A. baumannii is a Gram-negative opportunistic pathogen mainly associated with hospital-acquired infections in various patient populations including critically ill patients, typically in intensive care units (ICUs) wherein patients may have prolonged hospital stays with mechanical ventilation, central venous catheter placement or open wounds, as well as immunocompromised patients (Wong et al., 2017). Unfortunately, A. baumannii clinical isolates responsible for these infections have become increasingly drug-resistant, especially to last resort antibiotics. The coupling of this increase in the number of drug-resistant A. baumannii isolates encountered clinically with the decreased number of new antibiotics in the developmental pipeline has led the World Health Organization (WHO) and Centers for Disease Control and Prevention (CDC) to identify this pathogen as a critical public health threat requiring the urgent development of novel antibiotics (Nguyen and Joshi, 2021). Clinical outcomes of A. baumannii patients have concomitantly worsened as the number of effective antibiotics have decreased and the frequency of infections caused by multidrug resistance strains have increased (Magiorakos et al., 2012; Vázquez-López et al., 2020).

Transmission of this pathogen, the ability of this bacterium to establish infection and its ability to evade immune destruction is due to a myriad of virulence factors, many of which remain incompletely characterized but unfortunately are still more than can be comprehensively articulated in this perspective. However, it is of importance to highlight some of these factors to illustrate the success of A. baumannii as a pathogen. Amongst these virulence factors are pilins; some of which are utilized by A. baumannii to colonize abiotic surfaces and therefore play roles in transmission and others that aid in the establishment of infection through adherence and potentially biofilm formation on biotic surfaces (e.g. host cells). Abp1 and 2 pili, for example, allow the establishment of biofilms on fibrinogen-coated catheters associated with catheter-associated urinary tract infections (Tamadonfar et al., 2023). CsuA/B pili are also utilized by A. baumannii for adherence and biofilm formation on abiotic surfaces (e.g. medical equipment) while also providing protection against desiccation and antimicrobial agents (Tomaras et al., 2003; Espinal et al., 2012; Ahmad et al., 2023). Bacterial colonization of medical devices and surfaces such as this facilitates pathogen transmission. Once transmitted to the human host, FimA pili have been demonstrated to aid in bacterial adherence to host cells such as A549 human alveolar epithelial cells, and PilA pili are likely involved in the continued colonization and spread of this pathogen in the human host, as PilA has been associated with biofilm formation and twitching motility (Ronish et al., 2019; Mahmoudi et al., 2020).

A. baumannii also has a broad repertoire of virulence factors for survival, persistence and overall virulence within the host. A. baumannii phospholipase Cs for example have been shown to be involved in epithelial cell invasion, host cell cytotoxicity, hemolysis and overall in vivo virulence, while A. baumannii phospholipase Ds have been associated with epithelial cell invasion and in vivo virulence as well, in addition to serum resistance and resistance to cationic antimicrobial peptides (Camarena et al., 2010; Jacobs et al., 2010; Stahl et al., 2015; Fiester et al., 2016; Kareem et al., 2017; Pfefferle et al., 2020). In addition to phospholipases, outer membrane protein A (OmpA) has been associated with many virulence roles within the host including adhesion and subsequent invasion and apoptosis of host cells, serum resistance and drug resistance. Overproduction of OmpA is an independent mortality predisposing factor during nosocomial A. baumannii bacteremia. OmpA has apoptotic ability through mitochondrial membrane potential destabilization as well as endonuclease-mediated DNA fragmentation (Choi et al., 2005; Choi et al., 2008; Sánchez-Encinales et al., 2017) which may lead to increased immune cell death, a risk factor for multiple-organ failure and mortality in sepsis (Hotchkiss and Nicholson, 2006; Luan et al., 2015). OmpA has also been associated with the biogenesis of outer membrane vesicles (OMVs) which then in turn have been shown to carry OmpA as part of their payload (Moon et al., 2012).

OMVs carry several proteins which may act as pathogen-associated molecular patterns (PAMPs), inducing sharp, dose-dependent upregulation of pro-inflammatory cytokine genes including MIP-1α, MCP-1, IL-8, IL-6, and IL-1β in Hep-2 epithelial cells (Jun et al., 2013; Oh et al., 2025). Of particular concern is the implication of OMVs carrying resistance genes and drug-metabolizing enzymes thus propagating and contributing to drug-resistance. Similarly, as a Gram-negative pathogen, A. baumannii lipopolysaccharide (LPS) can bind host toll-like receptor 4 (TLR4) stimulating the release of pro-inflammatory cytokines such as TNF-α, IL-1β, IL-6, IL-8 in human neutrophils (Kamoshida et al., 2020). A. baumannii cells deficient in LPS demonstrate decreases in inflammatory cytokine levels, bacterial load in tissue and show increased susceptibility to macrophage killing in mice. In fact, mice infected with LPS-deficient A. baumannii had complete survival, attributed to a lack of the TLR4-mediated cytokine storm often associated with lethal sepsis due to systemic hyperinflammation (Erridge et al., 2007; Lin et al., 2012).

Current research on these virulence factors is constrained by a remarkable heterogeneity between strains leading to difficulty when attempting to generalize results. Established strains commonly used in experiments including AB5075, ATCC 17978, ATCC 19606 and DSM30011 do not fully represent the heterogeneity seen in modern clinical isolates (Valcek et al., 2023). Inversely, many studies using only contemporary isolates exclude established strains making comparisons to previous studies difficult if not impossible. Future experiments aiming to elucidate the general pathophysiology of A. baumannii will therefore require data from isolate collections including both established and contemporary strains that more fully encompass the vast phenotypes represented in this species while also allowing for comparisons to previously published works. More comprehensive elucidation of these virulence factors will uncover new targets for novel therapeutics. This perspective describes the burden of A. baumannii in healthcare and shares the authors’ perspectives on areas requiring increased attention in research and clinical management.

Patient-level risk factors for A. baumannii infection are consistent worldwide and include prolonged hospitalization, ICU admission, use of invasive medical devices such as mechanical ventilators and indwelling catheters, invasive procedures, immunosuppression, advanced age, antibiotic overuse and underlying chronic conditions (Ang and Sun, 2018; Benaissa et al., 2023). A. baumannii infections constitute a substantial burden on global healthcare systems due to this bacterium’s genetic plasticity and resultant ability to acquire antimicrobial resistance genes ultimately resulting in limited treatment options. A. baumannii resistance phenotypes including multidrug resistance (MDR), defined as non-susceptibility to at least one agent in three or more antimicrobial classes; extensive drug resistance (XDR), denoting non-susceptibility to all but one or two classes; and pan-drug resistance (PDR), reflecting resistance to all clinically available antimicrobial agents, have been reported (Magiorakos et al., 2012). Treatment of A. baumannii isolates displaying these resistance phenotypes is severely limited contributing to the often-higher mortality, morbidity and healthcare costs associated with A. baumannii infections specifically.

In the United States alone, hospital-based incidence of A. baumannii averaged approximately 1 case per 100 patients between 2019-2022, with a slight decline in 2022 following an increase during the COVID-19 pandemic (Ellis et al., 2022; Lodise et al., 2025). Carbapenem-resistant A. baumannii (CRAB) remains a particularly concerning phenotype showing an increase from 0.39 cases per 100 hospitalized to 0.53 cases per 100 hospitalized over the same period (Lodise et al., 2025). CDC surveillance in 2017 documented approximately 8,500 cases and 700 associated deaths from CRAB infections, underscoring the continuous threat posed by resistant isolates (Centers for Disease Control and Prevention).

Globally, A. baumannii resistance rates are highest in the Middle East, the Mediterranean, Northern Africa, parts of Asia and South America reflecting geographic disparities in infection control practices and antibiotic stewardship programs (Ma and McClean, 2021). The WHO, in collaboration with the European Centre for Disease Prevention and Control (ECDC), based on 2021–2023 surveillance data, reported only 25.5% of A. baumannii isolates remain susceptible to antibiotics included in their report, while 2.9% showed resistance to one antimicrobial class, 4.9% to two classes and 66.6% to three or more antimicrobial classes, making two-thirds of A. baumannii isolates MDR (European Centre for Disease Prevention and Control, 2023). Outbreaks of A. baumannii are typically nosocomial, occurring in ICUs or other hospital units, and are commonly associated with contaminated surfaces, medical equipment and passive transmission, clearly demonstrating the environmental persistence of A. baumannii. Although community transmission is rare, isolated outbreaks, such as recorded in Queensland, Australia, reported a 28.6% mortality rate, underscoring the potential for wider spread (Riddles and Judge, 2023). Carbapenem and ampicillin-sulbactam-resistant (CASR) infections notably demonstrate higher mortality (43% vs. 20%) and ICU admission rates (44% vs. 27%) compared to non-resistant cases (Chopra et al., 2013). Mortality in A. baumannii bacteremia remains high overall, ranging from 37% to 52% in U.S. studies, and exceeding 50% in some studies with international cohorts (Assimakopoulos et al., 2023).

The spread of resistant A. baumannii isolates poses a significant challenge to effective treatment. This resistance, largely driven by genetic plasticity, limits available antimicrobial options, thereby hindering treatment and contributing to high morbidity and mortality rates (Kyriakidis et al., 2021; Karampatakis et al., 2024). For example, a six-year study conducted in Naples, Italy, reported that 89.5% of 191 A. baumannii isolates were classified as MDR (Foglia et al., 2025). Current therapeutic approaches underscore the need for targeted interventions and innovative strategies, as many Acinetobacter isolates have developed resistance to agents once considered last-resort therapies, such as carbapenems (Vázquez-López et al., 2020). Notably, carbapenemase genes have been identified in approximately 66.9% to 92.2% of A. baumannii isolates globally (de Souza et al., 2025).

Historically, carbapenems served as the primary therapy for A. baumannii infections; however, the global rise of CRAB isolates, now accounting for approximately 45% of cases worldwide, creates a critical need for alternative treatments (De Oliveira et al., 2020). The potent activity of polymyxins, particularly colistin, against MDR strains has caused its resurgent use as a last resort agent. Colistin interacts electrostatically with negatively charged components of the bacterial outer membrane and LPS, disrupting the outer and inner membranes and inducing bacterial cell lysis. Resistance can arise however from the inactivation of the LPS biosynthetic pathway eliminating the target and conferring resistance (Novović and Jovčić, 2023). Nephrotoxicity, variable pharmacokinetics, poor lung penetration and overall toxicity of colistin, especially in critically ill patients, restrict clinical use and require careful dosing and monitoring. Renal toxicity is also a frequent adverse effect, as colistin is mainly excreted via the kidneys, where it increases tubular epithelial permeability, leading to cellular lysis and acute tubular necrosis (Spapen et al., 2011; Kilic et al., 2023).

Newer therapeutics for the treatment A. baumannii infections include sulbactam–durlobactam (SUL/DUR) and cefiderocol. Among β-lactamase inhibitors, SUL/DUR, approved by the U.S. Food and Drug Administration (FDA) in 2023 for ventilator and hospital acquired pneumonia, is associated with lower nephrotoxicity, fewer adverse events and decreased 28-day mortality; however, evidence is limited regarding its effectiveness in the treatment of bloodstream infections (Arshad et al., 2025). Sulbactam-durlobactam clinical trial data specific to septic shock remains limited, however, with persistent concerns regarding durability of response and emergence of resistance (El-Ghali et al., 2023; Kaye et al., 2023). Cefiderocol, the first siderophore cephalosporin, inhibits penicillin-binding proteins (PBPs) and disrupts cell wall synthesis by exploiting iron transport while resisting hydrolysis by serine and metallo-β-lactamases (Zhang et al., 2024). Cefiderocol has expanded treatment options; however, heterogeneous outcomes and variable resistance mechanisms highlight the need for comparable trials across global isolates (Petropoulou et al., 2021; Principe et al., 2022; Halim et al., 2025). Nevertheless, cefiderocol is often administered in combination regimens to enhance bacterial killing, improve clinical efficacy and help prevent the selection of resistant isolates as monotherapy may not completely eradicate all bacteria (Yin et al., 2025).

Novel therapeutics in the developmental pipeline for the treatment of multidrug-resistant A. baumannii infections include cefepime-zidebactam, zosurabalpin and the antimicrobial peptide (AMP) OMN6. The emerging agent, cefepime–zidebactam, a fourth-generation cephalosporin in combination with a β-lactamase inhibitor, is currently in advanced international clinical trials and has shown promise against CRAB isolates. Zosurabalpin is a first-in-class broad-spectrum macrocyclic peptide effective against both Gram-positive and Gram-negative bacteria. Another experimental therapy showing promise is OMN6, an AMP that binds and penetrates bacterial membranes inducing cell death. OMN6 specifically demonstrates efficacy in mouse models of MDR A. baumannii bacteremia and pneumonia (Arshad et al., 2025). AMPs, while exhibiting broad-spectrum antibacterial and immunomodulatory effects, have been prone to enzymatic degradation, limiting their clinical application (Zhang et al., 2024).

These novel therapeutics present promising prospects as alternatives to contemporary antibiotics and highlight the potential for precision-targeted and combination strategies in the treatment of A. baumannii infections with drug-resistant etiologies. Development of novel therapeutics to treat A. baumannii infections faces challenges however as translational effectiveness is limited due to the reliance on a narrow set of established strains by studies that do not capture the heterogeneity observed in modern clinical strains (El-Ghali et al., 2023; Valcek et al., 2023; Zhang et al., 2024; Arshad et al., 2025). Taken together, the management of A. baumannii infections requires an integrated approach using optimized antimicrobial combination therapies, prudent stewardship and novel adjunctive therapies to improve patient outcomes and reduce the positive selection of resistant isolates.

The global rise of A. baumannii infections represents a growing epidemiological and healthcare challenge, largely attributed to its persistence in clinical settings and increasing antimicrobial resistance (Peleg et al., 2008). Early identification and timely administration of appropriate antibiotic therapy are associated with lower mortality in patients with A. baumannii sepsis (Zilberberg et al., 2016). In practice, however, confirming A. baumannii as the etiologic agent of infections typically requires 48–72 hours which also delays targeted therapy of A. baumannii thereby worsening outcomes when empiric coverage is insufficient (Tabak et al., 2018). Diagnostic delays nonetheless remain common because of traditional blood cultures, which are standard for pathogen detection, taking 48–72 hours to yield definitive results (Tabak et al., 2018). A study conducted in Thailand between 2003 and 2015 found that delays of even one day in initiating concordant antibiotic therapy for hospital-acquired Acinetobacter bacteremia was associated with a 6.6% absolute increase in 30-day mortality (Lim et al., 2021). Adding to the diagnostic challenge, the presence of A. baumannii in clinical specimens does not necessarily indicate pathogenicity, as the bacterium commonly exists as a co-colonizer (Martín-Aspas et al., 2018).

Antimicrobial misuse also remains a global concern, and antimicrobial resistance represents one of the most serious challenges facing modern healthcare. Prior to the 1970s, A. baumannii isolates were susceptible to most antibiotics. Since then, resistance to virtually all currently available antimicrobial agents (e.g. PDR) has been reported (Peleg et al., 2008). The increasing prevalence of antibiotic-resistant bacteria is associated with inappropriate and excessive antibiotic use which has become an escalating concern in low- and middle-income countries (LMICs) (Kyriakidis et al., 2021). The WHO has reported that the consumption of broad-spectrum antibiotics, typically reserved for MDR infections, increased by 165% from the years 2000–2015 indicating weak antimicrobial stewardship or regulatory oversight in these countries (Klein et al., 2021). Inadequate empiric antibiotic coverage against MDR A. baumannii pneumonia or sepsis is strongly associated with elevated hospital mortality (Zilberberg et al., 2016).

Management of A. baumannii infection in LMICs remains challenging due to severe gaps in resources and technology. One study highlighted the diagnostic limitations in 24 LMICs, showing that critical lactate tests were unavailable in 19% of hospitals studied, and 11% did not have access to culture tests, limiting clinician’s ability to diagnose infections and initiate narrow-spectrum antibiotics thereby contributing to patient deterioration and progression to sepsis (Williams et al., 2025). ICU capacity is also affected by resource constraints with bed availability ranging from 0.1–2.5 ICU beds/100,000 and access to respiratory support often rationed (Williams et al., 2025). These systemic deficiencies hinder timely intervention and are associated with increased sepsis mortality. WHO findings demonstrate that LMICs carry the highest global sepsis burden characterized by an inverse correlation between socioeconomic status, sepsis incidence and mortality (Rudd et al., 2020; World Health Organization, 2020). Given the global health context, the spread of resistant isolates from these regions represents a global concern as air travel facilitates the transnational dissemination of resistant isolates.

Despite recent advances, therapeutic and clinical management of A. baumannii infections are challenging. Another major limitation is the delay in differentiating colonization from invasive disease, since A. baumannii often coexists in hospital environments without causing infection. Current diagnostics cannot rapidly distinguish benign carriage from life-threatening infection (Tan et al., 2017; Boutzoukas and Doi, 2025). Rapid antimicrobial susceptibility testing is similarly constrained, contributing to delays in appropriate therapy.

Troubling also is the finite research and development of new therapeutics to treat A. baumannii infections, likely as an artifact of the limited number of investigators consistently researching this pathogen as well as the few interdisciplinary collaborations occurring within this relatively small cohort of investigators. The majority of A. baumannii research in primary literature focuses upon trends in and mechanisms of drug-resistance. While this research is of paramount importance, it does not aim to elucidate the underlying virulence mechanisms of this critically important pathogen which leads to a stagnation in the identification of novel therapeutic targets thereby stifling the development of novel therapeutics. The discovery of new therapeutics will originate from studies at the interface of microbiology, epidemiology, bioinformatics and chemistry. Looking forward, the growing number of resistant A. baumannii isolates necessitates multi-faceted advancement in several areas including the: 1) incorporation of genomics, transcriptomics and host-response profiling into diagnostics to aid clinicians in quickly distinguishing harmless colonization from true infection and to identify patients at risk from hypervirulent strains, 2) prioritization of interdisciplinary research to identify and characterize novel therapeutics to treat these infections and 3) continued investigation of innovative experimental treatment strategies such as immunotherapies and drugs that block virulence factors (Tan and Lahiri, 2022; Anastassopoulou et al., 2024). Success in combating this critical pathogen will require a collective investment in all of these areas and will depend on pairing new antibiotics with rapid diagnostics, host-directed therapies and equitable access to ensure reductions in mortality (Boutzoukas and Doi, 2025). There is an insurmountable need for A. baumannii studies that further characterize the molecular mechanisms of virulence to aid in further understanding this bacterium’s success as a pathogen. It is only by gaining this perspective that this pathogen can be effectively combatted.