Chapter 157: Acinetobacter Infections

Acinetobacter species were first described in 1911 and named Micrococcus calcoaceticus. Thereafter, the genus was renamed multiple times; since 1950, it has been known as Acinetobacter. Acinetobacter species are gram-negative, oxidase-negative, nonmotile, nonfermenting coccobacilli that are easily recovered on standard culture media. Differentiation among Acinetobacter species on the basis of phenotypic characteristics alone is very difficult. Molecular-based methods such as matrix-assisted laser desorption–ionization–time-of-flight mass spectrometry (MALDI-TOF-MS) and quantitative real-time polymerase chain reaction (PCR) are usually necessary to identify Acinetobacter baumannii, the most clinically relevant species of the genus.

Acinetobacter species are naturally encountered in water and soil and have also been recovered from fruits and vegetables. In humans, Acinetobacter can be found on the skin and in the respiratory and gastrointestinal tracts. A. baumannii is capable of surviving environmental desiccation for weeks; this characteristic is important from an infection-control perspective as it allows this organism to persist in the hospital environment and on equipment.

Acinetobacter was historically considered a pathogen of hot and humid climates. In recent years, however, hospital outbreaks caused by A. baumannii have been reported worldwide, even in temperate climates. In the United States, the Centers for Disease Control and Prevention (CDC) estimates that 12,000 Acinetobacter infections occur every year, 7300 of which are caused by multidrug-resistant strains, with 500 attributable deaths. The increase in the number of infections with A. baumannii is suspected to be due to the rapid spread of certain genetically distinct lineages; of the three international clonal lineages (ICLs), ICL I and ICL II are multidrug resistant. The predominance of these lineages remains unexplained, although it has been proposed that this population structure is the result of two waves of expansion. The first wave followed a bottleneck (possibly linked to a restricted ecologic niche) that occurred in the distant past. The second wave is ongoing and is being driven by the rapid expansion of a limited number of multidrug-resistant clones.

Analysis of the A. baumannii pangenome (the sum of the core and dispensable genomes) has shown that its organization is characterized by a small core genome and a large accessory or disposable genome. This organization reflects A. baumannii’s high plasticity, which enables it to acquire exogenous genetic material. With few exceptions, gene functions associated with virulence are found in the core genome; this observation suggests a limited role for the acquisition of new virulence traits in the recent nosocomial expansion of A. baumannii clones. Genes associated with resistance to antimicrobial agents are found in both the species core genome and the accessory genome. In the accessory genome, these genes have been found in alien islands, often flanked by integrases, transposases, or insertion sequences. This pattern suggests possible acquisition by horizontal gene transfer from other Acinetobacter strains or even from different bacterial species present in the immediate environment. Acquisition of these antimicrobial resistance genes is hypothesized to have led to the recent rapid expansion of highly homogeneous clonal lineages, whose main difference from nonclonal A. baumannii appears to be their antimicrobial resistance.

Health Care–Associated Infections

Infections caused by A. baumannii occur frequently among patients admitted to intensive care units (ICUs). Risk factors for colonization and infection with this pathogen include nursing home residence, prolonged ICU stay, central venous catheterization, tracheostomy, mechanical ventilation, enteral feedings, and treatment with third-generation cephalosporins, fluoroquinolones, and carbapenems. Acquisition of carbapenem-resistant A. baumannii is most common among patients exposed to carbapenems. Spread of A. baumannii across different regions is facilitated by the movement of patients between health care systems and throughout the continuum of health care. Within the hospital, environmental spread of A. baumannii occurs as a result of inappropriate hand hygiene among workers providing health care for infected or colonized patients and the contamination of hospital equipment, such as respiratory therapy and ventilation equipment. The air surrounding the patient may also play a role in environmental colonization with A. baumannii, especially in inpatient areas without physical barriers between patients and with an inadequate number of air exchanges.

A. baumannii strains identified during hospital outbreaks are typically resistant to more antibiotic classes than strains from the community. The prevalence of colonization with A. baumannii at the time of admission or during a stay in a long-term acute-care hospital (LTACH) or nursing home is variable and depends on regional flora. Outbreaks of A. baumannii in acute-care hospitals and LTACHs that “share” patients have been described in Ohio, Michigan, Illinois, and Indiana.

Community-Acquired Infections

Community-acquired infections caused by Acinetobacter have been described in Australia and Asia. Few cases have been reported in regions with a temperate climate, and even those few cases have taken place during warm and humid months. Risk factors for community-acquired pneumonia due to this organism include a history of alcohol abuse, diabetes mellitus, smoking, and chronic lung disease.

War Zone–Associated Infections

Infections caused by Acinetobacter in war zones include skin and soft tissue infections associated with traumatic injuries and bloodstream infections. Outbreak investigations of A. baumannii infections among military personnel returning from Iraq and Afghanistan suggested the acquisition of A. baumannii in field hospitals rather than colonization of the skin before an injury. This view is supported by the recovery of A. baumannii isolates with similar genetic characteristics from inanimate surfaces in field hospitals and from patients.

Disaster Medicine

A. baumannii is linked to infections among victims of trauma during tsunamis, earthquakes, and terrorist attacks. The types of infections most frequently observed in these settings are soft tissue injuries, but bloodstream infections and pneumonia have also been reported. In addition, outbreaks of A. baumannii infection in ICUs caring for disaster victims have been described.

Mechanisms of pathogenesis and virulence in Acinetobacter species have not been fully elucidated. However, A. baumannii seems to have greater virulence potential than other Acinetobacter species, as evidenced by its ability to grow at 37°C and to resist uptake by macrophages.

Initial A. baumannii colonization of the host and the environment is facilitated by the organism’s ability to adhere to surfaces and human cells and to create biofilms. The ability to form a biofilm is phenotypically associated with exopolysaccharide production and pilus formation. A quorum-sensing molecule encoded by the abaI autoinducer synthase gene has been implicated in A. baumannii biofilm formation on abiotic surfaces. Outer-membrane porins appear to mediate cell apoptosis. A. baumannii can survive in harsh environments within the host and on inanimate surfaces by modifying the structure of its lipid A, with a consequent decrease in susceptibility to antibiotics and antimicrobial peptides and an increase in survival upon desiccation.

Acinetobacter species produce an extracellular capsule that protects the bacteria from external threats, including complement-mediated killing. Studies of mouse models showed that Acinetobacter species can increase capsule production in the presence of subinhibitory levels of antibiotic—an ability that leads to increased resistance to complement-mediated killing and a hypervirulent phenotype.

Phospholipase C and phospholipase D have been identified as virulence factors in A. baumannii. These enzymes exert cytotoxic effects on epithelial cells and facilitate their invasion.

Iron-acquisition systems are also important virulence mechanisms in A. baumannii. Through secretion of siderophores (low-molecular-mass ferric-binding compounds), A. baumannii is able to grow despite iron deficiencies in the surrounding environment (e.g., in the human host).

Several protein-secretion systems have been identified in A. baumannii. The most recently described is a type II secretion system. The substrate for this system, the LipA lipase, is required for growth on medium containing lipids as a sole carbon source. Mutants lacking the genes for the type II secretion system or its substrate exhibit defective in vivo growth in a neutropenic murine model of bacteremia. A. baumannii also has a type VI secretion system whose primary function seems to be to secrete antibacterial toxins that kill competing bacteria, including other strains in the same species.

The type V autotransporter system has been characterized in A. baumannii. In a murine systemic model of Acinetobacter infection, the Acinetobacter trimeric autotransporter mediates biofilm formation and maintenance; adherence to extracellular matrix components such as collagen I, II, and IV; and virulence.

Outer-membrane vesicles (OMVs) play a special role in protein secretion. Many A. baumannii strains secrete OMVs containing various virulence factors, including outer-membrane protein A (OmpA), proteases, and phospholipases. The membrane proteins in OMVs are responsible for eliciting a potent innate immune response. Several studies have shown that A. baumannii OMVs could be used as an acellular vaccine to effectively control A. baumannii infections.

Nosocomial strains of Acinetobacter can deploy multiple mechanisms of resistance, including alterations in porins and efflux pumps and expression of β-lactamases. More specifically, Acinetobacter species can reduce the expression of porins, thus hindering the passage of β-lactam antibiotics into the periplasmic space. These species can overexpress bacterial efflux pumps and decrease the concentration of β-lactam antibiotics in the periplasmic space. Efflux pumps can also actively remove quinolones, tetracyclines, chloramphenicol, disinfectants, and tigecycline. Acinetobacter species possess chromosomally encoded cephalosporinases and are capable of acquiring β-lactamases, including serine and metallo-β-lactamases. AmpC β-lactamases are class C β-lactamases intrinsic to all A. baumannii strains. Although these enzymes are expressed at low levels and are not inducible, the addition of the insertion sequence ISAba1 next to the AmpC gene increases β-lactamase production, with resulting resistance to cephalosporins.

Carbapenem resistance in Acinetobacter species is mostly tied to the emergence of Ambler class D oxacillinases of group 2d, some of which are intrinsic and chromosomal (e.g., OXA-51-like) while others are acquired and are found in plasmids or are chromosomally encoded (e.g., OXA-23-like, 24 [33-like, 40-like], 58-like, 143-like, and 235-like).

Pneumonia

A. baumannii is a notorious cause of nosocomial pneumonia, most frequently among patients requiring prolonged mechanical ventilation. The onset of disease tends to be later than that caused by other gram-negative bacilli; however, clinical symptoms of hospital-acquired or ventilator-associated pneumonia due to A. baumannii are similar to those of nosocomial or ventilator-associated pneumonia due to other nosocomial pathogens. Thus, the most common indicators of infection include fever and increased sputum production. The positivity of respiratory cultures in most cases may present a challenge for the clinician, since airway colonization with A. baumannii is a risk factor for infection itself. Radiologic findings are nonspecific and can include lobar consolidations and pleural effusions, but cavitations are rarely seen. The crude mortality rates associated with nosocomial pneumonia due to A. baumannii are reported to be as high as 65%. However, since these infections occur in debilitated patients, their attributable mortality has been difficult to establish.

Community-acquired pneumonia due to A. baumannii is a relatively rare entity. Its clinical presentation is characterized by fever, severe respiratory symptoms, and multiple-organ dysfunction. Patients frequently have a cough productive of purulent sputum, shortness of breath, and chest pain. Imaging studies usually show lobar consolidation. Mortality rates associated with this process are >50%.

Bloodstream Infections

Bloodstream infections due to A. baumannii are most frequent among ICU patients and usually occur in the presence of a central venous catheter or as a secondary complication of hospital-acquired or ventilator-associated pneumonia. Polymicrobial growth has been reported in 20–36% of bacteremia episodes. Fever is the most common sign of infection (developing in >95% of cases), and presentation with septic shock and disseminated intravascular coagulopathy has been described in as many as 25 and 30% of patients, respectively. A. baumannii bloodstream infections often result in higher hospitalization costs and longer ICU stays. Crude mortality rates from this infection are as high as 40%; however, rates can be as high as 70% from infections caused by carbapenem-resistant isolates. In patients with infections caused by extremely drug-resistant strains, poor outcomes are thought to be driven by delays in the initiation of adequate antimicrobial therapy.

Skin and Soft Tissue Infections

Acinetobacter species have been described as part of the skin flora, yet the majority of the organisms from this genus that colonize the skin are not those associated with nosocomial infections. Discerning infection from wound colonization is challenging. Gunshot wounds and the presence of orthopedic external-fixation devices are common among patients with combat trauma–associated A. baumannii skin and soft tissue infections. The report on a case series of eight U.S. military patients described the clinical presentation of their infections as evolving from an edematous peau d’orange appearance to a sandpaper appearance with overlying vesicles and then to a necrotizing process with hemorrhagic bullae. Other case series have also included necrotizing fasciitis. A. baumannii is an important pathogen in burn units worldwide. Large burns provide ideal conditions for A. baumannii and facilitate patient-to-patient transmission. The presence of A. baumannii in wounds contributes to healing delays and graft loss. In addition, wound colonization is a risk factor for bloodstream infections among patients with extensive burn injuries.

A. baumannii infections resulting from trauma to soft tissues in the setting of natural disasters, such as tsunamis and earthquakes, have been reported. The implication is that A. baumannii should be considered in the differential diagnosis of soft tissue infections following exposure to tropical and subtropical environments.

Urinary Tract Infections

A. baumannii is an infrequent cause of urinary tract infections. The majority of cases reported are catheter-associated infections, reflecting the ability of A. baumannii to form biofilms on these devices. A few reports have described community-acquired infections occurring in the setting of nephrolithiasis and after renal transplantation.

Meningitis

Central nervous system infections with A. baumannii have been reported in the context of outbreaks, traumatic injuries, neurosurgical procedures, and external ventricular drains. One case series described a petechial rash in up to 30% of patients. Acinetobacter species may look similar to Neisseria meningitidis on a Gram’s stain of cerebrospinal fluid; both appear as gram-negative paired cocci.

Other Miscellaneous Infections

A few cases of A. baumannii keratitis associated with the use of contact lenses have been reported. Cases of native- and prosthetic-valve endocarditis have also been described.

TREATMENT

Infections caused by A. baumannii can be associated with high mortality rates. Factors contributing to higher mortality are thought to include severity of the patient’s underlying illness and drug resistance in the infecting strain.

Acinetobacter species are capable of surviving on hospital surfaces for prolonged periods. In the hospital environment, A. baumannii has been associated with establishment of a fecal patina; this term refers to a coating of enteric organisms that can cover the skin of colonized patients and extend to their surrounding environment. Concentrations of enteric organisms are highest in the colonized patient’s rectum, with spread in a target-like concentric pattern covering the patient’s body and the surrounding environment. High-frequency touch areas in rooms occupied by patients colonized with A. baumannii are more likely to be contaminated. The hands, gloves, and gowns of health care workers can be contaminated after entry into the room of a patient colonized with A. baumannii (Fig. 157-1).

Outbreaks caused by A. baumannii are frequently mono- or oligoclonal. A common source of infection has been identified in ~50% of outbreaks. These sources include respiratory therapy equipment, the hands of health care workers, bedside humidifiers, warm bathwater, hospital-prepared distilled water, bedpans, urine jugs, heparinized saline solution, mattresses, reusable pressure transducers in arterial lines, and fluids used for pressure lavage of wounds.

Control of multidrug-resistant Acinetobacter outbreaks starts with early recognition, with subsequent halting of the spread of infection throughout a facility and prevention of the establishment of an endemic strain. It is important to identify the outbreak strain and differentiate it from non-outbreak strains so that infection control activities can be better targeted. Traditionally, the strain was identified with phenotypic typing systems (biotyping) or by determination of antimicrobial susceptibility patterns. Molecular typing systems have ushered in an era of molecular epidemiology that allows more precise identification of outbreak strains through use of techniques such as ribotyping, pulse-field gel electrophoresis, repetitive sequence-based PCR, and multilocus sequence testing.

During outbreaks, the simultaneous introduction of multiple (“bundled”) measures makes it difficult to assess the impact of each individual measure. These interventions include aggressive cleaning of the general environment, active surveillance, contact isolation of colonized or infected patients, cohorting of medical staff, reinforcement of compliance with hand hygiene by health care workers, and use of aseptic care devices.

Colonization with A. baumannii is a strong predictor of subsequent clinical infection by this organism. Exposure to carbapenems is a risk factor for initial acquisition of this pathogen; therefore, efforts to curtail unnecessary use of antibiotics are fundamental to the prevention of A. baumannii colonization of patients and the organism’s establishment in health care facilities.

Additional Online References