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Among the last decades, bacteria of the genus "Acinetobacter" have designed important nosocomial pathogens, especially in ICU units. Acinetobacter spp are widespread present in water and soil as free-living saprophytes (Greenwood et al., 2001).
Acinetobacters were first described under the group of "Micrococcus calcoaceticus" by Beijerinck in 1911. In 1956 these bacteria were then classified under the name of "Moraxella" in France. In this period a group of France workers had detected a genus named Acinetobacter. In 1968 a phenotypic study of 106 strains was done by Baumann resulted in the recognition of only a single genus named Acinetobacter bummanii (Towner, 1997). In early 1970's, Acinetobacters were usually sensitive to many common antimicrobial agents (Greenwood et al., 2001). However in the same period many microbiologists in hospitals discovered that these organisms were pathogenic and involved in various nosocomial infections. In 1986, a basic subdivision of the genus Acinetobacter was done by Bovetand and Grimont who identified 12 genomic species by DNA- DNA hybridization method. However, today there are at least 19 genomic species of Acinetobacter (Murray et al., 2007).
Within the genus, Acinetobacter baumannii appears to be the species of greatest clinical importance, but other species of the 'A. baumannii complex' (comprising A. baumannii, Acinetobacter calcoaceticus, and the unnamed sp. 3 and sp. 13 of Tjernberg and Ursing) are also of clinical importance. The A. baumannii complex contains isolates that are multi-resistant to antibiotics and that have been responsible for many outbreaks of infection throughout the world (Towner, 1997). The A. baumannii complex should be considered to be as different from other Acinetobacter
spp. as S. aureus is from coagulase negative staphylococci. Other Acinetobacter spp. are involved only rarely in human disease and outbreaks of infection, and are generally isolated
from patients who are already suffering from severe underlying disease (Joly-Guillou, 2005).
Morphologically, they are aerobic, non motile Gram-negative coccobacilli and usually found in diploid formation or chains of variable length. They are strictly aerobic and grow easily on all common media at temperatures from 20 to 30 oC, with for most strains, the optimum at 33-35 oC. They are oxidase-negative, catalase-positive, indole-negative and nitrate-negative. It does not have capsule as it is not produce cytochrome oxidase. Furthermore, the initial clue of these bacteria is the observation of tiny (1.0x 0.7 Âµm) diplococci on gram stain (Koneman et al., 1997).
Colonies appear smooth, opaque, and slightly smaller than those of members of the family Enterobacteriaceae on blood agar. Most strains appear colourless, slightly pink or lavender in colour on MacConkey agar due to lactose oxidation (Engelkirk, 2007). Therefore, the genus of Acinetobacter can be subdivided into two groups. Acinetobacter that is able to oxidise glucose are called saccharolytic, with those that are unable called asaccharolytic (Engelkirk, 2007).
However, most glucose-oxidizing non-haemolytic clinical strains are A. baumannii, most glucose-negative non-haemolytic ones are A. lwoffii, and most haemolytic ones are A. haemolytic (Murray et al., 2007).
Clinical features of Acinetobacter infections:
Acinetobacter spp., particularly Acinetobacter baumannii, can cause many clinical disorders, including pneumonia, secondary meningitis, bacteraemia, wound infections in burn patients and urinary tract infections (Winn et al., 2005). It is also isolated from skin, throat and many secretions of normal people as commonsal flora (Hawkey & Bergogne-Berezin, 2006).
In case of wound infections it often leads to bacteraemia within 3-5 days following infection. In several large case series, 4-27% of all Acinetobacter bacteraemia occurred as a result of infected surgical or burn wounds (Gillespie, 2004; Hawkey & Bergogne-Berezin, 2006). Such infections are often difficult to treat because of the ability of Acinetobacters to become rabidly resistance to multiple antibiotics, including aminoglycosides, expanded-spectrum cephalosporins, carbapenems and fluoroquinolones (Towner and Gallego, 2001). Moreover, Acinetobacters which can easily obtain from soil, water, food and sewage (Towner, 1997) are able to survive for long periods in inanimate environments (Greenwood et al., 2001).
Inappropriate or excessive use of antibiotics therapy (i.e third generation cephalosporin), surgery, use of medical machinery (i.e ventilators), insertion of catheters intravenously or urinary, and prolonged hospital stay are all identified as risk factors for colonization/infection with Acinetobacter (Hawkey & Bergogne-Berezin, 2006).
Acinetobacter has been isolated in a large variety of clinical samples, including blood, urine, faeces, cerebrospinal fluid and sputum (Gillespie, 2004). It is opportunistic pathogens and is commonly found in patient samples. However, the severity of Acinetobacter infection depends upon the site of infection and the patient's susceptibility to infection as a result of underlying disease (Murray et al., 2007).
Chiang, et al., (2008) was added in their study increased serum creatinine level and malignancy as a risk factors associate with increased mortality in patient with bacteraemia caused by Acinetobacter.
A European survey of causative agents in nosocomial pneumonia carried out in seven countries using the same protocol has established an over all incidence of approximately 10% for Acinetobacter (Bergogne-Berezin, 2001).
A study period from 2003 to 2006 for over 270 patients admitted every year in burn clinic confirmed the increased trend of Acinetobacter stains, as multi-drug resistant potential pathogen (Babik et al., 2008).
Pathogenesis of Acinetobacter infection:
As Acinetobacter spp. are considered to be relatively low-grade pathogens, it has numerous virulence factors that have been identified; these include:
The production of exopolysaccharide:
It is thought that the presence of exopolysaccharide capsule helps in the protection of bacteria from host defences, resulting in lethality for mice and cytotoxicity for phagocytic cells. Approximately 30% of Acinetobacter strains produce exopolysaccharide. This process has
been studied in Acinetobacter spp. strain BD4, which synthesises a thick exopolysaccharide capsule composed of L-rhamnose, D-glucose, D-glucuronic acid, and D-mannose, which probably renders the surface of strains more hydrophilic (Joly-Guillou, 2005; Hawkey & Bergogne-Berezin, 2006). In experimental studies, exopolysaccharide-producing strains of Acinetobacter have been shown to be more pathogenic than non-exopolysaccharide-producing strains, especially in polymicrobial infections with other species of higher virulence (Joly-Guillou, 2005)
Quorum-sensing is a widespread regulatory mechanism among Gram-negative bacteria such
as Pseudomonas aeruginosa. Four different quorum sensing signal molecules capable of activating N-acylhomoserine-lactone biosensors have been found in clinical isolates of Acinetobacter, with maximal activity in the stationary growth phase. Quorum-sensing might be a central mechanism for auto-induction of multiple virulence factors in an opportunistic pathogen such as Acinetobacter, and this process should be studied for its clinical implications (Joly-Guillou 2005).
The property of adhesion to human epithelial cells via the capsule or fimbriae.
The production of lipase enzyme which may damage tissue lipids.
(Bergogne-Berezin & Towner, 1996; Hawkey & Bergogne-Berezin, 2006)
The potentially toxic role of the lipopolysaccharide component of the cell wall:
The lipopolysaccharide is involved in resistance to complement in human serum and acts in synergy with the capsular exopolysaccharide. Complement appears to play a role in the bactericidal activity of human sera. A relationship has been described previously for Gram-negative bacteria isolated from bacteraemic patients between their degree of resistance in vitro to the lytic activity of complement and their ability to survive in human fluids. Lipopolysaccharide O and capsular polysaccharide are both involved in this phenomenon.
Capsular polysaccharide is known to block the access of complement to the microbial cell wall and to prevent the triggering of the alternative pathway of complement activation, as demonstrated in experimental models of Gram-negative infections (Joly-Guillou, 2005).
Although, the outer membrane has special channels consisting of protein molecules called porins, that allow the passive diffusion of low molecular weight to penetrate through this membrane. Large antibiotics molecules penetrate slowly, which account for the high antibiotic resistance of A.baumannii. For example, the permeability of the outer membrane varies from one gram negative species to another, in Psudomonas aeruginosa, which extremely resistance to antibiotics, the outer membrane is 100 times less permeable than the E.coli (Brooks et al., 2001). A study showed when analyzed the permeability of the outer membrane of acinetobacter, they found that the permeability of cephalosporins drug was 2-7 times lower than it is found in Psudomonas aeruginosa (Vila, 1998).
Many parameters, including host factors, the bacterial burden and the virulence of individual
strain, may play important roles in causing infection in colonised patients. Considering that
Acinetobacter is often multi-resistant to antibiotics, the identification of factors influencing virulence could help to separate colonising strains into those of high and low potential virulence. Antibiotic therapy could be avoided for strains of low potential virulence, whereas identification of highly virulent colonising strains in the respiratory tract should lead to re-inforcement of preventive cross-infection measures and early antibiotic treatment for high-risk patients. Careful hand washing with soap and water, and also alcohol based gels, should always be encouraged (Joly-Guillou, 2005)
Emergence of Resistance:
A.baumannii and related species have acquired resistance to multiple antibiotics rather than being inherently resistant. When these species were first applied as human pathogens, many strains were susceptible to ampicillin and most were sensitive to the cephalosporins. In 1975, <20% of these strains were resistant to ticarcillin. However, these bacteria showed rapid resistance to second generation cephalosporins in the end 1970s and early 1980s, when these agents were being used to control nosocomial infections. When the third generation cephalosporins were introduced, A.baumannii developed resistance to cefotoxime and ceftazidime. Therefore, this bacterium has an excessive acquired resistance to Î²-lactam drugs (Towner, 1997). There are no specific treatment guidelines for Acinetobacter spp. due to the large variation in antibiotic resistance. To determine the best mode of treatment for a particular isolate, antimicrobial susceptibility testing must be performed (Forbes, 2007).
Although, carbapenems were the drug of preference in the treatment of acinetobacter infections. Numerous reports in the medical and scientific literature have documented resistance strain to carbapenems antibiotics such as imipenem and meropenem (Costa et al., 2000; Levin, 2002)
According to Health Protection Agency (HPA) survey 1,225 cases of bacteraemia due to Acinetobacter spp were reported from England, Wales and Northern Ireland in 2007, with an overall incidence rate of 2.2 per 100,000 populations. In the same survey 12% of Acinetobacter spp was shown resistance to imipenem. Whereas, prevalence of ciprofloxacin and gentamicin resistance was 16% and 12% respectively.
Currently, several surveys were studied the prevalence, mode of transmission and risk factors of multi-drug resistant A. baumannii in ICU and burn clinic. It was reported an increase incidence and a spread of an outbreak of epidemic clone of A. baumannii (Babik et al., 2008; Cootz & Marra, 2008; Fontana et al., 2008; Bacakoglu et al., 2009; Barchitta et al., 2009).
Carbapenems action on Acinetobacter:
Carbapenem antibiotics have the most extended spectrum of antibacterial activity among all ß-lactams and imipenem is one of the most important agents of carbapenems.
Imipenem is an active agent against many organisms including Gram positive and negative aerobes and anaerobes bacteria. It is a bactericidal agent that kills or destroys bacteria at 2-4 times the MIC for most species (Greenwood et al., 2001).
The initial step of drug action in destroying bacteria is the binding of the drug to cell receptors penicillin binding proteins (PBPs). After a Î²-lactam drug has attached to one or more receptors, the transpeptidation reaction is inhibited and peptidoglycan synthesis is blocked. Next step, involves the removal or inactivation of an inhibitor of autolytic enzymes in the cell wall. This activates the lytic enzyme which results in lyses of cells leads to cell death (Brooks et al., 2001).
Mechanisms of Carbapenems Resistance:
Some early reports described acinetobacters with ß-lactamase-independent carbapenem resistance, but most recent reports describe ß-lactamase-mediated resistance.
In the last few years, carbapenem-resistant A.Â baumannii isolates have been reported worldwide. However, most carbapenem-resistant Acinetobacters have OXA-type ß-lactamases with a weak activity against carbapenems which belong to class D ß-lactamase ; such enzymes have been found in A. baumannii isolates from Argentina, Belgium, Kuwait, Scotland, Spain and Singapore. Several of these enzymes have been sequenced and are found to form a subgroup among class D ß-lactamases, presently comprising the OXA-23, -24, -25, -26, -27 and -40 types (Song et al., 2004).
Major carbapenemases found in acinetobacter species were metalloenzyme and OXA-type enzymes (Bou et al., 2000). These enzymes can hydrolyse imipenem rapidly (Song et al., 2004).
There are several factors that determine the acquisition of multi resistance in A.Â baumannii, these are:
First, the intrinsic resistance of the microorganisms, which obtained from low level diffusion of certain antibiotics through the outer membrane due to low number of porins present (Levin, 2002). Second, the facility of acquiring genetics elements; there are 3 types of mobile genetic elements have been found in Acinetobacter. These are the plasmids, the transposons and the integrons (Vila, 1998). The plasmids contains 3 resistance genes; genes encoding ß-lactamase TEM-1, TEM-2, and CARB-5 (Bou et al., 2000). The plasmid encoded B-lactamases have a great attention in which the resistance of this bacteria occur by a single genetic event. However, this type of resistance occurs mostly in the highly selective environment of the hospital (Greenwood, 2000). Whereas, the integrons which are chains of genes have a great mobility to transfer from one location of A.baumannii chromosome to another with help of transposon that carry this gene (Vila, 1998). Third factor is the ability of Acinetobacter spp to survive in human and environmental reservoirs in which the genes of resistance may be transferred (Vila, 1998).
Acinetobatcer Treatment with Honey:
Due to the emergence of bacterial resistant to antibiotics, the bactericidal properties of manuka honey have been extensively researched. Currently, few studies were reported the antibacterial activity of honey against Acinetobacter. George & Cutting, (2007) initiated an in-vitro study of antibacterial activity of Medihoney against 130 clinical isolates of multi-drug resistant organisms including Acinetobacter. The study was shown that 8% (v/v) of honey concentration was required to inhibit the resistant Acinetobacter strains.
The more resent one was carried out using Malaysian tualang honey against wound pathogens including Acinetobacter and compare it with manuka honey. The antibacterial activity for both honeys was same as the MIC ranges between (11.25 & 12.5%) (Tan et al., 2009).
Although Acinetobacter have been found susceptible to the honey. It required more objective evidence of clinical trails and in animal models to determine weather honey has a similar antimicrobial effect in-vivo.