Acinetobacter

Etiology

The genus Acinetobacter is highly diverse, comprising oxidase-positive and -negative, nonpigmented, aerobic gram-negative coccobacilli. Although more than 50 species exist within the genus, most are nonpathogenic environmental organisms. The species most commonly associated with human infections is Acinetobacter baumannii, followed by Acinetobacter calcoaceticus and Acinetobacter lwoffii. Infections caused by Acinetobacter became prominent in the 1960s and 1970s with the expansion of intensive care practices. Initially considered a low-virulence opportunistic pathogen, Acinetobacter has emerged as a significant pathogen, driven by the increased use of mechanical ventilation, invasive devices, and broad-spectrum antibacterial therapy, leading to more frequent and severe infections.[3]

A baumannii was initially susceptible to antibiotic monotherapy, but resistance has steadily increased over time. Rising multidrug resistance prompted the Infectious Disease Society of America to designate a group of organisms—including Enterococcus faecium, Staphylococcus aureus, Klebsiella pneumoniae, A baumannii, Pseudomonas aeruginosa, and Enterobacter spp—as the ESKAPE pathogens, reflecting their capacity to evade antibiotic activity.[4] Carbapenem resistance is particularly concerning, as it has consistently been associated with markedly increased morbidity, mortality, and prolonged hospitalization, even in randomized controlled studies.

Epidemiology

Acinetobacter spp are widely distributed in wet environments, including soil, freshwater, wastewater, and seawater. Environmental strains frequently harbor antibiotic resistance mechanisms, such as carbapenemases and extended-spectrum β-lactamases, and may serve as reservoirs for resistance that later emerges in clinically significant strains. Medically relevant species have been isolated from food products and human skin, often demonstrating extensive antibiotic resistance. Notably, multidrug-resistant A baumannii has been detected in commercial foods and livestock, highlighting multiple environmental pathways for human transmission.

A baumannii is a clinically significant pathogen worldwide. In the United States (US), the organism accounts for approximately 2% of healthcare-associated infections but is an important cause of ventilator-associated pneumonia (VAP), central line–associated bloodstream infection, and urinary tract infections in hospitalized adults. Patients in intensive care units (ICUs), particularly those falling in the extremes of age or residing in long-term care facilities, are at increased risk.

Additional predisposing factors include recent surgery and the use of indwelling catheters, tracheostomy, mechanical ventilation, parenteral nutrition, and broad-spectrum antibiotics, such as carbapenems, fluoroquinolones, and ceftriaxone. In neonates, low birth weight, parenteral feeding, and catheter placement further increase susceptibility.[5][6] The worldwide prevalence of multidrug-resistant Acinetobacter in hospital-acquired pneumonia and VAP reaches 80%.[7]

Rates of CRAB infection vary by geographic region, with meropenem susceptibility lowest in Africa and the Middle East (17.2%) and higher in Europe and North America, reaching up to 80%.[8][9] In its 2022 report, the CDC estimated approximately 6000 to 7500 CRAB cases annually in 2019 and 2020, resulting in roughly 500 to 700 deaths per year. Despite recognition as a predominant healthcare-associated pathogen and a major contributor to morbidity, mortality, and healthcare costs, epidemiologic data on A baumannii and CRAB colonization among hospitalized adults in the US remain limited.

Data on reliable prognostic predictors for patients with Acinetobacter infections are also scarce. Mortality rates are frequently high, but attributable mortality is difficult to define because distinguishing colonization from true infection is often challenging. Even when infection criteria are met, death cannot be confidently attributed solely to Acinetobacter, given the presence of significant comorbidities and overall disease severity. Comparisons of otherwise similar ICU populations consistently demonstrate worse clinical outcomes among patients with Acinetobacter detection than among those without detection.[10][11]

Pathophysiology

Various mechanisms contribute to the virulence of Acinetobacter and its ability to cause disease. The organism produces lipopolysaccharide or lipooligosaccharide in its outer membrane.[12] Modifications in the synthesis of these structures confer antibiotic resistance and enhance survival under desiccation. Capsules present in Acinetobacter protect against complement-mediated killing.[13] Surface pili facilitate twitching motility, biofilm formation, and adherence to environmental surfaces.[14]

Acinetobacter secretes various proteins that mediate antibiotic resistance through efflux or degradation.[15] Porins, a major class of outer membrane proteins identified in multiple studies, modulate cellular permeability. Outer membrane protein A, in particular, promotes adhesion to host epithelial cells, resistance to complement, antimicrobial resistance, and biofilm formation.[16] Inherent resistance mechanisms, such as AmpC cephalosporinases, confer resistance to cephalosporins. Carbapenems subsequently became the treatment of choice for A baumannii infections, but selective pressure led to the emergence of carbapenem resistance.[17] Resistance to carbapenems primarily involves decreased expression of outer membrane channels, dysregulation of efflux pumps, reduced affinity of penicillin-binding proteins, and β-lactamase production.[18]

Biofilm formation enhances environmental persistence despite routine cleaning. Exposure to ethanol can increase growth and stress tolerance, and inhibitory salt concentrations may fail to eliminate the organism. DNA repair mechanisms contribute to desiccation resistance. Under dry conditions, A baumannii undergoes morphological adaptations, including cell wall thickening, which support prolonged survival on surfaces. Outbreak investigations and experimental studies demonstrate that epidemic strains can remain viable on hospital surfaces for months to years, emphasizing the significant challenge of preventing environmental transmission in healthcare settings.

Histopathology

Infections caused by Acinetobacter demonstrate histopathologic features similar to those of other gram-negative bacilli. Neither gross nor microscopic examination reliably identifies the organism, and culture is required for definitive diagnosis.[19]

History and Physical

The clinical presentation of infections caused by Acinetobacter is indistinguishable from that of infections caused by other bacteria.[20] Prolonged hospitalization and prior antibiotic exposure strongly predispose patients to Acinetobacter colonization. Since colonization is common and infection relatively uncommon, colonized patients typically exhibit no specific clinical findings. Most infections are hospital-acquired, with community-acquired infections by A baumannii being exceptional. The lung is the most frequently involved organ, primarily due to airway colonization and contamination of respiratory equipment used for mechanical ventilation. Acinetobacter most commonly causes pneumonia, particularly in patients with critical illness, followed by wound and surgical site infections, catheter-associated bloodstream infections, and, less frequently, urinary tract infections and nosocomial meningitis.

Acinetobacter is a leading cause of VAP in ICUs, with notable disparities in bacterial ecology across countries, accounting for up to 30% of all ICU VAP cases. VAP due to A baumannii typically demonstrates a delayed onset after intubation, although outbreaks may result in earlier presentation. Results from a recent study reported a mean delay to VAP onset of approximately 8 days (range 3–32 days).[21] Clinical manifestations are similar to other healthcare-associated pneumonias but are frequently related to severe disease, vasopressor requirement, and poor outcomes, with almost 90% of patients receiving antibiotics at diagnosis. Prolonged hospitalization, extended antibiotic courses, and longer mechanical ventilation durations substantially increase the risk of A baumannii pneumonia. Nosocomial sinusitis related to endotracheal intubation may also serve as a source of infection.

Bloodstream infections due to Acinetobacter are primarily nosocomial, occur predominantly in patients receiving care in the ICU, and are frequently associated with multidrug-resistant isolates and increased mortality. The respiratory tract, including pneumonia and tracheobronchitis, and intravascular catheters constitute the main sources of bacteremia, while the urinary tract and wounds are less common sources. Multiple factors increase risk, including prolonged ICU stay, invasive procedures, immunosuppression, trauma, burns, wounds, malignancy, prior surgery, and broad-spectrum antibiotic exposure. Septic shock occurs in approximately 30% of cases.[22] Acinetobacter species rarely cause infective endocarditis, typically affecting patients with prosthetic heart valves and presenting with an aggressive clinical course.

Acinetobacter has also been associated with delayed wound healing, graft failure, sepsis, and death. The organism may cause skin and soft tissue infections following trauma, blast injuries, or chronic ulcers. Contamination of surgical or traumatic wounds can result in severe soft tissue infection and osteomyelitis. However, A baumannii remains an uncommon cause of routine community- or hospital-acquired skin infections. The species is a well-known pathogen in burn units and is commonly isolated from wounds of combat casualties.[23][24][25] 

Acinetobacter can colonize the urinary tract, particularly in patients with indwelling catheters. True urinary tract infection (UTI) is uncommon, accounting for less than 2% of nosocomial UTIs, and is largely catheter-associated. Meningitis due to Acinetobacter is rare and primarily occurs following neurosurgical procedures, intracranial hemorrhage, or antibiotic exposure. Outbreaks have been linked to contaminated intrathecal medications. Typical signs of Acinetobacter meningitis include fever and altered consciousness, whereas meningeal signs, focal neurological deficits, and seizures are observed in a minority of patients.[26] Ocular colonization has been reported in contact lens users. Eye infections, including corneal ulcers, may develop, particularly following ophthalmologic surgery.[27][28]

Evaluation

Careful differentiation between contamination, transient bacteremia, colonization, and true infection is essential when a gram-negative organism such as A baumannii is isolated, given the organism’s ability to persist in hospital environments and colonize patients without causing disease. In intubated individuals, recovery from respiratory samples often reflects airway colonization rather than infection. Diagnostic confidence for VAP increases when high-quality lower respiratory tract specimens are obtained via bronchoalveolar lavage or protected specimen brush, demonstrate quantitative growth with minimal upper-airway contamination, and correlate with compatible clinical features and radiographic findings, including new or progressive infiltrates, consolidation, air bronchograms, or worsening oxygenation in the presence of systemic inflammation.

Following the isolation of A baumannii from blood cultures, contamination is suggested by growth in a single bottle or in a culture set in the absence of clinical deterioration. Transient bacteremia may occur following manipulation of colonized intravascular devices and is typically short-lived. True A baumannii bacteremia is more likely when multiple blood culture sets are positive, peripheral and catheter-drawn cultures are concordant with a shorter time to positivity from the catheter, and the patient exhibits persistent fever, hemodynamic instability, or other signs of sepsis, particularly in the presence of indwelling vascular devices.

For wound infections, growth in superficial swab cultures often reflects colonization, whereas true infection is supported by recovery from deep tissue or aspirate specimens in conjunction with local signs of invasion, including progressive erythema, necrosis, purulence, delayed healing, or systemic inflammatory response. In patients with indwelling urinary catheters, A baumannii isolated from urine most commonly represents colonization. Diagnosis of UTI should rely on compatible urinary symptoms, significant pyuria, and exclusion of alternative infectious foci.

Isolation of A baumannii from cerebrospinal fluid (CSF) in suspected nosocomial meningitis requires careful interpretation. CSF white blood cell counts typically range from 100 to several thousand cells per microliter, with higher counts often observed when clinical suspicion is delayed, usually demonstrating a marked polymorphonuclear predominance. CSF protein is usually elevated, and CSF glucose is normal or reduced. Although CSF is normally sterile, Acinetobacter can contaminate samples during collection. Pseudomeningitis, defined by positive CSF culture results in the absence of clinical or laboratory features of meningitis, has been well described. Repeated isolation of Acinetobacter from multiple CSF specimens, together with compatible clinical findings and inflammatory CSF indices, is highly suggestive of true central nervous system infection.

A retrospective cohort study of hospitalized individuals identified frequent coisolation of other gram-negative pathogens around the time of the index A baumannii culture. More than 45% of patients had another gram-negative organism, occurring more often with CRAB than non-CRAB isolates. The most common copathogens included Pseudomonas aeruginosa, Klebsiella spp, Stenotrophomonas maltophilia, and Enterobacter cloacae. Copathogens were usually recovered from the same anatomical site (>85%), and approximately 30% exhibited carbapenem resistance.

Treatment / Management

The CDC publishes reference minimum inhibitory concentration distributions for Acinetobacter spp, primarily for surveillance and laboratory benchmarking. For clinical interpretation, susceptibility is determined using Clinical and Laboratory Standards Institute breakpoints, as incorporated into the IDSA antimicrobial-resistance guidance. This guidance defines interpretive criteria for key agents, including carbapenems, ampicillin–sulbactam, and cefiderocol. In Europe, harmonized breakpoints are provided by the European Committee on Antimicrobial Susceptibility Testing, endorsed by the European Society of Clinical Microbiology and Infectious Diseases, supporting consistent reporting and surveillance across laboratories.[29]][30]

Acinetobacter spp are intrinsically resistant to several commonly used antibiotics, including aminopenicillins, first- and second-generation cephalosporins, and chloramphenicol. Globally, resistance to broad-spectrum β-lactams such as ceftazidime, cefepime, and piperacillin–tazobactam has risen markedly, reaching up to 90% in some settings. Ampicillin–sulbactam has traditionally been the most active β-lactam, but resistance rates approaching 70% worldwide have limited its use to combination regimens. Carbapenems were long considered preferred agents due to their efficacy and safety, but increasing resistance, now estimated at 70% to 80%, has substantially restricted their clinical role.

These resistance patterns are illustrated by a retrospective study of 77 CRAB isolates, which results demonstrated universal (100%) resistance to carbapenems, extended-spectrum cephalosporins, penicillins, and combinations of β-lactams with β-lactamase inhibitors. Resistance exceeded 90% for aminoglycosides, trimethoprim–sulfamethoxazole, and ciprofloxacin. Lower resistance rates were observed for levofloxacin (22%), minocycline (23%), and tigecycline (3%), indicating relative preservation of activity for these agents.

No available therapeutic regimen has consistently produced a substantial reduction in mortality in invasive CRAB infections. Results from randomized clinical trials report 28-day mortality exceeding 45%. Although colistin–meropenem combinations were commonly employed previously, 2 large randomized trials demonstrated no benefit over colistin monotherapy, prompting recent guidelines to abandon this approach. Current evidence supports treatment strategies centered on a sulbactam backbone, either combined with the novel β-lactamase inhibitor durlobactam or paired with 1 or more additional in vitro–active agents.[31]

The Infectious Diseases Society of America (IDSA) recommends combination therapy for CRAB infections, even when a single agent demonstrates in vitro activity. Step-down therapy to a single active agent may be considered in situations requiring prolonged regimens, such as osteomyelitis. The 2023 IDSA guidance prioritized high-dose ampicillin–sulbactam–based combination therapy (6–9 g/day of the sulbactam component) for all CRAB isolates, regardless of in vitro susceptibility, citing pharmacodynamic advantages and limitations of susceptibility testing. Following results from pivotal studies in pneumonia and bloodstream infections, the 2024 IDSA update designated sulbactam–durlobactam (8–12 g/day) plus a carbapenem (meropenem 2 g every 8 hours) as the preferred therapy. High-dose ampicillin–sulbactam (9 g/day of sulbactam) became an alternative for use in combination with polymyxin B, minocycline, or, as a last resort, cefiderocol.

Optimally dosed, non–sulbactam-based combination therapy should be considered if resistance to sulbactam–durlobactam is present (MIC ≥ 16/4 µg/mL), including cefiderocol, minocycline, tigecycline, or polymyxin B. Colistin-based combinations are preferred for UTIs. The guideline specifically recommends against the use of carbapenem or colistin monotherapy, rifampicin, and nebulized antibiotics.[32]

The European Society of Clinical Microbiology and Infectious Diseases 2022 guidelines recommend ampicillin–sulbactam only for sulbactam-susceptible CRAB isolates. Polymyxins or high-dose tigecycline are preferred for sulbactam-resistant isolates. Cefiderocol administration is generally discouraged, and combination therapy with at least 2 in vitro–active agents is recommended only for severe infections. The use of high-dose, extended-infusion carbapenems (meropenem 2 g every 8 hours) is suggested only when meropenem minimum inhibitory concentrations are 8 µg/mL or below.

The review by Richards, Perovic, and Brink provides a comprehensive discussion of therapeutic strategies and recommendations for the treatment of Acinetobacter infections.[33] Management of classical gram-negative infections requires removal of external devices, infected lines, shunts, or drains to promote cure. Collections of abscesses or necrotic tissue require thorough debridement to achieve effective source control.

Differential Diagnosis

The differential diagnosis of A baumannii infection primarily includes colonization and other hospital-acquired infections, particularly those caused by gram-negative pathogens. Distinguishing true infection from colonization requires careful clinical correlation and microbiological evaluation, incorporating specimen type and quality, quantitative or repeated culture results, and concordance with clinical, laboratory, and radiographic findings.

Prognosis

Reported mortality associated with CRAB infection varies widely. Estimates indicate that up to 24% of individuals with CRAB infection die within 30 days, with mortality reaching 40% or higher in cases of bacteremia. Septic shock is an independent predictor of ICU mortality in Acinetobacter VAP. Additional factors independently associated with mortality in patients in the ICU with A baumannii VAP include serum creatinine exceeding 1.6 mg/dL, inadequate initial antimicrobial therapy, CURB (confusion, urea, respiratory rate, blood pressure) score of at least 3, C-reactive protein of at least 120 mg/L, elevated SOFA (Sequential Organ Failure Assessment) score, and inappropriate empirical therapy.[34][35] In bacteremia, independent predictors of death include the presence of a rapidly or ultimately fatal underlying disease, septic shock at the onset of bacteremia, mechanical ventilation, severe liver disease, chronic kidney disease, carbapenem resistance, and higher Pitt bacteremia scores.[36][37][38]

Complications

Complications associated with Acinetobacter infections arise from multiple factors. Rapidly evolving antimicrobial resistance mechanisms have significantly limited the number of effective agents for treating multidrug-resistant isolates. The organism’s ubiquitous presence as a colonizer in healthcare environments increases the risk of transmission. Acinetobacter carriage can transition from colonization to invasive infection in vulnerable patients, particularly those with critical illness. Such infections are frequently associated with high rates of morbidity and mortality. Preventing severe outcomes depends on integrating antimicrobial stewardship, timely diagnosis, and proactive measures to limit colonization and transmission within healthcare settings.