Acinetobacter spp. are gram-negative, strict aerobic, non fermenting, non fastidious, nonmotile coccobacilli that are ubiquitous in nature, persistent in the hospital environment, and cause a variety of opportunistic nosocomial infections. They are short, plump, gram negative rods that are difficult to destain and may therefore be misidentified as either gram negative or gram positive cocci. A number of species of Acinetobacter are associated with human infection, including genomic species 3 and 13TU , although A. baumannii is generally regarded as the major pathogen. A. baumannii is a causative agent of nosocomial pneumonia, bacteremia, meningitis, and urinary tract infection and more recently has caused serious infections among American military personnel serving in Iraq and Afghanistan. Because it is often multi- or pan-drug resistant, infections are difficult to treat , resulting in attributable mortalities of up to 23% for hospitalized patients and 43% for patients under intensive care. Indeed, the Antimicrobial Availability Task Force of the Infectious Diseases Society of America recently identified A. baumannii, along with Aspergillus spp., extended-spectrum Î²-lactamase-producing Enterobacteriaceae, vancomycin-resistant Enterococcus faecium, Pseudomonas aeruginosa, and methicillin-resistant Staphylococcus aureus, as "particularly problematic pathogens" for which there is a desperate need for new drug development . In the case of A. baumannii, there is an additional unmet need for an understanding of its basic pathogenesis.
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A.baumannii infections have been a substantial clinical issue in many parts of Europe (Fig. 1). Since the early 1980s, hospital outbreaks of A. Baumannii infections in Europe, mainly in England, France, Germany, Italy, Spain, and The Netherlands, have been investigated using molecular epidemiological typing methods. In the majority of cases, one or two epidemic strains were detected in a given epidemiological setting. Transmission of such strains has been observed between hospitals, most probably via transfer of colonized patients. Spread of multidrug-resistant A. baumannii is not confined to hospitals within a city but also occurs on a national scale. Examples are the spread of the so-called Southeast clone and the Oxa-23 clones 1 and 2 in Southeast England , the dissemination of a multidrugresistant A. baumannii clone in Portugal , the interhospital spread of a VEB-1 ESBL-producing A. baumannii clone from a total of 55 medical centers in northern and southeastern France , and the spread of an amikacin-resistant A. Baumannii clone observed in nine hospitals in various regions in Spain . International transfer of colonized patients has led to the introduction and subsequent epidemic spread of multidrug-resistant A. baumannii strains from Southern into Northern European countries, such as Belgium and Germany. Intercontinental spread of multidrug-resistant A. baumannii has also been described between Europe and other countries as a consequence of airline travel. These events highlight the importance of appropriate screening and possible isolation of patients transferred from countries with A. bammunnii high rates of drug-resistant organisms.
FIG.1 . Countries that have reported an outbreak of carbapenem-resistant Acinetobacter baumannii. Red signifies outbreaks reported before 2006, and yellow signifies outbreaks reported since 2006.
The wide array of antimicrobial resistance mechanisms that have been described for A. baumannii is impressive and rivals those of other nonfermentative gram-negative pathogens . The rapid global emergence of A. baumannii strains resistant to all Î²-lactams, including carbapenems, illustrates the potential of this organism to respond swiftly to changes in selective environmental pressure. Upregulation of innate resistance mechanisms and acquisition of foreign determinants are critical skills that have brought A. baumannii great respect.
The genetic surroundings of these resistance determinants provided more evidence for genetic promiscuity, with an array of broad-host-range mobile genetic elements identified, including three class 1 integrons, transposon, transposons, and insertion sequence (IS) elements. Interestingly, no plasmid markers were identified in this resistance hot spot, and of the three plasmids found within the AYE strain, none contained any known resistance marker .
The most prevalent mechanism of Î²-lactam resistance in A. baumannii is enzymatic degradation by Î²-lactamases. However, in keeping with the complex nature of this organism, multiple mechanisms often work in concert to produce the same phenotype . Inherent to all A. baumannii strains are chromosomally encoded AmpC cephalosporinases, also known as Acinetobacter-derived cephalosporinases (ADCs). Unlike that of AmpC enzymes found in other gramnegative organisms, inducible AmpC expression does not occur in A. baumannii . The key determinant regulating overexpression of this enzyme in A. baumannii is the presence of an upstream IS element known as ISAba . The presence of this element highly correlates with increased AmpC gene expression and resistance to extended-spectrum cephalosporins. Cefepime and carbapenems appear to be stable in response to these enzymes. Extended-spectrum Î² -lactamases (ESBLs) from the Ambler class A group have also been described for A. baumannii, but assessment of their true prevalence is hindered by difficulties with laboratory detection, especially in the presence of an AmpC. More recent focus has been on VEB-1, which disseminated throughout hospitals in France (clonal dissemination) and was also recently reported from Belgium and Argentina (VEB-1a); PER-1, from France, Turkey, Belgium, Romania, Korea, and the United States; and PER-2, from Argentina . Interestingly, blaVEB-1 was found to be integron borne (class 1) yet encoded on the chromosome. This integron was identical to that identified in Pseudomonas aeruginosa in Thailand and was also associated with an upstream IS element(IS26), indicating the possible origin and mechanism of spread to A. baumannii . blaPER-1 is either plasmid or chromosomally encoded and also has an upstream IS element(ISPa12) that may enhance its expression . Other ESBLs identified in A. baumannii include TEM-92 and -116, from Italy and The Netherlands, respectively, and SHV-12 from China and The Netherlands (248, 387). Also, CTX-M-2 and CTX-M-43 have been described from Japan and Bolivia, respectively. Narrow-spectrum Î² -lactamases, such as TEM-1 and TEM-2, are also prevalent in A. baumannii, but their current clinical significance is limited given the potency of other resistance determinants. Of the Î²-lactamases, those with carbapenemase activity are most concerning and include the serine oxacillinases (Ambler class D OXA type) (fig 2) and the metallo- Î²-lactamases (MBLs) (Ambler class B).
FIG. 2. Summary of the distribution and genetic context of the OXA-type enzymes in Acinetobacter baumannii. The arrows and corresponding percentages represent the degrees of amino acid homology between the enzyme clusters. The enzyme clusters within large circles signify the acquired enzyme types, in contrast to the naturally occurring OXA-51 cluster within the large square.
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