Acinetobacter baumannii (A. baumannii) is a Gram-negative, strictly aerobic, non-fastidious, non-motile, catalase-positive, oxidase-negative, and non-fermentative coccobacillus. It is widely distributed in nature and environmental sources include: soil, water, vegetables, animals, and insects (1–3). The genus Acinetobacter comprises more than 30 different species. The four most common pathogenic types in humans are: A. baumannii, A. calcoaceticus, Acinetobacter genomic species 3, and Acinetobacter genomic species 13TU. These four species are very closely related and are difficult to be distinguished from each other by phenotypic properties (1–3). In 1911, Willem Beijerinck isolated an organism named Micrococcus calcoaceticus from soil after enrichment in a calcium-acetate-containing medium. The genus designation was initially proposed by Brisou and Prevot in 1954 then by Bauman et al in 1968. In the year 1974, the genus was finally listed in Bergey’s manual of clinical bacteriology and a single species, A. calcoaceticus, was described (1, 2).

Sources of A. baumannii infections include: skin and mucous membranes, burns and wounds, intravascular and urinary catheters, as well as gastrointestinal, urinary, and respiratory tracts. However, at times no source of infection or bacteremia can be identified (1, 3). Hospital sources of infection include: sinks, tables, mattresses, pillows, shower units, infusion pumps in addition to suction and resuscitation equipment (4).

The bacterium harbors a number of effective virulence factors that include: (1) attachment to and persistence on solid and dry surfaces, (2) ability to obtain nutrients such as iron, (3) adhesion and subsequent destruction of epithelial cells, (4) ability of some strains to produce gelatinases and proteinases that damage host tissues, (5) ability to colonize the skin of patients as well as health individuals without causing illness, and (6) ability to form biofilms that play an important role in the process of colonization (2).

Acinetobacter baumannii causes colonization, various infectious complications, and even epidemics. Community-acquired infections are less common than health care-associated infections (HCAIs) (2–4). There are several risk factors for A. baumannii infections and these are included in Table 1 (2–4).

The clinical manifestations of A. baumannii infections are very variable and include: non-specific features; soft tissue, skin, and wound infections; urinary tract infections; gastrointestinal tract (GIT) infections; respiratory tract infections including community-acquired and hospital-acquired or ventilator-associated pneumonia; infection of urinary or central venous catheters (CVCs); eye infections including keratitis and endophthalmitis; osteomyelitis; meningitis; endocarditis; and primary bacteremia where no source of infection is found (1–3, 5, 6). Infections caused by A. baumannii can be complicated by: extensive soft tissue necrosis, bloodstream infections, septic shock, acute respiratory distress syndrome (ARDS), disseminated intravascular coagulation (DIC), systemic or disseminated infection, multi-organ failure, and death (1, 3).

A variety of tools are used in the diagnosis of A. baumannii infections. Swabs, septic screens, and surveillance cultures should be taken from various sites. Blood cultures should be taken peripherally and centrally in patients having indwelling intravascular catheters. Susceptibility studies and minimal inhibitory concentrations (MICs) should be performed on positive cultures. Molecular methods such as polymerase chain reaction (PCR) are very productive diagnostically. Radiological tools such as chest x-rays and computed tomography (CT) scans of chest, abdomen, and pelvis are helpful in determining the site of infection (5). A recent systematic review and meta-analysis on the impact of antibiotic MIC on infection outcome in patients having susceptible Gram-negative bacilli (GNB) revealed that there is an association between high MIC values within the currently accepted susceptible range and adverse outcome of infections caused by Gram-negative organisms. Therefore, not only susceptibility data but also MIC values are required to efficiently control infections caused by GNB (7).

Treatment of A. baumannii infections includes the following: (1) removal of vascular and urinary catheters, (2) surgical treatment such as drainage of abscesses and debridement of wounds, (3) use of appropriate antimicrobial agents, (4) growth factors in neutropenic patients, (5) ICU admission and mechanical ventilation may be required, and (6) transfusion of blood products in cytopenic patients (3). The drug of choice for treatment of A. baumannii infections is not yet established, so prospective and randomized controlled are needed (1, 3, 6, 8, 9). The most effective drugs in treating A. baumannii infections are: carbapenems such as imipenem and meropenem, β-lactam inhibitors such as ampicillin–sulbactam in addition to piperacillin–tazobactam and cephalosporins such as ceftazidime (1, 3, 6, 8, 9). For community-acquired A. baumannii (CAAB) infections, the following antibiotics have been reported to be effective: cephalosporins such as ceftazidime, cefepime and cefpirome; carbapenems; aminoglycosides; and fluoroquinolones (3).

New treatment options for A. baumannii infections include: (1) polypeptide antibiotics such as colistin, polymyxin B, and polymyxin E, (2) minocycline derivatives such as tigecycline, (3) new carbapenems such as doripenem, and (4) new generation cephalosporins such as ceftobiprole and ceftaroline (1, 3, 6, 8, 9). New experimental trials are needed to evaluate the activity and safety of peptides and other novel antimicrobial agents for A. baumannii infections (1, 3, 6, 8, 9). Treatment of complicated infections in severely ill and septic patients having A. baumannii is usually in the form of combination therapies that include: piperacillin–tazobactam and amikacin, piperacillin–tazobactam and colistin, or colistin and rifampicin (10).

Tigecycline is a first-in-class extended-broad-spectrum glycylcycline that has activity against many Gram-positive and Gram-negative organisms (11, 12). It overcomes the two key tetracycline resistance mechanisms, efflux pump, and ribosomal protection, and is unaffected by other bacterial mechanisms of resistance such as extended-spectrum β-lactamases (ESBL). Unfortunately, the use of tigecycline monotherapy has been associated with increased mortality, adverse effects, and emergence of drug resistant isolates (11, 12). However, tigecycline is still reserved as a last-resort drug in the treatment of severe and complicated infections caused by A. baumannii (12, 13). Data regarding the clinical use of tigecycline in the treatment of Acinetobacter species are scarce and are confounded by the use of the drug in combination regimens. Also, the potential development of resistance to tigecycline during the course of therapy is of a concern (14). Although tigecycline has shown considerable, though not consistent, antimicrobial activity against multidrug resistant (MDR, including carbapenem resistant) Acinetobacter species, the ultimate role of tigecycline in the treatment of MDR Acinetobacter species remains undefined (13–15). Therefore, well designed studies on the clinical use of tigecycline in the treatment of infections caused by MDR Acinetobacter species are warranted (14).

Polymyxins such as colistin can be also used as last-resort drugs in severe infections caused by A. baumannii (16). However, studies have shown that colistin monotherapy is unable to prevent resistance and does not influence the 30-day mortality in patients with MDR A. baumannii (MDRAB) bloodstream infections (17, 18). Therefore, combination therapy such as colistin and rifampicin or colistin and carbapenem may be the best antimicrobial strategy against colistin resistant A. baumannii infections (17).

Decreasing the incidence of A. baumannii infections can be achieved by applying the following preventive measures: (1) strict infection control and contact precaution policies, (2) appropriate use of invasive procedures, and (3) appropriate utilization of antimicrobial agents (2, 3, 5, 8). Spread of MDRAB can be limited by: (1) enforcement of aggressive infection control measures, (2) development of innovative control strategies, (3) education of staff, patients, and visitors, (4) hand washing and use of antiseptics, (5) surveillance cultures from patients, staff, and environment, and (6) cleaning and disinfection of hospital equipment (2, 3, 5, 8). Eradication of Acinetobacter species requires adherence to good infection control practices, prudent antibiotic utilization, and effective antimicrobial therapy (2, 3, 5, 8).

The prognosis of A. baumannii infections varies considerably. Good prognostic factors include: local infection or trauma, absence of MDR strains, medical conditions other than malignancy or burns, and prompt as well as efficient antibiotic therapy (3). Poor prognosis is associated with: age >65 years, underlying medical condition being malignancy or burns, presence of virulent or MDR strain, late or inappropriate antimicrobial therapy, DIC or coagulopathy, bacteremia or septic shock, mechanical ventilation, and rapidly progressive or ultimately fatal illness (3). In patients having A. baumannii infections, high mortality rates are associated with: pneumonia, bacteremia, and inappropriate medical treatment. The ultimate outcome of A. baumannii infections correlates well with: the type of underlying medical illness, presence or absence of polymicrobial bacteremia, and appropriate or inappropriate antimicrobial therapy (3).

Acinetobacter baumannii is characterized by frequent MDR due to multiple mechanisms. Isolates of A. baumannii have shown high levels of antimicrobial resistance, particularly to β-lactam agents (3, 19). Antimicrobial resistance among Acinetobacter species has substantially increased in the last decade. In a European survey, resistance of A. baumannii rated number 5 among the evolving bacterial resistance to antimicrobial therapy (3, 19). The patterns of antimicrobial resistance exhibited by A. baumannii isolates vary among distinct geographical regions, especially for nosocomial isolates. Approximately 11% of nosocomial isolates of A. baumannii are resistant to carbapenems (20).

With the advent of whole-genome sequencing, important gains in the insights of genetic complexity of A. baumannii have been obtained (1). Its wide array of drug resistance determinants and its ability to effectively regulate these according to selective environmental pressures clearly demand respect. The global epidemiology of A. baumannii is of a concern for widespread dissemination, most often in a clonal manner within institutions, cities, and sometimes between countries (1). In patients with bacteremia caused by A. baumannii, complex genotype 2 is associated with greater resistance and higher mortality compared to other genospecies, particularly genospecies 13 TU. In critically ill patients with A. baumannii bacteremia, genospecies 2 is significantly associated with pneumonia while genotype 13 TU is associated with primary bacteremia (21).

Acinetobacter baumannii has various mechanisms of resistance for different classes of antimicrobials. Examples of mechanisms of drug resistance to various classes of antibiotics are shown in Table 2 (1, 22–27). MDR determinants as well as genetic determinants of drug resistance for A. baumannii are shown in Table 3 (22, 24–27).

Acinetobacter species possess a wide array of β-lactamases that hydrolyze and confer resistance to penicillins, cephalosporins, and carbapenems (3). MDR is defined as non-susceptibility to at least three antimicrobials; such as ampicillin–sulbactam, piperacillin–tazobactam, ceftazidime, imipenem, meropenem, aminoglycosides, ciprofloxacin, aztreonam, and trimethoprim–sulfamethoxazole; which are routinely tested in the clinical laboratory and to which A. baumannii would have been expected to be susceptible (22, 28, 29). Risk factors for evolution of MDRAB infections include: (1) previous use of carbapenems and third generation cephalosporins, (2) recent insertion of a CVC, (3) endotracheal intubation and mechanical ventilation, (4) recovery of A. baumannii from various sites, and (5) bacteremia caused by other microorganisms (3, 28, 29). MDRAB infections carry a high crude mortality rate and have a great impact on health care settings as they are most frequently encountered in severely ill patients (3). Several outbreaks of MDRAB have been reported in USA. The Infectious Diseases Society of America has recently identified A. baumannii as one of the six particularly problematic pathogens in terms of antimicrobial susceptibility issues arising from resistance (22). Sequence type 92 (ST92) and the associated clonal complex 92 represent the most sampled and widespread sequence types and are known as European clone 2 and worldwide clonal lineage 2. Three clonal complexes were initially described in Europe then documented in North America, Asia, Africa, and Australia (30). The coexistence of several resistance determinants may also present a significant threat (24).

The potentially effective antimicrobial agents against MDRAB infections include: carbapenems; aminoglycosides such as gentamicin and amikacin; tetracyclines such as doxycycline and minocycline; sulbactam; colistin; and tigecyclines. However, drug combinations are preferable and, in particular, the combination of carbapenems and colistin is becoming the treatment of choice (3, 6, 22). Therapeutic options for MDRAB infections are limited and there are no controlled trials to guide the therapeutic choice. Therefore, well designed clinical studies are necessary to guide clinicians on decisions regarding the best therapeutic option for patients with MDRAB infections (3, 6, 22).

Ciclopirox, a topical antifungal agent that was developed 40 years ago, has multiple potential uses including treatment of human immunodeficiency virus (HIV), enhancement of wound healing in diabetics, and potential use in the treatment of multiple myeloma. It has been found to be effective in the treatment of MDRAB infections (31). Recently, a number of studies have focused on non-antibiotic approaches that utilize novel mechanisms of action to achieve antibacterial activity against MDR bacteria (32). Modern advances in phage therapy, iron chelation treatment, antimicrobial peptides, prophylactic vaccination, photodynamic therapy, and nitric oxide-based treatments have also shown promising activity against MDRAB (32). The siderophore sulbactam [BAL 30072] has shown promising in vitro activity against MDRAB isolates harboring AmpC and OXA β-lactamases (33).

The emergence of carbapenem-resistant A. baumannii (CRAB) was first reported in USA in 1991 (34). CRAB has been linked to point multations in porin channels from the outer membrance. These point mutations alter bacterial targets of functions thus decreasing the affinity for antimicrobial agents or upregulating cellular functions by producing efflux pumps or other proteins (3). Spread of CRAB in Asia has been linked to global clone 2 (GC2) and Aba R-4 type resistance islands (35, 36). CRAB has also been attributed to the expression of β-lactamases; such as OXA-23, OXA-24/40, and OXA-58; which inactivate carbapenems (37). Outbreaks of CRAB infections in hospital settings illustrate the important role of post-acute care facilities in dissemination of MDR bacterial pathogens (37).

Although imipenem is the most active agent against A. baumannii, resistance to imipenem is becoming increasingly common and hospital outbreaks of imipenem resistant MDRAB (IR-MDRAB) have been increasingly reported since the early 1990s. Risk factors for the development of IR-MDRAB infection include: previous ICU admission, exposure to third generation cephalosporins, and use of carbapenems (3). The time at risk, the period of time at risk for appearance of IR-MDRAB, is a very important confounding factor to be adjusted because the probability of appearance increases with the length of time (3). The best therapeutic approach for CRAB infection is to use colistin in combination with tigecycline or cefoperazone–sulbactam or piperacillin–tazobactam (38).

Pandrug resistant A. baumannii (PDRAB) has emerged as an important cause of both endemic HCAIs as well as epidemic outbreaks (39). PDRAB infections are associated with high morbidity and mortality. In addition, their treatment has high costs due to the utilization of ICU facilities and potent antimicrobial therapies (39). Isolates of PDRAB were first reported in 1998 in Taiwan (34). PDRAB strains are usually resistant to all antibiotics that are routinely used including: ampicillin–sulbactam; ceftazidime and cefepime; piperacillin–tazobactam; aztreonam; fluoroquinolones including ciprofloxacin, travofloxacin, and moxifloxacin; garenoxacin as well as amikacin and carbapenems including imipenem and meropenem (34, 40–42). The increased utilization of carbapenems and fluoroquinolones as well as clonal dissemination may explain the recent spread of PDRAB strains (40–42).

The British Society of Antimicrobial Chemotherapy has provided criteria to designate MICs for tigecycline-susceptible-and-resistant A. baumannii isolates as ≤1 and >2 μg/ml, respectively. Implementation of these breakpoints would limit the use of tigecycline to salvage therapy for certain infections caused by PDRAB (16). Novel therapies for PDRAB or extensively drug resistant A. baumannii (XDRAB) infections include: (1) drug combinations containing colistin or polymyxin B, which are composed of two or three drugs including imipenem, rifampicin, amikacin, or ampicillin–sulbactam in addition to colistin or polymyxin B and (2) drug combinations that are composed of tigecycline in addition to two other drugs including: imipenem, amikacin, and cefepime (43, 44). Aggressive early treatment of PDRAB with adequate doses of drugs in combinations such as carbapenem–sulbactam may prevent the emergence of PDRAB strains (45). A multifaceted approach or intervention that includes active surveillance, environmental cleaning, and appropriate utilization of antimicrobials appears to be efficient and cost–effective in the management of PDRAB infections (39).

Acinetobacter baumannii bacteremia may be primary, where no cause is found, or secondary to infections involving wounds, respiratory, and urinary tracts in addition to other sites of infection (1, 3). A. baumannii bloodstream infections are more common in ICU settings than in general hospital wards and are more frequent in hospitals than in the community. They usually develop at a mean of 26 days from the time of hospital admission (1). In a large study of nosocomial blood stream infections in the USA (1995–2002), A. baumannii ranked the 10th most common etiological agent being responsible for 1.3% of all monomicrobial bloodstream HCAIs (1). However, only 62% of A. baumannii bacteremias in hospitalized patients are considered clinically significant. Therefore, it is essential to perform thorough clinical evaluation of patients to eliminate the possibility of pseudobacteremia (3). Additionally, approximately 30% of patients with A. baumannii bacteremia have polymicrobial bacteremia or other infections (3).

There are several risk factors for the development of A. baumannii bacteremia and these are shown in Table 4 (3, 29, 46). The risk factors for mortality related to A. baumannii bacteremia are variable and they include: (1) advanced age, (2) recent surgery,(3) immunosuppressive status, (4) invasive procedures such as CVC, urinary catheterization, pulmonary catheterization, mechanical ventilation, and nasogastric tubes, (5) presence of complications such as septic shock, DIC, acute renal failure, and acute respiratory failure, (6) use of inappropriate antibiotic therapy, (7) genotype 2, (8) low platelet count, (9) low serum albumin concentration, (10) the number of comorbid medical conditions, and (11) high acute physiology and chronic health (APACHE) Π and Hilf’s severity scores on admission to ICU (21, 47–50).

In patients with A. baumannii bacteremia, the overall mortality rate ranges between 25 and 54% and mortality depends on a number of factors that include general clinical condition of the patient, whether the patient is managed in general wards or in ICU and whether the organism is susceptible or resistant to antimicrobial therapy (1, 3, 48, 49, 51, 52). Studies have shown that crude mortality rate ranges between 5 and 16.3% outside ICU while in ICU, it ranges from 34 to 70% and may even reach 91.7% in case the organism is MDR. However, in critically ill patients, attributable mortality to A. baumannii bacteremia ranges between 7.8 and 19% (1, 3, 48, 49, 51, 52).

Risk factors for MDRAB bacteremia include: prior ICU admission and prior use of broad-spectrum antibiotics, particularly carbapenems, β-lactams, and inhibitors of β-lactamases. Independent risk factors for mortality in patients having MDRAB bacteremia include high APACHE Π score and presence of secondary rather than primary bacteremia (52). Septic shock has been reported in 42% of patients having A. baumannii bloodstream infections. Complicated clinical course and life-threatening complications are more likely to evolve in immunocompromised individuals (3). In patients with A. baumannii bacteremia, good prognosis is associated with infections related to CVCs where survival may reach 96.2% while poor outcome is associated with inappropriate utilization of antimicrobial therapy and presence of respiratory tract infections where mortality rate may reach 39.2% (48, 50). Sources of A. baumannii bacteremia in ICU settings include primary bacteremia, respiratory tract, wounds, and intravascular catheters (47). Risk factors for A. baumannii in ICU patients include invasive procedures, use of broad-spectrum antimicrobials, and the critical condition of the patient i.e., immunosuppression and comorbid medical conditions. In ICU patients, A. baumannii bacteremia carries a high mortality rate and although imipenem is active against A. baumannii infections, the increasing resistance to carbapenems, particularly in ICU setting, is alarming (47).

Sequential organ failure assessment (SOFA) and APACHE scores determined at the onset of A. baumannii bacteremia are reliable risk stratification tools that predict 14-day and in-hospital mortality (3). The invasive procedure index, the number of invasive procedures performed everyday during the ICU stay before the onset of A. baumannii bacteremia divided by the number of days spent in the ICU before the onset of A. baumannii bacteremia, is also important in determining the outcome of patients having bacteremia (46). Early identification of patients at high risk of mortality based on a variety of risk factors is important. Consequently, treatment strategies should be based on risk stratification of patients having A. baumannii bacteremia (50).

The treatment of choice for A. baumannii bacteremia is not yet established. In patients having infected CVCs, removal of these catheters is indicated (48). Concerns have been raised about the use of tigecycline is treating A. baumannii bloodstream infections thus leaving colistin as the only therapeutic option for some of these infections (1).

In recipients of HSCT, the risk factors for the development of A. baumannii bacteremia include: (1) severe underlying illness such as hematologic malignancy, (2) immunosuppressive therapies such as corticosteroids and cyclosporine-A, (3) graft versus host disease (GVHD), (4) colonization of respiratory, gastrointestinal, and urinary tracts, (5) prolonged use of broad-spectrum antibiotics, and (6) invasive instrumentation such as CVCs and endotracheal intubation (3, 53). In a single center retrospective study that included 483 HSCT recipients and performed over 6 years, 19 patients developed MDRAB bacteremia after engraftment, pneumonia was the origin of bacteremia in all patients and 95% of patients with bacteremia and 8.3% of patients without bacteremia died. The risk factors for the development of MDRAB bacteremia in HSCT recipients were history of care in ICU after HSCT and the time duration between admission to hospital and HSCT (53).