Managing Acinetobacter baumannii infections: continuing therapeutic challenges
– by Mohamed Yasmin and Robert Bonomo

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Acinetobacter baumannii is a formidable nosocomial pathogen that causes ventilator-associated pneumonia, bloodstream infection, and other severe hospital-acquired infections. Carbapenem-resistant A. baumannii (CRAB) is classified as a critical priority pathogen by the World Health Organization and an “urgent threat” by the Centers for Disease Control and Prevention.¹ In some regions, 60-90% of isolates are multidrug-resistant (MDR).² Its clinical “success” as a pathogen also reflects environmental hardiness: A. baumannii attaches to abiotic surfaces, forms biofilms, and can survive desiccation and disinfectants for weeks to months, enabling persistence in intensive care units and on medical equipment³; it can also be aerosolized, which may facilitate spread within clinical environments.

Current challenges in treatment

A. baumannii is resistant to many antibiotics and readily acquires additional resistance determinants, leaving clinicians with few reliable options. Polymyxins (e.g., colistin) re-emerged as last-resort therapy for CRAB, but their use is constrained by nephrotoxicity and neurotoxicity.² In some studies, it is difficult to discern if polymyxins actually make a difference. Tigecycline and other tetracyclines often test “active” in vitro, yet performance in severe infection is limited by pharmacokinetics (e.g., low serum concentrations and variable lung exposure).² This problem has extended to newer agents. Cefiderocol (FDC) shows potent in vitro activity against A. baumannii, but early clinical data raised concern for higher mortality in patients with serious CRAB infections compared with best available therapy.⁴

Heteroresistance (resistant subpopulations within an otherwise susceptible isolate) further complicates both susceptibility testing and clinical decision-making; iron availability and host milieu (e.g., human serum albumin and human pleural fluid) can promote heteroresistant subpopulations, and shift observed FDC minimum inhibitory concentrations (MICs), accompanied by induction of high-affinity iron uptake systems and β-lactam resistance determinants.^4,17

In practice, clinicians have often relied on combination regimens, commonly colistin plus high-dose sulbactam (SUL), carbapenems, aminoglycosides, or tigecycline, to improve the probability of early active therapy.² Many institutions use high-dose ampicillin/sulbactam as part of therapeutic regimens; the Infectious Diseases Society of America (IDSA) Guidance suggests 9 grams of ampicillin/sulbactam every 8 hours. These combinations may help in select cases, but toxicity and inconsistent efficacy remain major limitations. Overall, CRAB therapy remains unsatisfactory: colistin is toxic, tetracyclines underperform in critical illness, and the clinical impact of “salvage” agents such as FDC has been variable. This underscores the need for safer and more effective therapeutic options.²

Mechanisms of resistance

A. baumannii multidrug resistance reflects overlapping intrinsic and acquired mechanisms. The outer membrane has low permeability, and constitutive efflux pump activity further limits intracellular antibiotic accumulation.³ The organism also produces a chromosomal AmpC β-lactamase (Acinetobacter-derived cephalosporinase, ADC) that inactivates many β-lactams.³ A defining feature of CRAB is OXA-type carbapenemase production (Ambler class D β-lactamases). While all A. baumannii carry OXA-51-like enzymes intrinsically, clinically significant carbapenem resistance is usually driven by acquired OXA genes such as blaOXA-23, blaOXA-24/40, or blaOXA-58; these enzymes hydrolyze carbapenems and are a major cause of carbapenem failure.³ Recent large-scale genome-based surveys highlight extensive β-lactamase allelic diversity and frequent co-occurrence of multiple enzymes in A. baumannii. Acquired carbapenemases are common across regions and are driven largely by blaOXA 23 family alleles; importantly, certain β-lactamase combinations can overcome otherwise effective β lactam/β lactamase inhibitor pairings, complicating resistance prediction and inhibitor design.¹⁸

Acquired carbapenemases are common globally (roughly two thirds to >90% of isolates across regions), largely driven by blaOXA 23 family alleles, and their prevalence has increased over time.

Durlobactam (DUR) was developed to inhibit the most problematic OXA enzymes⁵ and is paired with sulbactam (SUL), which has intrinsic activity against A. baumannii through binding PBP3, PBP1a and PBP1b.^6,7 SUL-DUR represents a targeted β-lactam/β-lactamase inhibitor approach with strong activity against many CRAB isolates. In rare circumstances, A. baumannii acquires metallo-β-lactamases (MBLs) such as New Delhi metallo-beta-lactamases (NDM) or other serine carbapenemases, which broaden β-lactam resistance and are not inhibited by most current β-lactamase inhibitor combinations.³ Target modification also contributes specific amino-acid changes in PBP3 that can reduce sulbactam activity, threatening therapies that rely on sulbactam as the active backbone (including SUL-DUR).⁸ Finally, the organism’s genomic plasticity enables rapid acquisition of resistance determinants via plasmids and genomic islands (e.g., AbaR), adding resistance to aminoglycosides, sulfonamides, tetracyclines, and other classes.³ Biofilm formation on abiotic surfaces and medical devices, together with capsule and surface glycoproteins, further promotes persistence and tolerance to both disinfectants and antibiotics. Taken together, these features make A. baumannii difficult to eradicate once established in a patient or hospital environment.

Therapeutic advances

After years of testing and investigation, SUL-DUR is an important recent advance for CRAB. Sulbactam has intrinsic activity against A. baumannii through preferential binding to essential PBPs (notably PBP1a, PBP1b, and PBP3) but is frequently neutralized by co-produced β-lactamases. DUR is a diazabicyclooctane β-lactamase inhibitor designed to inhibit class A, C, and D enzymes, including OXA carbapenemases and ADC, thereby restoring sulbactam activity. In the phase 3 ATTACK trial, SUL-DUR (with imipenem-cilastatin background therapy) achieved non-inferior outcomes versus colistin-based therapy while reducing nephrotoxicity.⁹ SUL-DUR is now FDA approved and has become a preferred option for CRAB in settings where MBLs are not present and a carbapenem backbone is feasible.^8,9

FDC remains a potential option in selected scenarios. As a siderophore cephalosporin, FDC enters Gram-negative bacteria via iron transport systems and, once in the periplasm, binds PBPs (primarily PBP3) to inhibit cell wall synthesis.¹⁰ In vitro activity against CRAB is often favorable, but early clinical trial data raised concern for higher mortality signals in pathogen-focused cohorts that included Acinetobacter infections.^4,11 The recently published GAME CHANGER randomized trial provides a more contemporary comparator: FDC was non-inferior to standard therapy for hospital-acquired or healthcare-associated Gram-negative bloodstream infection (14-day mortality 8% vs 7%).¹² In the prespecified subgroup with Acinetobacter bloodstream infection, 14-day mortality was not higher with FDC (11% vs 20%), and in carbapenem-resistant Acinetobacter bloodstream infection it was 9% vs 21%.¹² These data support a more balanced interpretation of FDC’s performance in Acinetobacter bacteremia, while recognizing that outcomes vary by syndrome and host factors.

In parallel, clinical reports describe successful use of FDC to treat severe CRAB infections, including pneumonia and mixed infections, usually as salvage therapy and sometimes as combination treatment.¹³ These reports do not replace randomized evidence, but they reflect how FDC is used when alternatives are limited. Resistance to FDC can emerge through defects in iron transport and other permeability-related mechanisms. Target-based mechanisms are also clinically plausible because FDC’s primary target is PBP3.¹⁰ Susceptibility testing must be performed under appropriate iron-depleted conditions, and heteroresistance and assay variability can complicate MIC interpretation.⁴

An important antibiotic in the pipeline is zosurabalpin (RG6006), a first-in-class tethered macrocyclic peptide antibiotic targeting the LptB2FGC lipopolysaccharide transport complex. In preclinical work, zosurabalpin showed potent activity against contemporary CRAB isolates and efficacy in animal infection models, supporting clinical development for invasive CRAB infection.¹⁴

Beyond antibiotics, non-traditional approaches remain investigational. Monoclonal antibodies targeting A. baumannii surface carbohydrates are advancing: the humanized monoclonal antibody MAb5 demonstrated broad binding across large panels of U.S. and international isolates and likely targets O antigen capsular carbohydrates. In murine infection models, MAb5 protected against otherwise lethal infection, supporting development of antibody cocktails as adjunctive therapy.¹⁵ Phage therapy has also been used in compassionate settings and is being evaluated as an adjunct for difficult-to-treat infections and for environmental decontamination, but challenges remain in strain matching, dosing, and resistance emergence.¹⁶

Strategies for prevention and control

While new treatments are crucial, preventing A. baumannii infections and limiting spread remains foundational. Since this organism persists on surfaces and equipment, outbreak control typically requires bundled infection prevention interventions (contact precautions, enhanced environmental cleaning, cohorting when needed).³ Antimicrobial stewardship reduces selective pressure and helps preserve novel agents, especially in settings with endemic CRAB.¹

In some regions, 60-90% of isolates of A. baumannii are multidrug-resistant (MDR)

Rapid diagnostics and timely directed therapy matter. Delays in active therapy are associated with worse outcomes in A. baumannii bacteremia; early appropriate therapy improves survival and likely reduces the duration of high-burden infection, narrowing the window for onward transmission.^17,18 In ICU settings, rapid screening with early precautions has been shown to reduce CRAB transmission compared with conventional approaches.¹⁸ Together, early detection, rapid isolation, and timely active therapy are practical measures that complement emerging therapeutic advances.

Perspective

CRAB will remain a “moving target”. SUL-DUR is a meaningful step forward and FDC can be considered in selected scenarios, especially where options are constrained and when susceptibility testing is performed and interpreted carefully. At the same time, resistance mechanisms will continue to evolve. A central challenge is the breadth of the A. baumannii β lactamase resistome. Acquired carbapenemases are common globally (roughly two thirds to >90% of isolates across regions), largely driven by blaOXA 23 family alleles, and their prevalence has increased over time. In addition, β lactamase allele distributions are dominated by a few common enzymes but include a long tail of rare variants, and certain enzyme combinations can defeat otherwise effective β lactam/β lactamase inhibitor strategies, making durable coverage difficult to achieve.²⁰ Progress will depend on pairing new drugs with surveillance, rapid diagnostics, antimicrobial stewardship, and consistent infection prevention. Molecules with novel mechanisms such as zosurabalpin are promising, but the field needs continued development of agents with reliable clinical efficacy against CRAB and strategies that reduce transmission in high-risk hospital environments.

References

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