Acinetobacter species

Among Acinetobacter genus, Acinetobacter baumannii, Acinetobacter nosocomialis and Acinetobacter pittii are the most clinically relevant species. Infections caused by A. baumannii are associated with higher mortality and morbidity because of its relatively high virulence and antimicrobial resistance compared to other Acinetobacter species. The general information regarding Acinetobacter genus was provided in the following chapter; more detailed information regarding A. baumannii was repeatedly emphasized due to its imperative clinical importance.

MICROBIOLOGY

Acinetobacter spp. are aerobic Gram-negative coccobacilli commonly present in soil and water as free-living saprophytes. Some species are also common commensals of skin, throat and secretions of healthy people. The genus Acinetobacter has undergone extensive and confusing changes in taxonomic nomenclature over many years, with strains being designated previously as Bacterium anitratum, Herellea vaginicola, Mima polymorpha, Achromobacter, Micrococcus calcoaceticus, Diplococcus, B5W and Cytophaga. The use of modern molecular-based taxonomic methods has allowed the identification of at least 34 different named species (www.bacterio.cict.fr) (Table 1), with the likelihood that further species will be discovered in the future.

Molecular methods used in species identification included DNA-DNA hybridization (21), amplified ribosomal DNA restriction analysis (ARDRA) (184), high-resolution fingerprint analysis by amplified fragment length polymorphism (AFLP) (87), ribotyping (72), tRNA spacer fingerprinting (53) restriction analysis of the 16S-23S rRNA intergenic spacer sequences (51), sequence analysis of the 16S-23S rRNA gene spacer region (28), and sequencing of the rpoB gene and flanking spacers (110). ARDRA and AFLP analysis are the reference methods for species identification in all Acinetobacter spp. but intergenic spacer, rpoB sequencing, and ribotyping are also highly accurate and less labor-intensive (152). Matrix-assisted laser desorption/ionization mass spectrometry (MALDI MS) has recently been applied for the Acinetobacter identification but in general, the accuracy is not always satisfactory (6, 54). Efforts are undertaken to improve the accuracy (169, 176) . Currently, molecular methods will still be required for confirmation of species.

Members of the genus Acinetobacter are usually found in diploid formation, or chains of variable length. They are non-motile, but some strains display a 'twitching motility' associated with the presence of polar fimbriae. They are strictly aerobic and grow easily on most common microbiological isolation media, with the optimum temperature for most clinical isolates being 33 – 37°C. Growth at 41 – 44°C occurs for a few species, while some environmental species are unable to grow above 30°C.  Acinetobacter spp. are oxidase-negative, catalase-positive, indole-negative, and nitrate-negative. Some strains produce acid from D-glucose, D-ribose, D-xylose, and L-arabinose (utilized oxidatively as carbon sources). These and other phenotypic characters are incorporated in various commercial identification systems (e.g., API 20NE, VITEK, Phoenix, MicroScan WalkAway); however, while these systems are relatively accurate at identifying isolates as members of the Acinetobacter genus, putative identification of an acinetobacter isolate to the species level by current automated, semi-automated or manual commercial systems should be regarded with caution.

Acinetobacter spp. first began to be recognized as significant healthcare-associated pathogens during the 1970s. Many of these infections involve multidrug-resistant (MDR) strains, and occur in intensive care or high-dependency units in which severely-ill or debilitated patients are treated extensively with broad-spectrum antibiotics. These early clinical isolates were not identified to an adequate species level, and it is now recognized that A. baumannii and its close relatives (A. nosocomialis and A. pittii, together forming the ‘A. baumannii complex’) account for the vast majority (90 – 95%) of clinically significant infections. It should be noted that the well-known genomic species 3 and 13TU have been replaced by A. pittii and A. nosocomialis, respectively (146). Acinetobacter calcoaceticus is also phenotypically close to the A. baumannii complex, and has therefore been grouped with these three species as A. calcoaceticus-baumannii(Acb)complex. However, the use of the name “Acb complex” in clinical settings or researches may lead to confusion because A. calcoaceticus is a soil organism that has only very rarely been implicated in human infections. The members of the A. baumannii complex are very difficult for routine diagnostic laboratories to distinguish accurately; therefore, reports of A. baumannii in the scientific and medical literature should be assumed to include the other members of the complex unless this possibility has been specifically excluded by the use of modern molecular taxonomic methods.

EPIDEMIOLOGY

Members of the genus Acinetobacter are widely distributed in nature and can be isolated from soil and fresh-water samples, as well as from humans and animals. Certain Acinetobacter spp., chiefly A. johnsonii, A. lwoffii and A. radioresistens, are part of the bacterial flora of the skin, where they are found predominantly in moist skin areas. In contrast, it is believed A. baumannii is usually isolated from patients and hospital environmental sources, but not outside hospitals (152). However, recent surveillances using molecular methods to identify A. baumannii showed this pathogen has the ability to reside outside hospitals (55). In an infected patient, A. baumannii colonizes the skin, oral cavity, respiratory tract, and the intestinal tract (10). The infected patient forms the primary reservoir of infection; such patients often shed into their surrounding environment a large number of A. baumannii cells, which contaminate the medical equipment (Table 2) and are carried by the hospital staff. Colonization in susceptible patients, carriage by medical staff, prolonged survival in the hospital environment, and resistance to common antibiotics and antiseptic agents results in frequent outbreak of A. baumannii that is difficult to contain. In addition to indirect contact, airborne transmission and patient-to-patient transmission have also been demonstrated (5, 145).  

Severe nosocomial infections and hospital outbreaks associated with Acinetobacter spp. have occurred worldwide. In European intensive care units (ICUs), 21.8% of pneumonia, 17.1% of bloodstream infections, and 11.9% urinary tract infections were caused by Acinetobacter spp. (1). Infections and outbreaks in the long-term care facilities or nursing homes have been more commonly reported recently 172). Most have been attributed to A. baumannii, particularly in the ICU setting, and to a lesser extent to A. nosocomialis and A. pittii. Healthcare-associated infections caused by other named Acinetobacter spp. such as A. bereziniae, A. guillouiae, A. haemolyticus, A. johnsonii, A. junii, A. lwoffii, A. parvus, A. radioresistens, A. schindleri, A. soli and A. ursingii are rare, and are restricted mainly to catheter-related bloodstream infections (17, 197, 198)  or point source infections (18, 92, 185).  They are generally more susceptible to antimicrobials and are usually considered to be of minor virulence. These latter infections usually run a benign clinical course and their associated mortality is low. Small-sized outbreaks caused by Acinetobacter spp. other than A. baumannii complex have been observed occasionally, and are often found to be related to contaminated infusion fluids such as heparin solution. There have also been a few reports of community-acquired infections due to A. baumannii, usually in patients with co-morbidities in tropical or sub-tropical areas (152).

The dissemination of A. baumannii in one institution or in a nation-wide level has been repeatedly documented. Three clones which successfully spread in European hospitals were originally named as European clones I–III (206). Latter epidemiological surveillance revealed they disseminated worldwide and predominated in geographically distinct areas; they are therefore re-named as international clones I–III. A. baumannii evolves quickly (200)  and isolates belonging to the same international cone may diverge greatly; therefore, international clones I–III is not capable of delineating the epidemiological relationship. The epidemiological relationship among A. baumannii isolates is better differentiated by multilocus sequence typing (MLST) (11) , pulsed-field gel electrophoresis (PFGE) AFLP analysis (87), whole-genome sequencing analysis (121) , and other molecular methods (206) . Studies using these methods found outbreaks in each institution are commonly caused by a single clone, but polyclonal outbreaks may not be rare (174).  Majority of strains causing outbreaks are MDR since the multidrug resistance in A. baumannii is very common worldwide. The definitions of multidrug resistance in the literature varied greatly. Currently, multidrug resistance is defined as being non-susceptible to at least 1 agent in ≥ 3 antimicrobial categories (aminoglycosides, antipseudomonal carbapenems, antipseudomonal fluoroquinolones, antipseudomonal penicillins, extended-spectrum cephalosporins, trimethoprim-sulphamethoxazole, ampicillin-sulbactam, polymyxins, and tetracyclines) (132).  By 2010, half of A. baumannii in the United States were MDR (156). Compared to susceptible strains, outbreaks of these MDRs pose a greater threat to healthcare system, causing huge economical cost, morbidity and mortality.

Several studies have analyzed risk factors for colonization and infection with A. baumannii. They include major surgery, major trauma, burns, premature birth, previous hospitalization, stay in an ICU, length of hospital or ICU stay, mechanical ventilation, indwelling foreign devices (e.g., intravascular catheters, urinary catheters and drainage tubes), the number of invasive procedures performed, and previous antimicrobial therapy (67).  Studies also found Acinetobacter infections exhibited seasonal variation, with highest rates in summer. One plausible reason is that higher temperature and humidity may promote the growth of Acinetobacter spp. (140).  Failure to comply with infection control guidelines and the use of broad-spectrum antibiotics especially carbapenems and third-generation cephalosporins are major factors for the development of an MDR phenotype in A. baumannii (56).

CLINICAL MANIFESTATIONS

The main problems caused by Acinetobacter spp. in the hospital setting mostly concern critically-ill patients in ICUs, particularly those requiring mechanical ventilation, and patients with wound or burn injuries (trauma patients). Infections associated with Acinetobacter spp. include ventilator-associated pneumonia, skin and soft-tissue infections, wound infections, urinary tract infections, peritonitis, secondary meningitis and bloodstream infections (17, 152).   Such infections are caused predominantly by members of the A. baumannii complex; infections caused by other species belonging to the genus Acinetobacter are relatively unusual and are restricted mainly to catheter-related bloodstream infections and rare outbreaks related to point-source contamination. Rarely, A. baumannii causes community-acquired infections (152).

Healthcare-associated Infections

Respiratory Tract

Ventilator-associated pneumonia is the most frequent clinical manifestation of  healthcare-associated A. baumannii infection, although it is sometimes difficult to distinguish upper respiratory tract colonization from true infection. In large series of A. baumannii infections, pneumonias represent 26.7 – 47.9% of Acinetobacter infections (83, 116).   Data from the National Nosocomial Surveillance System (NNIS) have revealed a substantial increase in the number of cases of A. baumannii-associated pneumonia, with 5 – 10% of cases of ICU-acquired pneumonia in the USA being caused by A. baumannii (70).  Bacteremic pneumonia carries a particular poor prognosis (170).  Acinetobacter pneumonia does not differ clinically from other pneumonias caused by Gram-negative bacteria, with fever, leukocytosis, purulent sputum production and appearance of new infiltrates on radiograph or CT scan. The organism can be isolated from pulmonary procedures, including bronchial brushings or bronchoalveolar lavage (31).  Acinetobacter respiratory tract infections occur predominantly in mechanically ventilated patients (27, 68, 83, 143) and elderly patients with underlying diseases (119).   Patients with prolonged hospitalization or receiving antibiotics are also risk group for developing Acinetobacter pneumonia (69, 82).  The mortality is usually high (20-40%) and affected by the comorbidities, diseases severity of patients, and the appropriateness of initial antibiotics (29).

Bloodstream Infections

A. baumannii ranks 10th among the most frequent organisms causing nosocomial bloodstream infections in the USA, being responsible for 1.3% of all monomicrobial nosocomial bloodstream infections (198).  Risk factors predisposing to bacteremia are pneumonia, trauma, surgery, presence of catheters or intravenous lines, dialysis and burns (111, 119, 197).  Immunosuppression or respiratory failure at admission increases the risk of bacteremia three-fold, with increased risk for nosocomial pneumonia (67).  Bacteremic episodes are characterized by fever, leukocytosis and successive positive blood cultures with the same genotypic isolate of Acinetobacter (49, 101, 126, 191, 197). The prognosis is determined by the underlying condition of the patient, but A. baumannii bloodstream infection may be associated with considerable morbidity and overall mortality as high as 58% (39).   Risk factors for a fatal outcome are severity-of-illness markers, such as septic shock at onset of infection, elevated APACHE II score, and ultimately fatal underlying disease.  However, a recent study revealed that about 30% of bloodstream infections attributed to A. baumannii were actually caused by lower virulent members of A. baumannii complex (A. nosocomialis and A. pittii) and that the organisms involved were misidentified by commercial identification systems (39).  Mixed infections with other bacteria are common in cases of Acinetobacter bacteremia. Whether these mixed infections increased the pathogenicity of A. baumanniicomplex is unknown (123).  It should also be noted that 10-15% of Acinetobacter isolates from blood cultures typically belong to species other than those included in the A. baumannii complex.  Such isolates are often associated with skin contamination and should be regarded with caution unless repeat cultures are obtained.

Skin and Soft Tissue Infections

It has long been known that A. baumannii may cause wound colonization and infection in patients with severe burns or trauma (10, 78, 195).  In recent years, nosocomial A. baumannii wound infection has also been associated particularly with natural catastrophes or man-made disasters (e.g., earthquakes, floods, the tsunami catastrophe of 2004, terrorist attacks and military campaigns) when hospitals’ capacities for patient care are overloaded and standard hygiene procedures can no longer be enforced (167,168).  A. baumannii first came to wider public attention when severe wound infections, burn wound infections and osteomyelitis were reported in soldiers who had suffered major injuries during military operations in Iraq or Afghanistan, and who were then repatriated to the USA or the UK (45, 167, 168).  The isolates from these infections were often MDR. It was speculated that the organism might have been inoculated at the time of injury, either from previously colonized skin or from contaminated dust or soil. However, it is now considered that the soldiers acquired their infecting organism during emergency care at field hospitals or following cross-transmission during their hospitalization in military hospitals (151, 167).

Miscellaneous

Urinary tract infection due to A. baumannii becomes more common and is often related to indwelling Foley catheters. These infections are usually benign and occur more frequently in rehabilitation centers than in ICUs (50).  Nosocomial meningitis is a not infrequent manifestation of Acinetobacter infection (62, 63, 101).  It is usually introduced by invasive procedures or neurosurgery (usually 1-40 days after surgery, median 12 days) (97).  Neonatal cases are not exceptional (144).  This includes ventriculoperitoneal shunt infections, epidural infections, intraventricular and intrathecal infections (13, 62, 63, 144, 147).  Risk factors for acquisition of Acinetobacter meningitis include a continuous connection between ventricles, a ventriculostomy or a CSF fistula, and the external environment. Prolonged surgical time, infected surgical sites, surgery involving a sinus, the immunological condition of the patient, and a contaminated environment are also contributing factors (23, 48, 103, 104).  Mortality ranges from 15% to 71%. Neonates and patients infected by resistant isolates have the highest mortality (84, 141).  Community-acquired meningitis occurs in patients with underlying factors such as alcoholism and diminished immune defenses (30).  A range of other unusual case reports involving Acinetobacter spp. have appeared in the literature, including suppurative thyroiditis, necrotizing enterocolitis, and peritonitis (16, 131, 205), as well as a case of Acinetobacter pericarditis with tamponade that occurred in a patient with systemic lupus erythematosus (112).

Community-Acquired Infections

Acinetobacter spp. have been reported occasionally as causative agents of community-acquired infections such as pneumonia, bacteremia, wound infection, urinary tract infection, otitis media, eye infections, meningitis and endocarditis. A. baumannii complex is responsible for most of the cases. The role of Acinetobacter spp. other than A. baumannii complex are uncertain; these species are normal commensals, often colonizing the skin and mucous membranes of humans, and their isolation may therefore have been misinterpreted as being indicative of agents causing infection. A. baumannii,  identified by molecular methods, is recognized as a rare but important cause of severe community-acquired pneumonia in tropical areas of Asia and Australia (44).  Such patients typically have severe underlying disease, such as chronic obstructive pulmonary disease, as well as diabetes mellitus or a history of excessive alcohol consumption or heavy smoking. These cases often run a fulminant clinical course with a high incidence of bacteremia and a high mortality rate of 40 – 64% (32).

Clinical Impact

Rapid emergence of multidrug resistance in A. baumannii is observed worldwide, leaving only limited therapeutic choices.  These have led to severe impact in clinical settings, as inappropriate therapy greatly compromised the patients’ outcome, especially in critically ill patients (117).  Whether the high overall mortality rates in patients with A. baumannii bacteremia or pneumonia is attributed to inappropriate therapy, severity of diseases or virulence of A. baumannii remains a matter of continuous debate in the literature. Recent studies adjusting for comorbidities, drug resistance and appropriateness of empirical antibiotics suggested that A. baumannii be more pathogenic than A. nosocomialis or A. pittii (39, 108, 118, 203). The clinical impact of A. baumanii is coupled with its propensity for nosocomial cross-transmission and outbreak, perhaps because of its multidrug resistance and its capacity for long-term survival in the hospital environment.

LABORATORY DIAGNOSIS

Examination of specimens taken from any site of Acinetobacter infection constitutes the reference method for isolating and identifying the infecting organism. The genus Acinetobacter comprises Gram-negative (albeit sometimes ‘Gram-variable’), non-motile, oxidase-negative, glucose non-fermenting, strictly aerobic, catalase-positive bacteria with a G+C content of 39 – 47%. The bacterial shape varies from coccoid to coccobacillary, depending on the growth phase. Most Acinetobacter spp. are metabolically versatile and can be grown easily on simple microbiological media, forming domed, smooth colonies of ~2 mm diameter, with some species being pigmented pale yellow or grey. The temperature range is typical of mesophylic bacteria; clinically relevant species grow optimally at ~37°C, while environmental species may prefer lower temperatures. Culture in slightly acidic mineral medium containing acetate and nitrate as carbon and nitrogen sources, respectively, or in Leeds selective medium (88) or on similar commercially available selective agars, can improve the recovery of Acinetobacter spp. from complex microbial communities, and can be used for enrichment of clinical and environmental specimens.  Hemolytic activity on 5% sheep blood agar plates is observed occasionally, and hydrolysis of gelatin and urea, as well as formation of acid from glucose are also variable traits.

The above tests permit identification to the genus level, but identification of Acinetobacter spp. to the individual species level is difficult for routine microbiology laboratories. Phenotypic identification schemes are inadequate for identification of individual Acinetobacter spp. This holds true even for the commercially available automated identification systems (e.g., API 20NE, VITEK, Phoenix, MicroScan WalkAway) that are now used routinely in many clinical microbiology laboratories. Therefore, clinical and epidemiological studies in which species identification of Acinetobacter isolates is achieved only by chemotaxonomic systems should be interpreted with caution. Considerable effort has been dedicated to the development of new and user-friendly molecular techniques for precise identification of individual Acinetobacter spp., in order to better delineate their ecology, epidemiology and pathogenicity (152), especially for A. baumannii and A. nosocomialis and A. pittii. In the clinical laboratory, PCR amplification of species-specific DNA regions (e.g., the blaOXA-51 carbapenemase gene intrinsic to A. baumannii) can be a valuable tool for confirmatory identification of individual pathogenic species (182). Similarly, it has proved possible to distinguish members of the Acb complex by using specific primers to amplify distinguishing regions of the gyrB gene or 16S-23S rRNA ITS region (33, 34, 79, 80).

PATHOGENESIS

Acinetobacter was initially considered to be an organism of low virulence, but the high mortality of patients infected by A. baumannii suggested the possibility of innate factors causing virulence.   Relative to other pathogenic Gram-negative organisms, little was known about virulence mechanisms in A. baumannii and host responses to infection. Model systems have now been established to study A. baumannii pathogenesis; they include in vitro abiotic and biotic models, and in vivo systems in invertebrates and mammalians (138, 153). The success of A. baumannii has so far been attributed to several factors:

(i) the ability to adhere biotic and abiotic surfaces, to form biofilms, and to survive for a long time (127, 129, 187, 188).  The easy attachment of A. baumannii to different medical equipment or epithelial cells is important for its persistence in hospitals and invasion to susceptible hosts (114, 115).  The attachment and biofilm formation requires multiple signals or cues and mechanisms. One prominent virulence factor, outer membrane protein (OmpA) of 38 kDa, plays a role in the attachment to biotic and abiotic surfaces (64); CsuA/BABCDE usher-chaperone assembly system, regulated by a two-component system (BfmS/BfmR) has been involved in the production of pili, which mediates  the initial attachment to abiotic surface (46, 180, 181).  Formation of biofilms is under the regulation of host (growth condition, cell density, and so on) and environmental factors (free iron, light, etc.); quorum sensing system (149) has been implicated in the regulation. Poly-β-1,6-Nacetylglucosamine (PNAG) constitutes the majorcomponent of exopolysaccharide in biofilms (35).  

(ii) multiple virulence factors facilitate infections in humans. The most well-known in A. baumannii is the multifunctional virulence factor, OmpA. In addition to adhesion and biofilm formation, OmpA contributes to invasion of epithelial cell, induction of cell apoptosis, and serum resistance (36, 37, 64, 98).  Like other Gram-negative bacilli, lipid A of lipopolysaccharide (LPS) from A. baumannii readily induces inflammatory response via Toll-like receptor 4; intriguingly, A. baumannii mutants with truncated polysaccharide residual had attenuated virulence, indicating the role of polysaccharide in the pathogenesis (130).  Outer membrane vesicles are secreted by bacteria and contain OmpA, LPS and periplasmic materials. In addition to delivery of virulence factor into host cells (89), resistance genes could also be transferred to another bacterium by means of outer membrane vesicles (162). Siderophores, low molecular-mass ferric binding compounds, allow A. baumannii to acquire iron under iron-deficient environment (202). Recent studies also described the role of capsular polysaccharide (164), phospholipase D (86), or penicillin-binding proteins (163) in the pathogenicity.

iii) the repertoire of antibiotic resistance mechanisms that can be up-regulated as required (7, 152, 157); and its ability to acquire foreign genetic material through lateral gene transfer to promote its own survival under antibiotic and host selection pressures (2, 173).  Presence of innate resistance mechanisms and acquisition of clusters of foreign genes for resistance (from plasmid, transposon, or integrons) are reasons for the rapid emergence of MDR or extensively drug-resistant A. baumannii worldwide (133, 138, 152, 157).

SUSCEPTIBILITY IN VITRO AND IN VIVO

Single Drug

Infection caused by A. baumannii is often severe and difficult to treat due to high rates of resistance among clinical strains to major antibiotic classes (7, 161, 183, 190).  Successive surveys have shown increasing resistance among clinical isolates, and high proportions of isolates are now insusceptible to clinically achievable concentrations of most commonly used antibacterial agents, including aminopenicillins, ureidopenicillins, broad-spectrum cephalosporins, aminoglycosides, fluoroquinolones, and chloramphenicol. Although sulbactam is bacteriocidal to Acinetobacter spp., its resistance rate is also rising (60, 90).  Carbapenems (especially imipenem and meropenem) were once very effective in vitro; now its resistance rate in clinical isolates ofA. baumannii has increased to more than 50% in Latin America, Europe, Asia, and Australia (60, 65, 90, 106).  These carbapenem-resistant isolates are usually non-susceptible to other conventional antimicrobial agents (41, 57, 154, 157).  The susceptibility to polymyxins or tigecycline now remains acceptable (60, 65, 90, 106). The susceptibility of minocycline is also high; a global surveillance during 2007-2011 showed the susceptibility ranged from 72.5%-91.7% (26).

Combination Drugs

Combination therapy is suggested when the infections are caused by A. baumannii non-susceptible to all conventional drugs. In vitro and in vivo (animal) studies have shown that combinations of drugs can sometimes be synergic and highly bactericidal against clinical isolates of drug-resistant A. baumannii (42, 135, 175).  Such synergic combinations usually include any two or three classes of the following antibiotics; polymixins, rifampin, tigecycline, sulbactam, aminoglycosides or a β-lactam (broad-spectrum cephalosporins, or carbapenems) (42, 93, 113, 120, 122, 148, 158, 165, 193, 204).  However, the existence of multiple diverse mechanisms of resistance in clinical isolates means that each strain must be tested against individual and combined antibiotics, using appropriate in vitro techniques.

ANTIMICROBIAL THERAPY

Drug of Choice

Drugs of choice and dosage recommendations are not based on rigorous clinical trials but based on in vitro susceptibility surveys. The spread and persistence in geographical locations of particular epidemic lineages of A. baumannii means that knowledge of the prevalent local susceptibility pattern is essential when selecting antibiotic therapy for Acinetobacter infection. If susceptible, A. baumannii could be readily treated with conventional antibiotics, including 3rd or 4th generation cephalosporins, carbapenems, or fluoroquinolones. Although aminoglycosides may show moderate activity against A. baumannii in vitro and in vivo, their use is generally described in combination with other classes of antimicrobial agents for the treatment of bacteremia or meningitis (93). Some clinical and experimental supports  the use of tetracyclines for the treatment of A. baumannii infections (93, 160).

It is important to emphasize that clinical isolates of A. baumannii are now frequently MDR, and that some isolates are non-susceptible to all conventional antimicrobial agents (41, 57, 154, 157).  So, full laboratory susceptibility testing is required in order to identify the optimal drug or combination of drugs. In the absence of susceptibility data, a carbapenem had been the empiric drug of choice for treating A. baumannii infection for the past 20 years. However, recent years have seen the emergence and worldwide spread of epidemic lineages with diminished susceptibility to carbapenems. A carbapenem, in combination with another antibiotic class (polymyxins, sulbactam or tigecycline), is probably a better choice for empiric therapy of patients with suspected A. baumannii infections before the identification and susceptibility is available. For the treatment of isolates non-susceptible to all conventional antibiotics, the following agents, either alone or in combination, have been used with some success.

Polymyxins

Polymyxin and colistin (Polymyxin E) compounds are cationic polypeptides that interact with the lipopolysaccharide molecules in the outer cell membranes of Gram-negative bacteria. Colistin itself is available in two forms, colistin sulphate for oral and topical use, and colistin sulphomethate sodium for parenteral use, with the latter being a non-active prodrug that is used for parenteral administration because of its lower toxicity (77).  Intravenous polymyxins, either alone or in combinations have produced favorable clinical responses in patients with various types of infections, including ventilator-associated pneumonia and nosocomial meningitis (93, 96, 152).  Rate of colistin toxicity, particularly nephrotoxicity are generally lower than previously reported (93) but some studies using strict criteria reported rates of acute kidney injury up to 50% (109).  Failure to monitor the renal function, lack of comparative antibiotics, and different criteria for renal injury make results of these studies difficult to assess. One pragmatic approach is to monitor the renal function and adjust the dosages accordingly since this side effect is reversible. The pharmacokinetics/ pharmacodynamics of polymyxins is similar to that of aminoglycosides; one small-scale prospective study showed the efficacy and safety of high dose, extended-interval colistin in critically ill patients (43).  Aerosolized polymyxins can also be administered in combination with other intravenous antibiotics, and several studies have reported clinical effectiveness in patients with nosocomial pneumonia caused by A. baumannii (93, 96, 152).  One prospective studyaccessed the aerosolized colistin and intravenous antibiotics for the treatment of ventilator-associated pneumonia due to MDR Gram-negative bacteria.The bacteriological and clinical response was 83.3% andthe attributable mortality was only 16.7% although the good efficacy may be due to the low severity of disease in these patients (142).  Aerosolized colistin improved the outcome when combined with intravenous colistin or other antibiotics in anecdotal reports (9, 102); however, in a randomized study, addition of intravenous colistin had no discernable benefit (100). 

Of concern is the fact that increasing use of polymyxins to treat A. baumannii infections in critically-ill patients may lead rapidly to the emergence of resistance (99), and heteroresistance of A. baumannii isolates to colistin has also been described (24, 178). Therefore, combination therapy with polymyxins and other antibiotics has been recommended.

Sulbactam

Sulbactam has in-vitro and in-vivo activity against A. baumannii . The presence of ampicillin in the clinical formulation does not contribute to the bacteriocidal activity or synergy. In vitro susceptibilities of A. baumannii to sulbactam vary widely, according to the precise geographical region (120).  There has been no adequate randomized clinical trial with sulbactam. Nevertheless, favorable clinical outcomes have been reported with sulbactam, or a combination of sulbactam and other antibiotics, in patients with various types of nosocomial infections caused by MDR strains of A. baumannii, including ventilator-associated pneumonia, bacteremia and nosocomial meningitis (93, 152).  Current data showed the sulbactam alone or in combination with other antibiotics has similar efficacy in treating drug-resistant A. baumannii compared to other effective antibiotics (19, 38, 42, 91, 199).  Higher dose (>6g/day) has been suggested in critically ill patients (3) and sulbactam of 9 g/day has been used successfully without prominent side effects (19).  However, the antimicrobial activity of sulbactam against A. baumannii isolates has declined significantly, perhaps in response to the increased clinical use of this compound, with sulbactam resistance appearing to be common in certain geographical areas (93, 106).

Tigecycline

Tigecycline was found to have good in vitro activity against carbapenem-resistant A. baumannii isolates. Clinical reports have described the use of tigecycline, often in combination regimens, to treat patients with A. baumannii infections such as skin and soft tissue infections, ventilator-associated pneumonia, and primary or secondary bacteremia (8, 66, 74, 76, 94, 166, 177).  High tissue penetration and  US FDA-approved  indications for intra-abdominal infections and skin and soft tissue infections justify its use in these infections and clinical data generally showed positive results.  The correlation between microbiological and clinical outcomes seems to be rather poor, particularly among patients treated for respiratory tract infection (66, 74, 94).   Controversy exists for its clinical efficacy for ventilator-associated pneumonia (40, 94).  Failure of tigecycline to clear A. baumannii bacteremia has been noted in a few cases, perhaps because of sub-optimal concentrations of tigecycline in blood. High dose tigecycline may be more effective than low-dose regimen by pharmacokinetic/pharmacodynamic data and limited clinical data supports its effectiveness and safety (59).   Tigecycline is not excreted via urine and is not regarded as a suitable choice for the treatment of urinary tract infections (22).  The development of resistance during therapy with tigecycline (74, 94) and superinfection with Pseudomonas aeruginosa had been reported  It therefore seems prudent to avoid the use of tigecycline as monotherapy for the empiric treatment of infections caused by A. baumannii.

Tetracyclines

Minocycline may retain in vitro activity against strains that are resistant to tetracycline or doxycycline (93). Several studies have suggested that >90% of recent A. baumannii isolates have susceptibility to minocycline (4, 59). Due to the apparent in vitro activity and favorable pharmacokinetic profile, anecdotal reports have supported intravenous combinations using minocycline in serious MDR Acinetobacterinfections  (73, 160).  However, comparative studies with a larger number of patients are required to confirm its efficacy.

Combination Therapy

Clinical data are too few to recommend the use of specific combination regimens for the treatment of infections caused by MDR strains of A. baumannii, but various combinations of antimicrobial agents have been used to treat individual patients, albeit with somewhat mixed results (93).   Some in vitro reports have described successful combinations of sulbactam and other antibiotics, such as  tigecycline,  polymyxins, carbapenems,  and rifampicin (42, 113, 120, 148, 158, 165).  In vitro studies have also suggested that colistin in combination with rifampin, minocycline, carbapenems, and/or sulbactam might provide good therapeutic results (93, 113, 122, 179, 193, 204).  Similarly, time-kill assays identified a synergic interaction between tigecycline and levofloxacin, amikacin, imipenem, sulbactam and colistin (148, 158).  In addition to in-vitro studies, combination of carbapenems, sulbactam, tigecycline, or polymixins has been shown to have good clinical response, as previous sections described. A combination of rifampicin and colistin has been used with good results to treat critically-ill patients with pneumonia and bacteraemia caused by A. baumannii resistant to all antibiotics except colistin(12) but a recent multicenter, randomized clinical trial did not observe the benefit (52).

Fosfomycin, an inhibitor of peptidoglycan biosynthesis, although having no activity against A. baumannii, exhibits in vitro synergy with colistin and sulbactam for the treatment of carbapenem-resistant A. baumannii  (165).  Intriguingly, daptomycin and glycopeptides, including vancomycin, teicoplanin, and telavancin, apparently inactive against Gram-negative bacteria, showed in vitro synergy with colistin for the treatment of A. baumannii (81, 150, 194). 

Overall, it seems that combination regimens should strongly be considered by clinicians in severely-ill patients for whom therapeutic options are limited.

Novel Agents

Lycosin-I, an antimicrobial peptide, displays potent in vitro antibacterial activities against MDR A. baumannii (192).   Recently, Arbekacin sulfate, an aminoglycoside discovered in Japan in 1972, has attracted attention for its in vitro activity and synergistic effect with carbapenems (136) and its clinical activity merits further evaluation. Two novel serum-associated antibiotic efflux inhibitors, A. baumannii efflux pump inhibitor 1 (ABEPI1) and ABEPI2, represent promising structural scaffolds for the development of new classes of efflux pump inhibitors that can be used as potent adjunctive therapy for A. baumannii infections (20).

Special Infections

Meningitis

Removal of infected shunt or other CNS devices improved patient outcomes. Intravenous carbapenems with addition of intrathecal aminoglycosides injections has been suggested as a better  regimen, because of greater clinical evidences and better pharmacodynamic profiles (97).   Successful treatment of drug-resistant Acinetobacter meningitis has been frequently reported following the use of intrathecal colistin (polymyxin E) (58, 95).  Theoverall successful rate reached  89% in selected cases. The most common toxicity is meningeal irritation  (around 11%), presented as reversible ventriculitis/meningitis (95).   Intravenous ceftazidime, cefepime, aminoglycosides, tigecycline, or sulbactam has been used with success in limited cases; however, these antibiotics usually cannot attain the pharmacodynamic target under the maximum therapeutic dose (97).  At present, no evidence supports the role of steroid in Acinetobacter meningitis.

VACCINES

There are currently no vaccines for use in humans available against A. baumannii or other members of the genus Acinetobacter.  Many studies have identified promising vaccine candidates in A. baumanniiincluding inactivated whole cells (137), outer membrane vesicles (139), rOmpA (125), surface autotransporter Ata (15), PNAG (71), and biofilm associated protein (61).  Passive immunization with antibodies K1 capsular polysaccharide (164), Ata (15), or PNAG (14) increased in vitro opsonophagocytolysis and therefore reduced tissue bacterial amount.

ADJUNCTIVE THERAPY

Adjunctive therapy in ICU patients includes standard ICU care and infection control measures. The clinical benefits of aerosolized antibiotics mentioned in the previous section are under debated (107).  Selective digestive decontamination has been advocated to prevent translocation of Acinetobacter and other intestinal colonizing flora to other infection sites, but confirmation of the efficacy of this procedure in controlled trials is lacking (75).

PREVENTION

Once endemic in a healthcare unit, A. baumannii is extremely difficult to eradicate. Nevertheless, it is still possible to eradicate these organisms from a unit when an uncompromising approach is taken to infection control. Normal infection control measures are often insufficient to halt the transmission of MDR A. baumannii, and the incorporation of a range of enhanced measures with the commitment of all levels of healthcare personnel has shown some evidence of success (93, 133, 196).  Identification of transmission source, timely feedback of information, cleaning of environment and disinfection of medical equipment, reinforcement of hand hygiene and standard precaution are all required. The patients should be isolated; use of a closed tracheal suction system for all patients receiving mechanical ventilation is advised to prevent contamination. Nevertheless, there are also numerous examples in which it has been necessary to implement ward closures for periods of up to 4 weeks in order to combat A. baumannii outbreaks (25, 47, 48, 85, 105, 128, 134, 155). 

Detailed guidance concerning contact isolation precautions, risk factors for colonisation or infection, antibiotic prescribing policies, patient transfer procedures (internal and external), use of dedicated equipment, screening strategies, and cleaning and decontamination procedures has been made available at:

·                  https://www.gov.uk/government/publications/infection-prevention-and-control-in-care-homes-information-resource-published (United Kingdom)

·             http://www.who.int/csr/bioriskreduction/infection_control/publications/en/ (WHO)

·             http://www.cdc.gov/hicpac/mdro/mdro_toc.html (United States)

To reiterate, the most important source of A. baumannii in a potential outbreak situation is the already colonized or infected patient. If an increase in the number of cases is detected, the isolates should first be identified and typed, the patients involved should be traced and isolated where possible, hygiene and infection control procedures should be re-emphasized and enhanced, antibiotic policies should be reviewed, and the unit should be cleaned thoroughly.

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Tables

Table 1. Validly Described Named Species of Acinetobacter (www.bacterio.cict.fr)

A. baumannii	A. kookii
A. baylyi	A. lwoffii
A. beijerinckii	A. nectaris
A. bereziniae	A. nosocomialis
A. boissieri	A. parvus
A. bouvetii	A. pittii
A. brisouii	A. puyangensis
A. calcoaceticus	A. qingfengensis
A. gerneri	A. radioresistens
A. grimontii	A. rudis
A. guillouiae	A. schindleri
A. gyllenbergii	A. soli
A. harbinensis	A. tandoii
A. haemolyticus	A. tjernbergiae
A. indicus	A. towneri
A. johnsonii	A. ursingii
A. junii	A. venetianus

Table 2. Examples of Potential Environmental Sources of A. baumannii During Hospital Outbreaks

Patients	Hands of staff
Blood pressure cuffs	Parenteral nutrition solution
Gloves	Humidifiers
Respirometers	Lotion dispensers
Rubbish bins	Air supply
Bowls	Hand cream
Bedside charts	Service ducts/dust
Computer keyboards	Cell phones
Ventilators and tubing	Oxygen analysers
Bronchoscopes	Bed frames
Sinks	Jugs
Soap	Plastic screens
Bed linen, pillows and mattresses	Resuscitation bags

What's New

Castaneheira M, et al.  Update on Acinetobacter species: Mechanisms of Antimicrobial Resistance and Contemporary In Vitro Activity of Minocycline and Other Treatment Options. Clin Infect Dis 2014;56 (Suppl 6):S367-S373.

Gabriel M. Ortiz and David Graham:  Acinetobacter in military personnel

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