CHAPTER 59: ACINETOBACTER INFECTIONS

Infections with bacteria of the genus Acinetobacter are established as a significant problem worldwide. Acinetobacter baumannii is particularly formidable because of its propensity to acquire antibiotic resistance determinants. Endemic infections caused by strains of A. baumannii resistant to multiple antibiotic classes, including carbapenems, are a serious concern in many specialized hospital units, especially intensive care units (ICUs). The foremost implication of infection with carbapenem-resistant A. baumannii is the need to use “last-line” antibiotics such as colistin, polymyxin B, or tigecycline; these options have the potential to render these bacteria resistant to all available antibiotics.

Acinetobacter species are oxidase-negative, nonfermenting, short, gram-negative bacilli. They were traditionally thought of as nonmotile—a characteristic from which the genus name was derived (from the Greek akineto, meaning “nonmotile”). However, recent work has shown that Acinetobacter organisms demonstrate motility under certain growth conditions. The bacteria grow well at 37°C in aerobic conditions on a range of laboratory media (e.g., blood agar). Some species may not grow on MacConkey agar. Differentiation of Acinetobacter species is difficult with the means typically available to most clinical microbiology laboratories, including commercial semiautomated identification systems. The commonly used matrix-assisted laser desorption ionization–time of flight mass spectrometry (MALDI-TOF MS) systems are undergoing evaluation for species-level identification of Acinetobacter. DNA–DNA hybridization is a method used for speciation in reference laboratories. Naturally occurring oxacillinase genes (bla_OXA) have been identified in several Acinetobacter species, and their detection by polymerase chain reaction can aid in species identification.

Widely distributed in nature, Acinetobacter species can be found in water, in soil, and on vegetables. Acinetobacter is a component of the human skin flora and is sometimes identified as a contaminant in blood samples collected for culture. Fecal carriage can be detected in both healthy and hospitalized individuals. However, despite the ubiquity of some Acinetobacter species, the natural habitat of the most clinically important species, A. baumannii, remains to be fully defined.

A. baumannii infections have been diagnosed in patients on all inhabited continents. The vast majority of infections occur in hospitalized patients and other patients with significant health-care contact. Outbreaks of carbapenem-resistant A. baumannii are particularly problematic. A significant issue is the introduction of carbapenem-resistant A. baumannii into hospitals as a result of medical transfers, especially from hospitals where the organism is highly endemic.

The Americas

In 1991 and 1992, outbreaks of carbapenem-resistant A. baumannii infection occurred in a hospital in New York City. Subsequently, numerous other hospitals in the United States and South America have had outbreaks of carbapenem-resistant A. baumannii. Infections with A. baumannii among military personnel from the United States and Canada injured in Iraq or Afghanistan were widely observed beginning in 2002. Acinetobacter was one of the most common causes of bloodstream infections and bone and soft tissue infections after war-related injury. An epidemiologic investigation revealed that A. baumannii could be grown from environmental sites in field hospitals and that the environmental strains were closely related genotypically to clinical isolates.

Europe

A. baumannii infections have posed a substantial clinical challenge in many parts of Europe since the early 1980s. Three clones (European clones I, II, and III) have been the predominant causes of A. baumannii infection in hospitals in Europe. Carbapenem resistance in A. baumannii is a significant issue in many European countries, most notably the United Kingdom, Greece, Italy, Spain, and Turkey.

Asia, Australia, the Middle East, and Africa

Although surveillance data are sparse from many countries in these regions, problems with carbapenem-resistant A. baumannii abound. Community-acquired infections are well described in northern Australia and some parts of Asia. These infections may be more likely in men >45 years of age who have histories of cigarette smoking, alcoholism, diabetes mellitus, or chronic obstructive airway disease. Community-acquired strains are more susceptible to antimicrobial agents than are hospital-acquired strains, but the clinical presentation of community-acquired disease is quite distinct and is characterized by overwhelming infection with severe pneumonia, septic shock, and multiorgan failure.

A. baumannii colonizes patients exposed to heavily contaminated hospital environments or to the hands of health care workers in these locations. Emerging data suggest that the organism can be found in the air in rooms of patients infected with Acinetobacter. Colonization of the upper airways in mechanically ventilated patients may lead to nosocomial pneumonia. Colonization of the skin may lead to central line–associated bloodstream infection, catheter-associated urinary tract infection (UTI), wound infection, or postneurosurgical meningitis. Throat carriage and microaspiration may be involved in the pathogenesis of community-acquired pneumonia due to A. baumannii.

Much less is known about the virulence mechanisms of and host responses to A. baumannii than about these aspects of other pathogenic gram-negative bacteria. Because of the emergence of multidrug-resistant strains, including those resistant to all available antibiotics, the impetus to study A. baumannii pathogenesis has grown. Novel targets for antibacterial drug development are desperately required, and drugs that have antivirulence mechanisms may provide new therapeutic options. Specific virulence mechanisms in A. baumannii include iron acquisition and transport systems; outer-membrane protein A (OmpA), which mediates mammalian cell adhesion, invasion, and cytotoxicity through mitochondrial damage and initiation of caspase-dependent apoptosis; lipopolysaccharide (LPS); and proteins important in the formation of biofilm on abiotic and biotic surfaces. Biofilm formation on abiotic surfaces is dependent on a pilus assembly system, which in turn is controlled by a traditional two-component regulatory system mediated by bfmR. Also important in biofilm formation are a gene that encodes a biofilm-associated protein (Bap); OmpA; the quorum-sensing gene abaI, which controls the secretion of 3-hydroxy-C₁₂-homoserine lactone; and the pga locus, which is essential for the production of the polysaccharide poly-β-1,6-N-acetylglucosamine. Most recently, a global virulence regulator known as GacSA was described as important in regulating A. baumannii biofilms, motility, growth in human serum, and virulence in a mammalian infection model.

New model systems for the study of A. baumannii infection, including both nonmammalian (invertebrate) and mammalian models, have been described. Furthermore, the use of A. baumannii transposon-generated mutant libraries to screen for mutants with attenuated growth in human biologic fluids (serum and ascites fluid) has allowed the identification of new virulence mechanisms. These include phospholipase D; capsule production mediated by ptk and epsA; penicillin-binding protein 7/8 encoded by the pbpG gene; and a glycosyltransferase important for LPS biosynthesis encoded by the lpsB gene.

The LPS of A. baumannii appears to play a significant role in eliciting host responses. In studies with knockout mice, Toll-like receptor 4 and CD14 were shown to be important in host recognition, signaling, and cytokine production in response to A. baumannii. Humoral responses targeting iron-regulated outer-membrane proteins and the O-polysaccharide component of LPS also have been described.

Pneumonia

It may be difficult to distinguish between upper-airway colonization with A. baumannii and hospital-acquired pneumonia. An estimated 5–10% of cases of ventilator-associated pneumonia are due to A. baumannii, although much regional variation exists. Typically, patients with A. baumannii ventilator-associated pneumonia have had a prolonged stay in an ICU; in outbreak situations, however, patients may acquire the infection within days of arrival in an ICU.

Community-acquired pneumonia due to A. baumannii has been described in tropical regions of Australia and Asia. The disease typically occurs during the “wet” season among people with a history of alcohol abuse. Infection may result in fulminant pneumonia requiring admission to an ICU, with a mortality rate of ~50%.

Bloodstream infection

Although A. baumannii accounts for only ~1–2% of nosocomial bloodstream infections, crude mortality rates from these infections may be as high as 40%. Sources of bloodstream infection are typically a central line or underlying pneumonia, UTI, or wound infection.

Traumatic battlefield and other wounds

A. baumannii is a well-known pathogen in burn units. This organism is commonly isolated from wounds of combat casualties; it was the most commonly isolated organism in one assessment of combat victims with open tibial fractures but did not appear to contribute directly to persistent nonunion or the need for amputation.

Meningitis

A. baumannii may cause meningitis following neurosurgical procedures. Patients typically have an external ventricular drain in situ.

Urinary tract infection

A. baumannii is an occasional cause of catheter-associated UTI. It is highly unusual for this organism to cause uncomplicated UTI in healthy women.

Other clinical manifestations

A small number of case reports describe Acinetobacter prosthetic-valve endocarditis and endophthalmitis/keratitis. The latter is sometimes related to contact lens use or eye surgery.

Acinetobacter infection should be suspected when plump coccobacilli are seen in Gram’s-stained respiratory tract secretions, blood cultures, or cerebrospinal fluid. Sometimes the organisms are difficult to de-stain. Given their small size, they may be misidentified as either gram-negative or gram-positive cocci.

Given the propensity of A. baumannii to cause infections in seriously ill patients in ICUs, it is not surprising that A. baumannii infections are associated with high mortality rates. Thus a pertinent question is whether A. baumannii infections are associated with high attributable mortality rates after the severity of illness is controlled for. A number of studies have addressed this issue but have had disparate results. Whether the discrepant results can be explained purely by methodologic differences is unknown at present.

Multidrug-resistant A. baumannii clearly causes outbreaks of infection and then establishes endemicity. In endemic situations, a small number of strain types predominate. In the 1991–1992 outbreaks in New York City, for example, two strain types accounted for more than 80% of carbapenem-resistant isolates. This “oligoclonality” plainly demonstrates the potential importance of infection control interventions in response to outbreaks of multidrug-resistant A. baumannii infection.

The hospital environment is an important reservoir of organisms capable of colonizing patients and causing infection. Environmental sources of A. baumannii include computer keyboards, glucometers, multidose medication vials, IV nutrition, inadequately sterilized reusable arterial pressure transducers, ventilator tubing, suction catheters, humidifiers, containers of distilled water, urine collection jugs, and moist bedding articles. Pulsatile-lavage wound treatment—a high-pressure irrigation system used to debride wounds—has been associated with an outbreak of A. baumannii infection.

Contaminated inanimate objects should be removed from the patient-care environment or subjected to enhanced environmental cleaning. Although contact-isolation procedures (use of gloves and gowns when dealing with colonized patients or their environment), accommodation of patients in single rooms, and improved hand hygiene are critical, attention to the patient-care environment may be the only measure that leads to control of outbreaks of A. baumannii infection. One study found that Acinetobacter can be cultured from the air in rooms of patients with A. baumannii infection; the infection-control implications are not yet clear.