanisms employed by A. baumannii, highlighting its enzymatic capabilities, particularly the production of Ambler class A, B, and D beta-lactamases, which confer resistance to beta-lactam antibiotics, including carbapenems. The prevalence of carbapenem-resistant A. baumannii is alarming, particularly in lowand middle-income countries, where the lack of adequate surveillance and infection control measures exacerbates the situation. The organism’s intrinsic resistance mechanisms, such as reduced outer membrane permeability due to the loss of porins and overexpression of efflux pumps from families like Resistance-Nodulation-Division, significantly contribute to its resilience against various antibiotic classes. Genetic factors, including plasmids and horizontal gene transfer, facilitate the rapid dissemination of resistant traits within bacterial populations that are discussed. The implications of these factors extend to therapeutic challenges, as traditional antibiotic treatments become less effective, leading to increased morbidity and mortality rates among infected patients. Due to the significant threat, A. baumannii has been classified as a priority pathogen by the World Health Organization, necessitating urgent research and development initiatives to tackle it. In this communication, we emphasize on resistance mechanisms of A. baumannii and budding approaches toward its mitigation.

Keywords

Acinetobacter baumannii
Mitigation strategies
Multidrug resistance
Resistance mechanisms

INTRODUCTION

Antimicrobial resistance (AMR) is a rising global threat. Many bacteria have evolved over the period of time and become potentially resistant against many classes of antimicrobials.[1-3] Among all bacteria, particularly Enterococcus faecium, Staphylococcus aureus, Klebsiella pneumoniae, Acinetobacter baumannii, Pseudomonas aeruginosa, and Enterobacter species (ESKAPE) are associated with a high risk of mortality and a significant economic burden, as identified by the Infectious Diseases Society of America due to their potential AMR.[4] Among these bacteria, A. baumannii is one of the commonly encountered infectious pathogens globally and has also been acknowledged as a critical priority pathogen by the World Health Organization (WHO).[1,5] Since the late 1970s, Acinetobacter has emerged as a significant pathogen in hospital-acquired infections (HAI), likely linked to the increased use of broad-spectrum antibiotics in healthcare settings. The most clinically relevant species is A. baumannii and its close relatives, which predominantly cause infections in high-risk areas such as intensive care units (ICU), burn wards, and high-dependency units where critically ill or immunocompromised patients are admitted.[6]

The genus Acinetobacter is a heterogeneous group of bacteria from the Moraxellaceae family and is a significant cause of HAI. It is responsible for a wide range of nosocomial infections, including hospital-acquired pneumonia (HAP), ventilator-associated pneumonia (VAP), urinary tract infections (UTIs), meningitis, bacteremia, as well as infections of the gastrointestinal tract, skin, and wounds.[7] The Acinetobacter genus includes over 50 species of Gram-negative, strictly aerobic, non-fermenting, and non-motile coccobacilli that are catalase-positive, oxidase-negative, and most species are non-pathogenic environmental organisms.[8] A. baumannii is the most virulent infectious species, followed by Acinetobacter calcoaceticus and Acinetobacter lwoffii. Phylogenetic studies reveal Acinetobacter nectaris and Acinetobacter brisouii as distant taxa, with the genus splitting into two main groups: One with A. baumannii, Acinetobacter parvus, and Acinetobacter baylyi and another with A. lwoffii, Acinetobacter johnsonii, and Acinetobacter guillouiae. The metabolic and ecological diversity of the genus reflects an ancient evolutionary history, dating back millions of years alongside the last common ancestor of Enterobacteriaceae.

Initially identified through biochemical profiling, Acinetobacter now comprises at least 33 genospecies. The A. calcoaceticus-A. baumannii (ACB) complex includes A. calcoaceticus (genospecies 1), A. baumannii (genospecies 2), Acinetobacter pittii (genospecies 3), and Acinetobacter nosocomialis (genospecies 13TU), which share phenotypic similarities. A. baumannii is the most clinically significant, while A. calcoaceticus is primarily environmental. The ACB complex also includes A. seifertii and A. dijkshoorniae. A. baumannii, a Gram-negative, aerobic, non-fermenting coccobacillus, exhibits high adaptability and rapid resistance acquisition in healthcare settings.[9] Notably, A. baumannii has emerged as a significant contributor to HAI, exhibiting a marked rise in AMR over the past decade.[10] A. baumannii was first documented in U.S. military medical facilities during the Iraq and Afghanistan conflicts and was commonly referred to as “Iraqibacter” due to its prevalence among American soldiers in the Iraq War.[11,12]

ROUTES OF TRANSMISSION AND RISK FACTORS

A. baumannii transmission is linked to prolonged ICU stays and use of invasive devices such as catheters and endotracheal tubes. The infection spreads primarily through respiratory droplets, with the respiratory system as a key infection route, while risk factors such as advanced age, mechanical ventilation, renal failure, and prolonged hospitalization further increase the risk of nosocomial infections.[7,13] In terms of mortality, factors such as inappropriate empirical antibiotic therapy, high Acute Physiology and Chronic Health Evaluation II scores, severe underlying conditions, prolonged ICU stays, and mechanical ventilation have been linked to poor outcomes. In particular, infections caused by carbapenem-resistant A. baumannii (CRAB) strains are associated with significantly higher mortality rates.[14] Once considered a relatively benign organism, A. baumannii has now become a critical nosocomial pathogen [Figure 1]. It is known for its ability to persist in challenging environments, such as dry, acidic, and low-temperature conditions, allowing it to efficiently colonize and invade necrotic or ischemic tissues. Prior Methicillin-resistant S. aureus colonization and the use of antibiotics, particularly beta-lactams or fluoroquinolones, also contribute to an increased risk of infection.

Transmission, risk factors, and mortality determinants of Acinetobacter baumannii infections. ICU: Intensive care unit, MRSA: Methicillin-resistant Staphylococcus aureus, APACHE II: Acute physiology and chronic health evaluation II, CRAB: Carbapenem-resistant Acinetobacter baumannii.
Figure 1:
Transmission, risk factors, and mortality determinants of Acinetobacter baumannii infections. ICU: Intensive care unit, MRSA: Methicillin-resistant Staphylococcus aureus, APACHE II: Acute physiology and chronic health evaluation II, CRAB: Carbapenem-resistant Acinetobacter baumannii.

GLOBAL PRIORITY PATHOGEN AND IMPACT ON PUBLIC HEALTH

The WHO classifies A. baumannii as a “critical priority” pathogen, emphasizing the urgent need for new antibiotic development.[15] The Centers for Disease Control and Prevention (CDC) has also designated Acinetobacter as an “urgent threat” due to increasing carbapenem resistance.[16] It is highly multidrug-resistant (MDR) and virulent, making it a part of the ESKAPE group, notorious for HAI.[4] Outbreaks have been reported since the 1990s, with Europe, Asia, and the Middle East showing high prevalence.[17] CRAB has exacerbated the crisis in Asia, the Middle East, and Latin America, where resistance rates exceed 90%, severely limiting treatment options.[18] The prevalence of A. baumannii infections strongly correlates with antibiotic resistance rates, as higher resistance leads to more frequent outbreaks. In hospitals, it primarily affects ICU patients, causing VAP, bloodstream infections, and meningitis, all linked to high mortality rates. During the COVID-19 pandemic, A. baumannii co-infections significantly worsened patient outcomes.[19] Rare but severe community-acquired infections of A. baumannii in tropical areas, along with rising resistance, stress the need for better control and novel treatments.

In India, the excessive use of last-line antibiotics, including tigecycline and polymyxins, has driven rising resistance,

thereby reducing therapeutic efficacy against severe A. baumannii infections and escalating public health concerns. Despite stringent infection control measures, MDR A. baumannii and CRAB outbreaks persist in hospitals, straining resources and challenging containment efforts. In India, the economic burden of AMR is significant, with many lacking health insurance. The high cost of prolonged treatments due to resistant infections often falls on patients, worsening their financial strain. The rise of MDR A. baumannii is both a clinical and socio-economic issue, exacerbating healthcare disparities.[20]

AMR

A. baumannii exhibits the highest AMR among Gram-negative bacteria (GNB) causing bacteremia, particularly against broad-spectrum cephalosporins and carbapenems. The rise of MDR A. baumannii (MDRAB) is a major public health concern, especially in healthcare settings where it spreads through fomites from patients, long-term care residents, and healthcare workers.[21] MDRAB co-infections in SARS-CoV-2 patients have worsened due to limited treatment options.[22] The COVID-19 pandemic facilitated secondary infections by A. baumannii, which thrives on respiratory equipment, humidifiers, and catheters.[23] Over time, A. baumannii has developed multiple antibiotic resistance mechanisms as detailed below.

Aminoglycosides (AGs) resistance

AG resistance in A. baumannii occurs through three mechanisms [Box 1]: Aminoglycoside-modifying enzymes (AMEs), 16S ribosomal ribonucleic acid (rRNA)methyltransferases, and reduced uptake due to permeability loss or efflux pump overactivity. AMEs-acetyl-, adenyl-, and phospho-transferases are key contributors. Acquired AG resistance affects 19–31% of cases.[24] AGs inhibit protein synthesis by targeting the 30S ribosomal subunit. Resistance genes spread through integrons, transposons, and plasmids. aph(3’)-VIa, aph(3’)-VIb, aac(6’)-I, and aac(6’)-Ib mediate resistance to amikacin, kanamycin, and tobramycin, while gentamicin resistance is linked to rmA. Efflux pumps, particularly AdeABC and AbeM, contribute to AG clearance, though membrane lipid changes and porins warrant further study.[25]

Box 1: Resistance to aminoglycosides.

  • A. baumannii resists AGs through AMEs, 16S rRNA methylation, and reduced permeability or efflux pump activity.

  • AMEs are categorized into acetyl-, adenyl-, and phospho-transferases based on their modification of AGs through N-acetylation, O-nucleotidylation, or O-phosphorylation.

  • AGs inhibit protein synthesis by targeting the 30S ribosomal subunit, while resistance spreads through integrons, gene cassettes, and plasmids.

  • aph (3’)-VIa, aph (3’)-VIb, and aac (6’)-Ibare AMEgenes linked to resistance to amikacin, kanamycin, and tobramycin, while armAmethylation mediates gentamicin resistance.

  • Efflux pumps such as AdeABCand AbeMare crucial for expelling AGs, especially gentamicin and netilmicin.

AG: Aminoglycosides, AME: Aminoglycoside-modifying enzyme, rRNA: Ribosomal RNA

Beta-lactams resistance

A. baumannii has acquired intrinsic resistance to a wide range of beta-lactam antibiotics. These antibiotics are resistant through a combination of mechanisms, including hydrolysis, reduced membrane permeability, active efflux pumps, and modification of target sites.

Beta-lactamases

Beta-lactamase production is a common mechanism of resistance [Box 2], where enzymes degrade or modify beta-lactam antibiotics before they can reach their target. These enzymes are widespread in both Gram-negative and Gram-positive bacteria. The Ambler classification system divides beta-lactamases into four main classes – A, B, C, and D, based on their amino acid sequences. Classes A, C, and D have a serine residue in their active sites, whereas class B enzymes have a metal ion in their active site.

Box 2: Beta-lactamase-mediated resistance against antimicrobials.

  • Class A β-lactamases resist penicillins, cephalosporins, monobactams, and sometimes carbapenems, while ESBLs target third-generation cephalosporins.

  • Plasmid-borne ESBLs (TEM, SHV, and CTX-M) drive MDR in GNB.

  • Class B MBLs (IMP, VIM, NDM, and SIM) degrade carbapenems through zinc, promoting resistance in A. baumannii.

  • Class C β-lactamases (ADCs) mediate cephalosporin resistance, upregulated by ISAba1.

  • Class D beta-lactamases (OXA) drive carbapenem resistance in CRAB with OXA-23, OXA-24, and OXA-51.

ESBL: Extended-spectrum beta-Lactamase, TEM: Temoneira, SHV: Sulfhydryl variable, CTX: Cefotaximase, MDR: Multidrug-resistance, GNB: Gram-negative bacteria, MBL: Metallo-β-lactamase, IMP: Imipenemase, VIM: Verona integron-encoded metallo-β-lactamase, NDM: New Delhi metallo-β-lactamase, SIM: Seoul imipenemase, ADC: Acinetobacter-derived cephalosporinase, OXA: Oxacillinase, CRAB: Carbapenem-resistant Acinetobacter baumannii

Class A beta-lactamases

Class A β-lactamases, either chromosomal or plasmid-borne, confer resistance to penicillins, monobactams, cephalosporins, and sometimes carbapenems. Narrow-spectrum Class A β-lactamases hydrolyze penicillins and are inhibited by clavulanic acid, but mutations can expand their substrate spectrum, leading to extended-spectrum β-lactamases (ESBLs) capable of degrading extended-spectrum cephalosporins such as ceftazidime, ceftriaxone, and aztreonam.[26]

Plasmid-encoded ESBLs facilitate horizontal gene transfer, accelerating resistance spread. ESBLs often co-exist with other resistance mechanisms, leading to MDR against AGs and fluoroquinolones, complicating treatment. Key ESBLs include Temoneira (TEM), Sulfhydryl variable (SHV), and Cefotaximase-M (CTX-M) β-lactamases, arising from genetic mutations.[27] Continuous mutations expand their substrate profiles, with variants such as blaTEM-92, blaSHV, blaGES-11, and Beta lactamase-pseudomonas extended resistance -1 (blaPER-1) detected in clinical isolates.[28,29] CTX-M-type β-lactamases and K. pneumoniae carbapenemases further enhance β-lactam resistance, including to carbapenems, highlighting the urgent need for stringent infection control policies guided by epidemiological data.[30]

Class B beta-lactamases

Class B beta-lactamases or Metallo-beta-lactamases (MBLs) hydrolyze broad-spectrum beta-lactams, including carbapenems, but not monobactams. These zinc-dependent enzymes are often plasmid-encoded, promoting horizontal transfer. Key MBLs in A. baumannii include Imipenemase (IMP), Verona-integron-encoded metallo-β-lactamase (VIM), New Delhi metallo-β-lactamase (NDM) and Seoul imipenemase (SIM).[31] Detection is challenging, with polymerase chain reaction being more reliable than phenotypic tests.[32] NDM is particularly concerning due to its minimal fitness cost, enabling global spread.[33] The emergence of blaNDM in MDR A. baumannii clinical isolates is a critical issue in India.[30]

Class C beta-lactamase

Acinetobacter-derived cephalosporinases (ADC), classified as Class C β-lactamases, confer resistance to cephalosporins. The upregulation of ADCs is often attributed to insertion sequences (IS) such as ISAba1 and ISAba125, which act as strong promoters driving the overexpression of these enzymes.[34] The bioinformatics tool panISa facilitates the detection of these IS in whole-genome sequencing (WGS) data, aiding in the study of resistance patterns. Certain ADC variants, such as ADC-30, are associated with resistance to a broader range of antibiotics, including cephalosporins, carbapenems, and sulbactam.[35]

Class D beta-lactamase

Class D beta-lactamases, commonly known as oxacillinases (OXAs) or carbapenem-hydrolyzing Class D beta-lactamases, are the primary resistance mechanism in CRAB. Enzymes such as OXA-23, OXA-24, and OXA-51 hydrolyze carbapenems and other beta-lactams while resisting inhibitors such as clavulanic acid, sulbactam, and tazobactam.[36] The blaOXA gene expression is significantly upregulated by ISAba1 insertion in promoter regions, enhancing resistance.

Tetracycline resistance

Tetracyclines inhibit protein synthesis by targeting the 30S ribosomal subunit. Tetracycline resistance in A. baumannii [Box 3] occurs through (i) enzymatic inactivation, (ii) ATP-dependent efflux, and (iii) ribosomal protection proteins (RPPs). The resistance-nodulationdivision (RND) efflux pump AdeABC significantly raises minimum inhibitory concentrations (MICs) for tigecycline, minocycline, and tetracycline, while AdeIJK and AcrAB-TolC contribute synergistically. Major facilitator superfamily (MFS) pumps tetA and tetB expel tigecycline into the periplasm for RND-mediated removal. RPPs like tetM/tetW/tetO/tetS counteract inhibition by modifying ribosomes, with tetM-linked minocycline resistance allowing translation to continue. Plasmid-mediated tet(X) variants, including monooxygenases tet(X3), tet(X4), and tet(X5), inactivate all tetracyclines, including tigecycline, eravacycline, and omadacycline, posing a growing resistance threat.[37]

Box 3: Resistance against Tetracyclines.

  • Tetracycline resistance in A. baumanniiarises from enzymatic inactivation, efflux pumps, and RPPs.

  • The AdeABCefflux pump drives resistance to tetracyclines, including tigecycline and minocycline.

  • RPPs like tetM dislodge tetracyclines, enabling protein translation.

  • Plasmid-mediated tet(X) variants inactivate all tetracyclines, including newer agents.

RPP: Ribosomal protection protein, ABC: Antibody-binding cassette

Fluoroquinolones resistance

Quinolone antibiotics, mostly fluoroquinolones, are broad-spectrum bactericidal antibiotics primarily effective against both GNB and GPB, functioning by inhibiting the ligase activity of DNA gyrase and topoisomerase IV. This disruption leads to DNA breaks and bacterial cell death.[38] A. baumannii resistance to quinolones arises through three main mechanisms [Box 4]: (i) plasmid-mediated resistance through Qnr proteins and AMEs; (ii) target mutations in gyrase and topoisomerase IV that diminish drug binding; and (iii) chromosomal resistance linked to reduced porin expression or overactive efflux pumps. Fluoroquinolone resistance in A. baumannii ranges from 50% to 73%, reaching 97.7% in developing countries.[24,39] The AdeABC RND efflux pump, enhanced by AdeR and AdeS mutations, drives resistance. Quinolone resistance-determining regions feature concurrent gyrA and parC mutations, significantly elevating resistance. Plasmid-mediated quinolone resistance genes, including qnrAI, qnrB, qnrB19, and qnrS, encode pentapeptide-repeat proteins that inhibit gyrase by blocking DNA binding, preventing cleavage by gyrase and topoisomerase IV. AMEs like AAC(6’)-Ib-cr and AAC(6’)-Ib-cr5 further contribute by modifying norfloxacin and ciprofloxacin. While plasmid-borne efflux pumps exist in other species, none are documented in A. baumannii.[29] Chromosomal mechanisms involve downregulated porins and efflux pumps over activity. Reduced Omp25 and CarO expression correlates with resistance, though their role remains unclear.

Box 4: Resistance exhibited against fluoroquinolones.

  • A. baumannii resists quinolones through Qnr proteins, target mutations, and efflux pump/porin changes.

  • Quinolone resistance-determining regions mutations in gyrAand parCsignificantly increase resistance.

  • Plasmid-mediated quinolone resistance genes such as qnrAI, qnrB, qnrB19, and qnrSprotect DNA gyrase from quinolones.

Polymyxins resistance

Polymyxin resistance in A. baumannii arises through multiple mechanisms reducing drug efficacy [Box 5].[40] A key method involves lipid A modifications in Lipopolysaccharides (LPS) and decreasing polymyxin binding. Mutations in the pmrCAB operon upregulate pmrC, while mcr genes encode PEA transferases that modify lipid A, reducing its negative charge. Mutations in lpxA, lpxC, and lpxD disrupt lipid A biosynthesis, further contributing to resistance. Alterations in lpsB, lptD, and vacJ affect outer membrane permeability. Biotin deficiency impacts LPS biosynthesis and polymyxin susceptibility. Efflux pumps such as MexAB-OprM expel polymyxins, lowering intracellular drug levels. Additional mutations in vacJ, zndP, and pheS are linked to colistin resistance.[40]

Box 5: A. baumannii resistance against polymyxins.

  • Polymyxin resistance arises from LPS modification.

  • Overexpression ofpmrC due to mutations in the pmrCAB reduces polymyxin binding.

  • Mutations in lpxA, lpxC, and lpxDdisrupt lipid A biosynthesis, while lpsB, lptD, and vacJreduce outer membrane permeability

  • MexAB-OprM efflux pump expels polymyxins.

  • Mutations in vacJ,zndP, and pheScontribute to colistin resistance.

LPS: Lipopolysaccharide, pmrCAB: polymixin resistant C A B

Macrolides resistance

Macrolide antibiotics, especially azithromycin, show limited effectiveness against A. baumannii infections, while azithromycin may inhibit mucin production and is used in combination with other antibiotics for nosocomial pneumonia in ICU patients. Beyond binding to the 50S ribosomal subunit, it suppresses Extracellular signal- regulated Kinase (ERK)/c-Jun N-terminal Kinase (JNK) phosphorylation and nuclear factor-kappa B (NF-κB) nuclear translocation.[41] Macrolide resistance in A. baumannii [Box 6] involves 23S rRNA methyltransferases (erm [B, C, and F]), the ABC-F RPP (msr [E]), and macrolide 2’-phosphotransferases (mph [A, E]). The first two modify the target site, while the latter inactivates the drug. Mph(A, E) confer resistance to multiple macrolides based on regulatory proteins. Efflux pumps play a key role, with WGS identifying the MFS transporter AmvA as crucial for erythromycin resistance. Resistance-related mef(E) genes were found in resistant strains, while the MacA-MacB-TolC and AdeABC efflux pumps, regulated by adeRS mutations, actively expel macrolides.

Box 6: Resistance exhibited against macrolide.

  • Azithromycin and other macrolides have limited effectiveness against A. baumannii.

  • Azithromycin suppresses ERK/JNK phosphorylation and NF-κB translocation.

  • Macrolide resistance involves 23S rRNA methyltransferases, ABC-F ribosomal protection protein, and macrolide 2’-phosphotransferases.

  • WGS identifies the MFS transporter AmvAas key to erythromycin resistance.

ERK: Extracellular signal- regulated kinase, JNK: c-Jun N-terminal kinase, MFS: Major facilitator superfamily

Carbapenems were the first-line treatment for MDR A. baumannii, but their increased use has driven carbapenem resistance.[42] Polymyxins are now preferred despite nephrotoxicity and neurotoxicity concerns.[43] Extensively drug-resistant (XDR) A. baumannii resists three or more antimicrobial classes, including penicillins, cephalosporins (with inhibitors), fluoroquinolones, AGs, and typically carbapenems. Pan-drug-resistant A. baumannii includes XDR isolates also resistant to polymyxins and tigecycline. The rise of XDR strains has accelerated novel antimicrobial development and treatment strategies.

VIRULENCE FACTORS INFLUENCING RESISTANCE

Lipooligosaccharide (LOS) and lipid A biosynthesis

The glycosyltransferase LpsB is crucial for LOS biosynthesis, a key structural component of A. baumannii. Unlike LPS, LOS lacks an O-polysaccharide region.[44] A. baumannii primarily produces hepta-acylated lipid A, enhancing resistance to cationic antimicrobial peptides in vertebrate mucosal secretions and promoting desiccation survival key virulence trait in hospitals. Unlike other GNB that utilize PagP to add a palmitoyl group to lipid A under stress, A. baumannii lacks this mechanism but achieves hepta-acylation through an independent pathway.[45]

Capsular polysaccharide

A. baumannii’s capsular polysaccharide serves multiple roles in virulence. It reduces adhesion to hydrocarbons while increasing attachment to epithelial cells, thus aiding in colonization. The capsule also provides protection against phagocytosis by immune cells. The key structural components of the capsule, L-rhamnose, D-glucose, D-glucuronic acid, and D-mannose, are synthesized by the ptk and epsA genes.[46]

Outer membrane proteins (OMPs) and host cell apoptosis

OMPs, particularly OmpA, are crucial for the pathogenicity and antibiotic resistance of A. baumannii. OmpA, a major outer membrane vesicle component, promotes adherence to epithelial cells, biofilm formation, and persistence in hospitals.[47] Once internalized, it induces apoptosis through caspase-3 activation, upstream caspase-8/9 signaling, and mitochondrial cytochrome C release.[48] It also triggers a Th1 immune response and upregulates inducible nitric oxide synthase through Toll-like receptor (TLR)-2 signaling. In addition, OmpA anchors beta-lactamases in the periplasm, enhancing resistance by concentrating antibiotic-degrading enzymes, while also evading complement attack.

Other OMPs, such as CarO and AbuO, contribute to resistance; CarO is vital for carbapenem uptake, and its loss reduces membrane permeability, causing carbapenem resistance. AbuO functions as an efflux pump, expelling antibiotics such as ceftriaxone and meropenem, driving MDR. Outer membrane carboxylate channels (Occ family and formerly OprD) facilitate both antibiotic resistance and host interactions. Collectively, these OMPs bolster A. baumannii’s antibiotic defense and virulence, making it a significant public health threat.

Efflux pumps

Efflux pumps in A. baumannii contribute to both antibiotic resistance and virulence. The AdeABC pump, part of the RND family, confers resistance to carbapenems and cephalosporins. It consists of three components: AdeB (expels antibiotics), AdeA (membrane fusion protein), and AdeC (OMP). AdeB transports diverse substrates, enhancing adaptability. Regulation by the AdeRS two-component system, with adeRS mutations, leads to overexpression and increased resistance. Other pumps such as AdeIJK and AbeM mediate resistance to imipenem and cephalosporins. These pumps also aid A. baumannii persistence and infection, increasing virulence.[29]

Immune evasion and cytotoxicity

Lipid A in A. baumannii plays a key role in immune system activation, triggering pro-inflammatory cytokine production in human monocytes via CD14, TLR-2, and TLR-4 pathways.[49] The lipolytic enzyme phospholipases plays a key role in the breakdown of phospholipids and forms the main virulence factor in various GNB. Two phospholipases C (A1S_0043 and A1S_2055) and three phospholipases D (Phospholipase D1 (PLD1), PLD2, and PLD3) possessing substrate specificity to eukaryotic membrane component phosphatidylcholine have been recognized in A. baumannii. The stability of host cell membranes was impacted due to the degradation of phospholipids, thereby resulting in interference in cellular signaling, hence bringing about alterations in the immune response of the host. Subsequently, the outcome due to bacterial phospholipases disturbs the immune response and triggers the establishment of infection or progression.[50] In case of A. baumannii, phospholipases D collectively stimulate serum resistance, invasion of epithelial cells, and pathogenesis in vivo. Fascinatingly, PLD1 and PLD2 seem to be the outcome of a gene duplication distinguished by the HxKx4Dx6GSxN (HKD) pattern analogous to eukaryotic cells and needed for catalytic action. Despite their resemblance, PLD2 plays a more important role in invasion and virulence than PLD1 and PLD3.[51] Thus, in A. baumannii, phospholipase D is crucial for its development in human serum, and phospholipase C enhances its cytotoxicity against epithelial cells.[52] These enzymes contribute to its ability to evade immune responses and increase its survival during infection.

Biofilm

A. baumannii forms biofilms on biological and abiotic surfaces, aiding its persistence in hospitals. Biofilms protect against immune responses and antibiotics, with fimbriae and pili playing key roles. Genes such as csuC and csuE facilitate pili formation, while biofilm-associated protein enhances maturation by increasing volume and thickness, promoting adhesion. Biofilms also confer desiccation resistance, enabling some clinical isolates to survive nearly 100 days in dry environments.[53,54]

Penicillin-binding proteins (PBPs)

PBPs in A. baumannii are membrane-bound enzymes crucial for peptidoglycan synthesis, cell division, and morphogenesis. Inhibiting PBPs disrupts cell wall integrity, impairing growth or causing lysis. PBPs are classified into low and high-molecular-weight groups; the former aids cell segregation and remodeling, while the latter drives peptidoglycan synthesis. A PBP-7/8 deficient mutant showed increased pathogenesis in rat soft-tissue infection models and enhanced survival in human ascitic fluid.[55] PBPs play a key role in A. baumannii pathogenesis.

APPROACHES FOR COMBATING A. BAUMANNII INFECTIONS

Potential strategies and novel approaches [Figure 2] are required to mitigate the public health impact of A. baumannii.

Potential approaches for combating Acinetobacter baumannii infections. CRISPR: Clustered regularly interspaced short palindromic repeats.
Figure 2:
Potential approaches for combating Acinetobacter baumannii infections. CRISPR: Clustered regularly interspaced short palindromic repeats.

Monotherapy

A. baumannii resistance is widespread against ureidopenicillins, AGs, aminopenicillins, fluoroquinolones, chloramphenicol, and cephalosporins, with sulbactam also showing declining efficacy.[56] Carbapenems, particularly meropenem and imipenem, were once reliable options but now face resistance, with imipenem exhibiting a higher affinity for certain OXA.[57] Despite this, monotherapy with tigecycline or polymyxins remains effective in many cases. Global surveillance (2007–2011) reported increasing minocycline susceptibility (72.5–91.7%), reinforcing its potential as a monotherapy option.[58]

Combination therapy

Combination therapy for A. baumannii infections has shown inconsistent clinical efficacy but is recommended when monotherapy fails. In vitro and in vivo studies indicate that combinations of two or three antibiotic classes, such as tigecycline, rifampin, polymyxins, sulbactam, AGs, cephalosporins, or carbapenems, can enhance bactericidal activity against MDR strains.[59] However, due to diverse resistance mechanisms, each antibiotic must be tested against the clinical isolate. Rifampin combined with tobramycin, imipenem, or colistin showed efficacy in a murine pneumonia model[60] but a clinical trial advised against rifampinimipenem for CRAB due to a 70% rifampin resistance rate.[61] Given inconsistent outcomes, further controlled studies are needed to determine the most effective combinations. Biofilm formation by A. baumannii aggravates the issue of its antibiotic resistance. The extracellular matrix, due to biofilm, acts as a physical barricade preventing antibiotic penetration, thereby shielding the bacteria from the immune system of the host. Combinations of antibiotics have revealed potential in fighting A. baumannii biofilms. However, the efficiency of such a tactic may differ based on the strain and its resistance pattern. The utilization of two or more antibiotics having different modes of action can augment the therapeutic effectiveness by affecting several targets. The amalgamation of rifampin and colistin has been more effective at eliminating biofilms produced by MDR A. baumannii isolates than either antibiotic alone.[50] Amalgamations of colistin-levofloxacin, colistin-tigecycline, and tigecycline-levofloxacin or these combinations with clarithromycin have been reported to be efficient in the treatment of catheter-related infections by A. baumannii. However, contender antibiotics were effective toward biofilm-embedded A. baumannii cells at 400-fold the MIC. Such concentration is unattainable in human serum; hence, those antibiotics become an inappropriate choice for systemic use in A. baumannii biofilm-related infections.[62] Synergetic effects have also been noticed on biofilm-embedded CRAB and carbapenem-susceptible A. baumannii strains. Meropenem was effective against biofilm-embedded carbapenem-susceptible A. baumannii, whereas meropenem plus sulbactam displayed synergism toward CRAB biofilm and produced pointedly more impairment to the biofilm configuration than tigecycline or colistin used alone. Furthermore, amalgamating polymyxin B and azithromycin exhibited synergetic action against biofilm-forming A. baumannii clinical isolates, enhancing antibiotic effectiveness.[50]

Sulbactam therapy

Sulbactam, a β-lactamase inhibitor, exhibits intrinsic activity against A. baumannii. In vivo and in vitro studies show its efficacy, but combining it with ampicillin has not significantly enhanced activity. Sulbactam-meropenem combinations reduce biofilm biomass and thickness, improving efficacy against biofilm-embedded CRAB. Antimicrobial susceptibility testing of 176 A. baumannii isolates with β-lactam/β-lactamase inhibitor combinations showed 99.4% susceptibility, highlighting potential therapeutic options.[63] However, sulbactam’s effectiveness varies regionally, and large randomized clinical trials are lacking. Despite its efficacy, increasing clinical use has led to rising resistance in some regions.[64]

Bacteriophages therapy

Bacteriophages target bacteria by binding to surface receptors, injecting genetic material, and replicating using the host’s machinery. With rising AMR, phage therapy is gaining attention for reducing resistance and virulence in MDRAB without disrupting the microbiome.[65] Successful treatment of necrotic pancreatitis caused by MDRAB has been reported.[66] However, resistance may develop through phage receptor mutations or outer membrane vesicle production. Standardization challenges include risks of bacterial toxin transfer. Combining phages with lysins may enhance efficacy, but dosage and elimination must be studied. Immune responses, including opsonization, may also limit effectiveness. Further research is needed to optimize clinical use.

Tigecycline

Tigecycline, a synthetic minocycline derivative, is bacteriostatic against CRAB, but resistance can develop through efflux pump upregulation. Used in combination regimens for bacteremia, VAP, and soft-tissue infections, its efficacy in HAP is limited by suboptimal lung concentrations. Higher dosing may improve outcomes, but poor urinary excretion makes it unsuitable for UTIs. Resistance concerns restrict its use to salvage therapy rather than monotherapy for A. baumannii infections.[67]

Polymyxins

Polymyxins, mainly colistin (polymyxin E) and polymyxin B, are reconsidered for A. baumannii infections due to limited options. Colistin disrupts the bacterial membrane by interacting with LPS, increasing permeability, and causing cell death. Colistin sulfate is used orally/topically, while colistin methanesulfonate is given intravenously. Polymyxins, alone or in combination, treat meningitis and VAP. Aerosolized colistin, especially with intravenous use, shows promise for A. baumannii pneumonia. However, rising resistance and heteroresistance necessitate combination therapy with other antimicrobials.[68]

AGs

AGs, such as tobramycin and amikacin, are valuable therapeutic options for infections caused by A. baumannii that retain susceptibility to these agents. They are often administered in combination with other potent antibiotics. Although some MDR Acinetobacter isolates exhibit intermediate susceptibility to tobramycin or amikacin, increasing resistance is primarily driven by efflux pump activity and AMEs. In vitro studies continue to report rising AG resistance.[69]

Tetracyclines

North India reported a synergistic effect of tetracycline combined with nalidixic acid against MDR A. baumannii isolates.[70] Minocycline has demonstrated promising results both in monotherapy and in combination with other antibiotics, particularly against CRAB. Minocycline possesses a significant susceptibility, and it is recommended for use in critically ill patients through the intravenous route due to its favorable in vitro activity and pharmacodynamics.[71]

Clustered regularly interspaced short palindromic repeats (CRISPR) system

CRISPR technology shows promise in combating A. baumannii resistance by targeting foreign genetic material, aiding strain subtyping, and increasing oxidative stress susceptibility. However, challenges include off-target mutations, protospacer adjacent motif sequence limitations, and delivery issues through bacterial membranes. Phages are explored as vectors, but immune neutralization and inactivation in vivo remain obstacles to therapeutic application.[72,73]

Vaccines

Whole-cell vaccines, both live-attenuated and inactivated, show promise in preclinical studies for A. baumannii. An attenuated live vaccine lacking thioredoxin A adhesin provided strong protection in mice, while formalin-killed whole-cell vaccines with adjuvants induced mixed Th1/Th2 responses and high survival rates. Subunit vaccines targeting OmpA demonstrate significant immunogenicity across age groups. Phospholipases are conserved across several A. baumannii strains and are important for host invasion; they may represent encouraging targets for the development of enzyme inhibitors and probable candidates for a vaccine to restrict the effects of human diseases. Multi-component and nucleic acid-based vaccines are under study, but none have reached clinical trials.[74]

CONCLUSION

The rise of A. baumannii as an MDR pathogen presents a critical challenge, particularly in HAI. Its rapid acquisition of resistance through β-lactamase production, efflux pump upregulation, and outer membrane alterations makes this pathogen a considerable threat to antimicrobial therapy. Biofilm formation further complicates treatment, leading to persistent infections. A. baumannii infections are linked to high morbidity and mortality, especially in critically ill patients.

Low-and middle-income countries face a severe impact, relying on last-resort antibiotics such as polymyxins and tigecycline, which are losing efficacy. In India, high carbapenem resistance, frequent outbreaks, and limited healthcare resources exacerbate the crisis, necessitating stringent surveillance and infection control. The WHO and CDC classify A. baumannii as a “critical priority” pathogen, emphasizing the need for urgent intervention.

A multifaceted approach, including enhancing diagnostics, developing novel therapeutics, and strengthening antimicrobial stewardship, is required. Public awareness and education for healthcare providers are crucial in mitigating resistance. Research into alternative treatments, including bacteriophage therapy and adjuvant use, holds promise. Combating A. baumannii demands global collaboration among clinicians, microbiologists, and public health officials. Vigilance and innovation are vital to sustaining effective treatments and preventing an escalating AMR crisis.

Acknowledgements:

The authors are grateful to the authorities of the host institution for their support and encouragement to carry out this work.

Author contributions:

JB: Manuscript writing, Literature review, Analysis of the contents. LSS: Conceived the idea and designed the manuscript, Reviewed and edited the manuscript, supervised the work and overall analysis of the contents. TS: Literature review, Content analysis, Editing and review. DB: Literature search and review, content editing, Assists in drafting. All the authors have discussed, duly checked and approved the manuscript before submission.

Ethical approval:

Institutional Review Board approval is not required.

Declaration of patient consent:

Patient’s consent was not required as there are no patients in this study.

Conflicts of interest:

There are no conflicts of interest.

Use of artificial intelligence (AI)-assisted technology for manuscript preparation:

The authors confirm that there was no use of artificial intelligence (AI)-assisted technology for assisting in the writing or editing of the manuscript and no images were manipulated using AI.

Financial support and sponsorship: Nil.

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