Acinetobacter baumannii: Epidemiology, Clinical Manifestations and Associated Infections

Abstract

Acinetobacter baumannii is a Gram-negative, non-flagellated bacterium belonging to the coccobacillus family that is readily found in the environment. It has rapidly evolved, from an apparently innocuous organism to an opportunistic pathogen causing infections in both the hospital and the community. A. baumannii has attained the status of a superbug being resistant to many, including the last-resort antimicrobial agents, such as carbapenems, colistin and tigecycline. The Centers for Disease Control and Prevention (CDC) has classified A. baumannii as an immediate threat to public health, while the World Health Organization (WHO) is calling for research and development of critically needed antibiotics to treat these infections. It has earned a place as one of the most problematic nosocomial ‘ESKAPE’ pathogens causing the WHO to designate it as first on the list of pathogens for which new antibiotics are urgently and critically needed. A. baumannii has several mechanisms with which it is able to develop resistance to different antibiotics. It persists in hospital environments due to its ability to form biofilms and resist drying and disinfection. There is genetic diversity among the isolates of A. baumannii, thus making the study of this organism even more complex and underscoring the importance of sustained surveillance and good antibiotic stewardship to safeguard the publics’ health.

1. Introduction

It was the Dutch microbiologist Martinus Willem Beijerinck who in 1911 began the story of the genus Acinetobacter. Using medium enriched with calcium acetate, he had isolated a new organism from soil and named it Micrococcus calcoaceticus [1]. He named the organism but without a proper description of it, his report was largely disregarded and the name he proposed poorly accepted [2]. Over time, the same organism was described by other researchers under different names, some of which are listed as follows: Micrococcus calcoaceticus, Moraxella lwoffi, Achromobacter mucosus, Alcaligenes haemolysans, Diplococcus mucosus and Neisseria winogradskyi [1].

Brisou and Prevot coined the name Acinetobacter in 1954 to denote non-motile microorganisms in an attempt to differentiate between motile and non-motile members in the genus Achromobacter [3]. Paul Baumann and co-workers in 1968 did a comprehensive survey and proposed that the species listed above were of a single genus with similar phenotypic properties and hence did not need to be further divided and then proposed the name Acinetobacter [2, 4]. The genus Acinetobacter became officially accepted in 1971 following the work done by the subcommittee on the naming of Moraxella and related bacteria [4]. In 1974, Bergey’s Manual of Systematic Bacteriology listed the genus Acinetobacter and further described it as a single species known as Acinetobacter calcoaceticus.

The Acinetobacter are Gram-negative, non-motile and non-fermenting strict aerobes. They are catalase-positive, oxidase-negative and non-fastidious bacteria whose DNA Guanine + Cytosine content ranges between 39 and 47% [1]. The genus Acinetobacter belongs to the Moraxellaceae family, Pseudomonadales order and is of the Gammaproteobacteria class of bacteria. Currently, about 74 species of Acinetobacter have been validated [5, 6]. A. baumannii is a highly ubiquitous and opportunistic coccobacillus with an extensive environmental spread. It has reservoirs in almost every environmental niche [5]. Although A. baumannii can be found in diverse milieus, such as soil, water, crude oil, sewage, inanimate objects and surfaces, skin and soft tissues, meat and dairy products and vegetables, among others, it thrives mostly in hospital environments [7]. Notwithstanding that the whole genome of A. baumannii had been sequenced in 2007 by Smith and co-workers (strain ATCC 17978) [8], its routine laboratory identification remains challenging because of the phylogenetic relatedness of the bacterium to many other species of the genus Acinetobacter known collectively as the A. baumannii-calcoaceticus (ABC) complex [1, 5, 7].

The species that originally constituted the Acinetobacter baumannii-calcoaceticus complex (previously called genomic species) are namely: Acinetobacter baumannii, Acinetobacter pittii (previously called genomic species 3), Acinetobacter nosocomialis (genomic species 13TU), Acinetobacter seifertii, Acinetobacter lactucae (also called A. dijkshoorniae) and Acinetobacter calcoaceticus. These species of Acinetobacter all belonged to the ABC complex [9]. These species are very difficult to distinguish phenotypically and share a very close genetic relatedness that makes molecular methods necessary for their identification [10]. Besides A. calcoaceticus whose pathogenicity is still somewhat unclear, other members of the ABC complex are established human pathogens. A. baumannii is the pathogen most frequently implicated in healthcare-associated infections (HAIs), with A. pittii and A. nosocomialis following closely [11].

Although A. baumannii was initially reasonably susceptible and responded well to antibiotic monotherapy, the bacterium has steadily demonstrated increasing rate of antibiotic resistance over the years [12]. This problem of increasing multidrug resistance (MDR) led the Infectious Disease Society of America (IDSA) to designate a group of bacteria consisting of Enterococcus faecium, Staphylococcus aureus, Klebsiella pneumoniae, A. baumannii, Pseudomonas aeruginosa and Enterobacter spp. as ‘the ESKAPE pathogens’ as a result of their ability to evade killing by antibiotics [13]. A. baumannii has become a superbug having developed resistance to virtually all known antibiotics in clinical use such as the fluoroquinolones, aminoglycosides and even the last-resort broad-spectrum carbapenems [13]. Multidrug-resistant A. baumannii (MDRAB) has attained a global epidemiology and is being encountered in hospital environments across the globe. Carbapenem-resistant A. baumannii (CRAB) had posed such a great burden on the healthcare system [13] that the World Health Organization (WHO) in 2017 listed it as a critical priority bacterium requiring the urgent development of new antibiotics [11]. Clinical outbreaks of A. baumannii infection have occurred in virtually every region of the world, with rates ranging between 1 and 30% with a greater burden on Eastern Europe [11].

The Middle East region has suffered a considerable number of outbreaks of MDRAB, for which it earned the “Iraqibacter” title [14]. These outbreaks of the bacterium were encountered during the Iraq war among US military hospitals in Iraq, Afghanistan and Kuwait [14]. In spite of extensive and continuing researches conducted to understand the antibiotic resistance mechanism of the bacterium, a clear and comprehensive understanding of the pathology, epidemiology and MDR mechanism of A. baumannii remains elusive. Added to these concerns are the very limited options available for the treatment of MDRAB infections. Until recently, Colistin was the only antibiotic still exhibiting therapeutic efficacy on strains of MDRAB, thus making its treatment very difficult with very limited therapeutic options [11]. Unfortunately, there have been reports on the emergence and continued rise of colistin-resistant A. baumannii in recent years [15, 16, 17], bringing to the fore the critical and urgent need for new antimicrobials, alternative treatment strategies, stricter infection prevention and control, and institution of rational antibiotic stewardship programmes. This chapter focuses majorly on the discussion of the current epidemiology of A. baumannii, its clinical manifestations and associated infections.

2. Species identification

Acinetobacter baumannii can be identified by cultural growth characteristics, biochemical characterization and molecular methods. They are classified as aerobic, Gram-negative, oxidase-negative, catalase-positive, indole-negative, urease-negative, haemolysis-negative, non-motile and non-lactose fermenting rods. Although it lacks flagella, A. baumannii can move along wet surfaces in an intermittent and jerky manner called twitching motility. It is non-fastidious and is easily grown in the laboratory on solid media such as sheep blood agar at an optimum temperature of 37°C. Growth can also occur at temperatures as high as 44°C. On blood agar, the colonies are about 1–2 mm in diameter and appear whitish, smooth or mucoid when the capsule is present. When grown on MacConkey agar, the colonies are light lavender in color, indicating non-lactose fermenting [18]. Some molecular methods that have been used for the identification of A. baumannii include restriction analysis and sequence analysis of the 16 s ribosomal RNA (rRNA) gene, ribotyping and transfer RNA (tRNA) spacer fingerprinting [19, 20, 21, 22, 23].

3. Epidemiology of Acinetobacter baumannii

Acinetobacter infections have a broad and global epidemiology. They have been implicated in outbreaks in both healthcare facilities and in the community; in temperate and tropical climates as well as in conflict and disaster situations [24, 25, 26]. Besides water and soil that constitute their natural milieu, they may also be found in pets, insects and other edible animals.

Common sites colonized in humans include the skin and soft tissues, blood, urinary, respiratory and digestive tract, wounds and the central nervous system [1]. The organism is also capable of surviving in biofilms from where it can migrate to the lower respiratory tract and trigger a pneumonia infection [27]. It is a common pathogen in the intensive care units (ICUs) and is associated with hospital-acquired pneumonia (HAP) and ventilator-acquired pneumonia (VAP) in patients with prolonged hospital stay. Tubing and other equipment involved in artificial ventilation can serve as a source of A. baumannii infection and result in lower respiratory tract infection. They are also responsible for other hospital-acquired infections (HAIs), such as wound infections, pressure ulcers, burn infections, septicaemia, urinary tract infections (UTIs), secondary meningitis and infective endocarditis [28]. A. baumannii is associated with skin and soft tissue infections and has been reported in traumatic injuries and postsurgical wounds.

Among members of the ABC complex, Acinetobacter baumannii has emerged as the best recognized and very important pathogen responsible for healthcare-associated infections as a result of its ability to survive under harsh environmental conditions. Its capacity to tolerate drying and thrive in the presence of minimal nutritional conditions confers on it a significant ability to acquire different mechanisms, which it uses to acquire resistance to various antimicrobial agents and to enhance its transmission in the healthcare setting [29, 30]. Complications arise leading to difficulty in treatment when burns get infected with A. baumannii. In some cases, a systemic infection can arise when the bacteria enter the bloodstream, leading to septicaemia. Prolonged use of catheters and antibiotic therapy have also been linked to A. baumannii infections. Although carbapenems, one of the broad-spectrum β-lactams with very high in vitro activity, used to be a preferred choice for treating infections due to A. baumannii, their clinical efficacy has suffered serious decline over time due to increasing resistance of the organism [31]. The organism had earlier developed resistance to many classes of antibiotics, such as β-lactam antibiotics, cephalosporins, aminoglycosides and fluoroquinolones. Only very few drugs, such as polymyxin B, colistin and tigecycline, are currently effective for MDRAB [32]. These drugs are expensive and are not readily available in resource-limited countries. Due to the high demand for colistin in the treatment of CRAB infections, colistin resistance has also been reported worldwide [33]. Resistance to polymyxin B and tigecycline has also been reported [34, 35].

Rates of carbapenem resistance differ according to geographic regions. The SENTRY Antimicrobial Surveillance Program observed that among Acinetobacter isolates collected between 2013 and 2016, susceptibility to meropenem was the lowest in Latin America (13.7%). This was followed by the Asia-Pacific region, Europe and the United States of America with 21.0, 22.2 and 54.9%, respectively [36]. In another study by Seifert and co-workers between 2016 and 2018, among Acinetobacter isolates collected, susceptibility to meropenem was the lowest for Africa and the Middle East (17.2%), closely followed by Latin America (19.6%). The susceptibility rates for Asia-South Pacific, Europe and North America were 31.4, 33.8 and 63.6%, respectively [37]. The WHO and the European Centre for Disease Prevention and Control (ECDC) in their latest report showed that year 2020 witnessed a wide variation in the percentages of carbapenem-resistant Acinetobacter spp. across Europe. Out of 38 countries and areas presenting data, less than 1% occurrence rate was seen in three countries, while the occurrence rate was 50% or greater in 35 others. Ireland, the Netherlands and Norway were the countries with the lowest rates, while in 21 countries, particularly in Southern and Eastern Europe, carbapenem resistance rates were as high as 50% or greater [31]. By means of molecular typing of A. baumannii isolates, the dissemination of three lineages of the organism in Europe was established and classified as European clones I, II and III [38]. These were later renamed international clones I, II and III (IC1, IC2 and IC3) in recognition of the fact that these lineages had already been disseminated globally [39, 40]. Nine international clones are presently recognized [41]. Two multilocus sequence type (MLST) schemes, known as Oxford and Pasteur, have also been used to characterize A. baumannii [31]. IC1 and IC2 are the most widely spread clones globally and often express the acquired carbapenemase oxacillin-hydrolysing (OXA)-23 [25, 26]. Regional variations do occur, with international clone V (IC5) and international clone VII (IC7) being more prevalent in Central and South America while international clone IX (IC9) is more prevalent in Africa and the Middle East [38, 41].

A higher CRAB colonization or infection was also observed in COVID-19 intensive care unit (ICU) in two studies in Italy. Another Italian study of 16 ICUs in the Piedmont area during the COVID-19 outbreak showed that 19% of COVID-19 infected patients became colonized or were infected by CRAB during their ICU stay, leading to a 67% mortality rate [42]. The United States of America, Argentina, Europe, Brazil, Japan, China, Hong Kong, Taiwan, Korea, Middle East, Nigeria and other African countries are areas where several epidemiological studies have documented the occurrence of infections due to A. baumannii [43, 44]. Some tropical regions of the world have experienced community-acquired pneumonia, particularly during warm and humid months [45]. An increase in the number of MDRAB was witnessed among the United Kingdom (UK) and US military personnel injured while on deployment to Iraq and Afghanistan [46].

The Middle East has also had its fair share of A. baumannii infection. MDRAB has been severally documented in hospitals in the United Arab Emirates (UAE), Bahrain, Saudi Arabia, Palestine and Lebanon and Egypt [47, 48]. In a retrospective study conducted to evaluate the prevalence of MDRAB responsible for infections in patients admitted at the ICU of the Riyadh Military Hospital, Saudi Arabia, A. baumannii was the most common bacterium isolated, representing 40.9% of the samples [39].

In Nigeria and other resource-limited countries in Africa, there is paucity of information regarding the molecular epidemiology and antimicrobial resistance status of A. baumannii, mainly due to lack of capacity for the isolation, identification and testing of antimicrobial susceptibility of these organisms. Nonetheless, a number of studies have been done to establish the molecular characteristics of A. baumannii isolates in Nigeria. In one such study conducted in Southwest Nigeria, the genetic diversity and molecular mechanisms of CRAB isolated from hospitals were characterized. All A. baumannii isolates submitted to the antimicrobial resistance surveillance reference laboratory in Nigeria between 2016 and 2020 had their genomes sequenced [49]. Eighty-six (86) A. baumannii isolates recorded belonged to 35 different Oxford sequence types (Oxf STs) and 28 Institute Pasteur STs (pas STs). Sixteen of the 35 distinct Oxford sequence types were novel. Thirty-eight of the isolates did not belong to any previously known international clone and more than half of the isolates expressed phenotypic resistance to 10 of the 12 tested antimicrobial agents. Fifty-four of the isolates were resistant to carbapenem, especially the IC7 and IC9 strains. In summary, the study recorded an increase in blaNDM-1 prevalence with widespread transposon-mediated dissemination of carbapenemase genes in different A. baumannii lineages in Nigeria’s Southwest region. Other studies in the same region also found MDRAB with widespread carbapenemase resistance [49, 50, 51].

Some strains of the genus Acinetobacter have developed mechanisms that enable them to survive for long periods under harsh environmental conditions. This ability to withstand adverse conditions promotes their transmission in healthcare settings through contaminated fomites [52, 53].

3.1 Climatic conditions

Originally, Acinetobacter was more prevalent in tropical environment and was recorded as causing 17% of pneumonias associated with ventilator use in the ICU of a Guatemalan hospital. Only Pseudomonas had a higher prevalence than Acinetobacter in that study with 19% [54]. Over the last 5 decades, members of the genus Acinetobacter have evolved to become frequent nosocomial pathogens of concern even in the temperate regions [55]. This evolution of Acinetobacter from a little known apparently innocuous organism to an opportunistic pathogen credited with causing infections in both the hospital and the community has been linked to their possession of several survival mechanisms and their ability to rapidly develop resistance to most available antibiotics [56]. HAIs due to Acinetobacter have been established to be more prevalent in the tropical weather in summer compared to other seasons [57]. Between 1987 and 1996, the CDC received a report that reviewed 3447 cases of infections involving Acinetobacter. The rates of infection were established to be about 50% more from July to October compared to other seasons of the year. This increase was thought to be probably due to higher humidity of the air and contaminants suspended and transmitted in the air as aerosols. It is worthy of note that the condensate from air-conditioning units has been found to predispose to epidemic Acinetobacter infections [57].

3.2 Disease associations

Acinetobacter attained global prominence as a major cause of nosocomial infections. Patients in intensive care and those with compromised immunity were most vulnerable to Acinetobacter infection. Acinetobacter infections have however not been confined to healthcare settings alone. Cases of community-acquired infections due to Acinetobacter were reported in Australia and Asia. Outbreaks of Acinetobacter infections were also reported among soldiers during the war in Iraq [14].

3.3 Nosocomial infections

Acinetobacter has established itself as a prominent cause of healthcare-associated infections worldwide. The National Healthcare Safety Network (NHSN) in a 2016 report evaluated the prevalence of antimicrobial-resistant pathogens associated with nosocomial infections in the United States of America [58]. Among the frequent Gram-negative isolates, Acinetobacter species accounted for 12.8 and 8.8%, respectively, for VAP infection isolates and central line-associated bloodstream infection isolates, while catheter-associated urinary tract infection isolates and surgical site infection isolates accounted for 1.3% each.

Patients in the ICU, particularly the young and the elderly, and those in long-term care settings are more susceptible to A. baumannii [58]. Other factors that may predispose patients to infections with A. baumannii include recent surgery, catheter use, tracheostomy, artificial ventilation, parenteral nutrition and treatment with broad-spectrum antibiotics like carbapenem, fluoroquinolones and ceftriaxone [59, 60]. For neonates, low birth-weight, parenteral feeding and catheter use may pose added risks [61, 62]. Outbreak investigations are a primary data source for information about healthcare-associated Acinetobacter infections [54].

There have also been Acinetobacter outbreaks traceable to common-source contamination such as air conditioner or contaminated ventilator [57]. Cross-infection by healthcare workers caring for colonized or infected patients who do not maintain proper aseptic techniques including hand washing and touching inanimate objects can also lead to infection outbreak [43, 45, 54]. Introduction of Acinetobacter into a hospital may lead to serial or overlapping outbreaks due to MDR strains often seen at such times. Multiple strains, which may become endemic, are established with a single endemic strain being prevalent subsequently [54]. Protracted colonization may enhance endemicity of A. baumannii following an outbreak. In one study, colonization persisted for up to 42 months and affected 17% of patients [46]. Multicenter outbreaks have been recorded across the globe, in the United States of America, Europe, South America, Africa, Asia and the Middle East [47, 48, 60]. In 2005, there was an outbreak of carbapenemase producing (OXA-40) Acinetobacter in Greater Chicago area. Several hospitals and long-term facilities were affected along with many patients [63].

Several factors can lead to monoclonal outbreaks happening in multiple hospitals. These may be spread between institutions, via movements of patients or personnel, or exposure to common-source contamination of food or equipment. For this reason, the importance of regular epidemiological surveillance as well as infection prevention and control measures to stop the transmission and spread of Acinetobacter in long-term care facilities cannot be overemphasized. There is a paucity of data with respect to the prediction of patients suffering from infections due to Acinetobacter. Although mortality rates may be high among such patients, it cannot be said with certainty that the mortality was due to Acinetobacter infection [64]. For example, the consequence of Acinetobacter infections on mortality was indeterminate in a paired cohort study of patients with trauma [65]. Compared to control patients who had other infections that were not Acinetobacter, a longer stay in the ICU and increased organ failure were observed among cases exposed to Acinetobacter. Resistance to imipenem, compromised immunity as seen in old age and diabetes mellitus, the female gender and septic shock constitute some of the risk factors that cause mortality in those suffering from Acinetobacter infections [52, 53].

3.4 Community-acquired infection

There have been reports of community-acquired Acinetobacter infection in Australia and Asia [26]. In Australia, pneumonia occurring in the community was more prevalent during the rainy season [66]. In northern Australia with tropical climate, A. baumannii was implicated in 10% of cases of severe pneumonia acquired in the community [67]. Infections acquired in the community have been distinguished by pharyngeal presence of the organism, pneumonia that is aggressive and high case fatality rates. Chronic obstructive pulmonary disease, alcoholism, tobacco use, diabetes and cancer are some noted risk factors [66, 67]. Bloodstream infections have also been reported [66, 68].

Between February 2012 and October 2013, Rafei and co-workers in Lebanon conducted a study to evaluate the epidemiology of A. baumannii in the community outside the human body. Using cultural methods, they tested for the presence of A. baumannii in different samples covering the environment, water, food and edible animals. Species were identified using rpoB gene sequencing and antibiotic susceptibility was evaluated.

The A. baumannii isolates were studied using two genotyping approaches, namely multilocus sequence typing (MLST) and bla_OXA-51 sequence-based typing (SBT). Varying amounts of A. baumannii were isolated in all the samples. But for one isolate that expressed a bla_OXA-143 gene, all isolates were phenotypically susceptible to antibiotics tested and harbored no carbapenemase-encoding genes. Using MLST, 36 sequence types (STs) were obtained, with 24 of them being novel STs reported for the first time. The bla_OXA-51 SBT demonstrated the presence of 34 variants; 21 of them were novel and all were of animal origin. Human genotypes such as international clones I and X (IC1 and IC10) were detected in water and animals and the possible involvement of these new animal clones in human disease poses a public health concern. The researchers then concluded that animals could serve as the possible reservoir for A. baumannii and the spread of new emerging carbapenemases to humans [69]. The report of community-acquired infections is rare in the United States of America. Although the reason for the greater prevalence of Acinetobacter infections in certain regions has not been fully elucidated, it does appear to be connected to climatic differences that drive bacterial colonization.

3.5 Conflicts and natural disasters

Acinetobacter infections have been established as a common feature in wars and conflict situations. A rise in infections due to this organism has been reported several times in different conflicts such as in Korea, Vietnam, Iraq and Afghanistan, leading to the suggestion for it to be added as part of differential diagnosis of infections encountered among soldiers in combat and after natural disasters in a tropical region [14, 70]. In a study involving US troops stationed in Iraq and Afghanistan between 2007 and 2008, A. baumannii made up 63% of all bacteria isolated from soldiers’ wounds [70]. In another report, Acinetobacter isolated from military personnel were less susceptible to imipenem than those isolated from individuals not actively engaged in war (63/87%) [70].

The genetic diversity and resurgence of Acinetobacter in personnel exposed to several military operations over many decades appear to suggest the involvement of multiple sources, such as local cuisines, contamination of wounds in combat, spread in the environment and cross-infection between the field and treatment centres [14, 70, 71]. Acinetobacter infections have also had an unusually high prevalence during natural disasters. During the 2004 tsunami in Southeast Asia, Acinetobacter resistant to several antibiotics were recovered from wounds, blood and respiratory fluids among 17 patients who sustained severe soft tissue injuries and fractures [72]. A. baumannii was also the most frequently isolated healthcare-associated pathogen in an ICU in Turkey after the 1999 Marmara earthquake in that country, despite having been only rarely isolated there previously [73].

4. Clinical manifestations of A. baumannii infections

Acinetobacter baumannii is of clinical importance partly due to its ability to survive in a broad range of temperatures and environmental conditions. It is highly resistant to desiccation and can survive for months on fomites. This makes them easy to spread in hospital settings where they can cause nosocomial outbreaks and contribute to the spread of MDRAB. Tubing and other equipment involved in artificial ventilation can serve as a source of A. baumannii infection and result in lower respiratory tract infection.

They are also responsible for other HAIs, such as wound infections, pressure ulcers, burn infections, septicaemia, UTIs, secondary meningitis and infective endocarditis [28]. A. baumannii is associated with skin and soft tissue infections and has been reported in traumatic injuries and postsurgical wounds. Complications arise leading to difficulty in treatment when burns get infected with A. baumannii. In some cases, a systemic infection can arise when the bacteria enter the bloodstream, leading to septicaemia. Prolonged use of catheters and antibiotic therapy have also been linked to A. baumannii infections.

Also, A. baumannii can develop resistance to many classes of antibiotics, such as β-lactam antibiotics, cephalosporins, aminoglycosides, fluoroquinolones and carbapenems. The increasing prevalence of CRAB and MDRAB has narrowed down therapeutic options making them a global concern. CRAB and MDRAB are associated with increased patient hospital stay and mortality [74]. Risk factors for high mortality include severity of infection, malignancy, older age, inappropriate use of antibiotics, renal failure, invasive procedures and prolonged stay in ICU [75, 76].

Only very few drugs, such as polymyxin B, colistin and tigecycline, are currently effective for MDRAB [32]. These drugs are expensive and are not readily available in resource-limited countries. Due to the high demand for colistin in the treatment of CRAB infections, colistin resistance has also been reported worldwide [33]. Resistance to polymyxin B and tigecycline has also been reported [34, 35].

5. Acinetobacter baumannii-associated infections

Gram-negative bacteria, such as Acinetobacter baumannii, Pseudomonas aeruginosa, Klebsiella pneumoniae and Escherichia coli, are common causes of many infections like pneumonia, bloodstream infections, wound and surgical site infections and meningitis in healthcare settings. A. baumannii is a common HAI and can infect various human anatomical sites. Clinical manifestations of A. baumannii infection are diverse, the most frequent ones being infections of the bloodstream and pneumonia associated with use of ventilators [77]. The severity and mortality rate of the infection and the patient outcome can depend on the virulence and antibiotic susceptibility of the infecting strain, such as MDRAB or CRAB, co-morbidities, length of hospital stay and other demographic characteristics [78].

5.1 Pneumonia

As A. baumannii can grow on a variety of environmental conditions, are tolerant to desiccants and can withstand many disinfectants and cleaning solutions, it is a common contaminant of hospital fomites. They are easily transferred from one patient to another or from a healthcare provider to a patient. Many of the hospital strains are resistant to many antibiotics due to constant exposure to antibiotics in the hospitals [79]. Hence, infections caused by these organisms are difficult to treat and are associated with longer periods of hospitalization. Acinetobacter infection is a major cause of pneumonia in patients in ICU who need assisted ventilation. A common feature of this pneumonia is delayed onset. In general, Acinetobacter pneumonia demonstrates other clinical manifestations that resemble those seen in pneumonia contracted in healthcare settings [24]. Pneumonia is a common and serious HAI, especially VAP, in patients in the ICU who are on artificial ventilation. Longer periods of antibiotic use, hospitalization and time on mechanical ventilators can increase the risk of A. baumannii infection [80]. Contaminated equipment and poor personal hygiene are common causes of transmission. In a prospective observational study conducted in nine countries in Europe across 27 ICUs, A. baumannii was established as one of the very common pathogens responsible for nosocomial pneumonia and it was actually the most prevalent isolate in Greece and Turkey [81]. Nosocomial pneumonia following Acinetobacter infection is linked with highly resistant isolates with mortality rates ranging between 35 and 70%.

5.2 Community-acquired pneumonia

Acinetobacter has been shown to cause severe community-acquired pneumonia that is distinguished by a stormy illness, in which the onset is abrupt and progression is rapid with resultant respiratory failure and uncertain haemodynamic parameters [24, 25, 26]. About a third of patients may experience septic shock. This situation, which appears to be more common in Australia and Southeast Asia when compared to other regions, has increasingly fatal outcome [82].

5.3 Bloodstream infections

Although bloodstream infections caused by Acinetobacter are responsible for a lower percentage of nosocomial infections, they are still a major public health concern since studies have revealed high mortality, especially in CRAB strains [83]. A retrospective observational study of bacteraemia caused by Acinetobacter spp. was undertaken in a UK hospital. A. baumannii was the most frequently isolated species. Most cases of bacteraemia occurred in patients in ICU and were associated with CRAB and MDRAB and these were associated with higher mortality rates, irrespective of appropriate empirical antibiotic therapy [84]. Vascular catheters and the respiratory tract are the most common sources of bacteraemia due to Acinetobacter infection [85, 86]. The urinary tract and wounds contribute to bloodstream infections to a lesser extent. Among factors that may predispose to Acinetobacter bloodstream infections are prolonged hospital or ICU stay, immunosuppression, trauma, burns, cancer, mechanical ventilation, previous surgery, previous use of broad-spectrum antibiotics, immunosuppression, trauma, burns, malignancy and invasive procedures [85, 86, 87, 88, 89].

5.4 Trauma, wound and surgical site infections

In healthcare settings, many organisms can infect the skin and soft tissue including A. baumannii. It has been associated with delay in wound healing, skin graft rejection and death from sepsis. Cases of skin and soft tissue infections caused by A. baumannii have also been recorded following a blast injury and chronic leg ulcer [90]. Fleming et al. in a wound infection mouse model demonstrated that iron depletion plays a crucial role in the pathogenesis of A. baumannii wound infections [91]. Exogenous supplementation of iron to the wound site prevented the activation of virulence genes involved in iron acquisition.

Contamination of surgical and traumatic injuries by Acinetobacter may result in severe infection of the soft tissue that may ultimately lead to osteomyelitis [92]. Acinetobacter is not commonly implicated in both community- and hospital-acquired skin infections like cellulitis and folliculitis [19, 93, 94]. MDRAB is, however, becoming more prevalent in injuries sustained during conflicts.

5.5 Endocarditis

Acinetobacter species have been implicated as a rare cause of infective endocarditis in people with artificial heart valves [89, 95, 96]. Acinetobacter was responsible for two cases of heart valve endocarditis due to nosocomial bacteraemia in a study that investigated 171 patients with prosthetic heart valve [97]. Acinetobacter endocarditis is typically characterized by acute onset with an aggressive course. Mortality tends to be higher in the setting of native valve endocarditis than prosthetic valve endocarditis, likely because of the low index of suspicion leading to delayed treatment in such cases [96].

5.6 Meningitis

Nosocomial meningitis may sometimes result from Acinetobacter infection [98, 99]. Prior antibiotic therapy, neurosurgical procedures and intracranial hemorrhage are some risk factors for meningitis [100, 101, 102]. Outbreaks of nosocomial Acinetobacter meningitis were documented in the course of administering contaminated methotrexate via the intrathecal route [103]. Survivors of nosocomial meningitis may suffer severe sequalae [104]. Though Acinetobacter meningitis is not commonly encountered in the community, it does occur majorly in hitherto healthy individuals in the tropics and is often not resistant to drugs [105]. Common symptoms seen in Acinetobacter meningitis cases include fever and meningeal signs with seizures sometimes present. Acinetobacter central nervous system infections may present other clinical manifestations similar to those generally seen in meningitis.

5.7 Urinary tract infection

Acinetobacter can readily colonize the urinary tract, especially when there is an indwelling urinary catheter although the incidence of infection is low [83, 106]. A study in the United States of America reviewed 5000 urinary tract infections in medical ICU. Only 1.6% of the infections were attributed to Acinetobacter and 95% of these were linked to urinary catheters [83]. Urinary tract infection acquired in the community may occur very sparingly [107, 108]. In the absence of other signs or symptoms of infection, isolation of Acinetobacter may be attributed to colonization.

5.8 Other infections

Acinetobacter colonization has been reported in wearers of contact lens, and eye infections such as corneal ulcers may occur [109, 110]. In a study of 750 cases of corneal ulcers, Acinetobacter was the third leading cause, responsible for 7% of the cases [111]. The infections usually occurred after cataract or other eye surgeries.

Patients admitted to the ICU may develop nosocomial sinusitis due to Acinetobacter for which mechanical ventilation is a very important predisposing factor [112]^. Acinetobacter sinusitis can progress to pneumonia since the infected sinuses serve as reservoirs for the organism, which can subsequently be disseminated to the lower respiratory tract [112].

6. Virulence properties

Acinetobacter baumannii is an opportunistic pathogen that has a high incidence among immunocompromised patients, especially those with a prolonged hospital stay. Virulence factors associated with the organism include an outer membrane protein A (OmpA), porin proteins, capsule formation, lipopolysaccharide (LPS) endotoxin, iron acquisition systems and biofilm formation [113]. OmpA is the most abundant surface protein on A. baumannii and contributes immensely to the pathogenic potential of the organism. It binds to receptors on the host cell surface, thereby inducing apoptosis. It also mediates resistance to complement proteins and is involved in biofilm formation [114, 115]. These functions help the bacterium to grow under unfavorable conditions and survive both within and outside the host. Fimbriae, phospholipases C and D are other cell surface structures and proteins that contribute to the virulence property of A. baumannii. Fimbriae like OmpA are involved in adhesion to host cell surface and promote colonization. Phospholipase C is toxic to host epithelial cells, while phospholipase D mediates serum resistance, evasion of host epithelial cells and promotes disease pathogenesis [116]. The virulence factors identified for A. baumannii are presented in Table 1, adapted from [117].

Virulence factor	Role in disease
Porin proteins, e.g., OmpA	Adherence and invasion
	Induction of apoptosis
	Serum resistance
	Biofilm formation
Polysaccharide capsule	Serum resistance
	Survival in tissue infection
	Evasion of host immune responses
	Biofilm formation
Lipopolysaccharide (LPS)	Serum resistance
	Survival in tissue infection
	Evasion of host immune responses
Outer membrane vesicle (OMV)	Delivery of virulence factors
	Horizontal transfer of antibiotic resistance gene
	Evasion of host immune responses
Outer membrane proteins (OMPs), e.g., metal (Fe, Zn, Mn) acquisition systems; protein secretion systems (Types II and IV); penicillin-binding proteins, etc.	In vivo survival
	Killing of host cells
	Host colonization
	Biofilm formation
	Serum resistance

Table 1.

Virulence factors in Acinetobacter baumannii and their role in pathogenesis.

7. Antibiotic resistance

Acinetobacter baumannii has intrinsic resistance to many antibiotics and also easily acquires resistant genes from other bacteria. Acquisition of antibiotic resistance is usually mediated via horizontal transfer of antibiotic genes from other organisms. Genome sequencing of some strains of A. baumannii revealed that resistant genes were acquired from species of Pseudomonas, Escherichia and Salmonella [24]. The major mechanisms of antibiotic resistance in A. baumannii are presented in Table 2.

Antibiotic class	Resistance mechanisms
β-Lactam	β-Lactamase production
	Carbapenemase production
	Loss of outer membrane porin proteins
	Efflux pump reduces antibiotic concentration inside the cell
	Altered expression of penicillin-binding proteins (PBPs)
Tetracyclines	Efflux pump reduces antibiotic concentration inside the cell
	Ribosomal protection
Glycylcylines	Efflux pump reduces antibiotic concentration inside the cell
Aminoglycosides	Enzymatic degradation
	16 s rDNA methyltransferases
Quinolones	DNA gyrase
	Efflux pump reduces antibiotic concentration inside the cell
Chloramphenicol	Efflux pump reduces antibiotic concentration inside the cell
Trimethoprim / Sulfamethoxazole	Efflux pump reduces antibiotic concentration inside the cell
	Dihydropteroate synthase inhibitor
	Dihydropteroate reductase inhibitor
Macrolides	Efflux pump reduces antibiotic concentration inside the cell
	Polymyxins

Table 2.

Major mechanisms of antibiotic resistance in Acinetobacter baumannii.

8. Treatment strategies

Acinetobacter baumannii is intrinsically resistant to many antibiotics and is capable of acquiring resistant genes via horizontal gene transfer. This makes the treatment of infections caused by A. baumannii challenging to treat. Carbapenems are generally considered as the antibiotics of choice for treating A. baumannii infections due to their efficacy and favorable safety profile. Polymyxin B, colistin and tigecycline are other antibiotics that can be used in cases of CRAB. Unfortunately, resistance to polymyxin B, colistin and tigecycline has also been reported. MDRAB has necessitated the search for other options including new drug discovery. Pan-drug-resistant A. baumannii that is resistant to at least one agent in all classes of antibiotics has rarely been reported. The organism is usually sensitive to one or more antibiotics. Thus, efficient combination therapy with at least one agent from different classes of antibiotics is currently used in the treatment of A. baumannii infections [117].

9. Conclusion

In conclusion, A. baumannii has become established as a pathogen of global dimension that is prevalent in various environmental niches. As it has developed resistance to many antibiotics including those that were considered to be the last resort, treatment of infections caused by this organism has become a major challenge for clinicians. Efforts in the research and development of new antibiotics and treatment strategies are yet to yield novel results and hence the need to revisit traditional methods. Effective public health policies in both the community and hospital can help control A. baumannii infections. The saying that ‘prevention is better than cure’ still holds true, thus in addition to concerted efforts to develop new and alternative treatment strategies, stringent infection prevention and control mechanisms along with continuous epidemiological surveillance should be instituted to curtail the transmission and spread of MDRAB.