The genus Acinetobacter is a heterogeneous group of organisms that comprises 17 named species and 15 species that have no valid names as of yet. Acinetobacter baumannii and the closely related genomic species 3 and 13TU are clinically the most important species.
A. baumannii is a major cause of hospital-acquired infections in patients who are critically ill. The most frequent infections are ventilator-associated pneumonia and bloodstream infection.
A. baumannii strains that are circulating in hospitals can be multidrug resistant (MDR) and can spread epidemically. A recent manifestation of MDR A. baumanniii is its association with wound infection in severely injured soldiers.
A. baumannii has an extraordinary capacity to develop resistance to multiple antimicrobial agents and many resistance mechanisms have been identified in this organism. An 86-kilobase genomic region that contains 45 resistance genes has recently been identified in A. baumannii and represents a unique structure that is found in human bacterial pathogens.
The treatment of A. baumannii infections is often hampered by the multidrug resistance of the causative organism, which can affect all systemic antimicrobials, including carbapenems and even polymyxins. Combination therapy remains the last alternative in such cases.
The study of the epidemicity and pathogenicity factors of A. baumannii is still at an elementary stage.
Since the 1970s, the spread of multidrug-resistant (MDR) Acinetobacter strains among critically ill, hospitalized patients, and subsequent epidemics, have become an increasing cause of concern. Reports of community-acquired Acinetobacter infections have also increased over the past decade. A recent manifestation of MDR Acinetobacter that has attracted public attention is its association with infections in severely injured soldiers. Here, we present an overview of the current knowledge of the genus Acinetobacter, with the emphasis on the clinically most important species, Acinetobacter baumannii.
Intensive care units (ICUs) of hospitals harbour critically ill patients who are extremely vulnerable to infections. These units, and their patients, provide a niche for opportunistic microorganisms that are generally harmless for healthy individuals but that are often highly resistant to antibiotics and can spread epidemically among patients. Infections by such organisms are difficult to treat and can lead to an increase in morbidity and mortality. Furthermore, their eradication from the hospital environment can require targeted measures, such as the isolation of patients and temporary closure or even reconstruction of wards. The presence of these organisms, therefore, poses both a medical and an organizational burden to health-care facilities.
One important group of bacteria that is associated with these problems is the heterogeneous group of organisms that belong to the genus Acinetobacter. This genus has a complex taxonomic history. Since the 1980s, in parallel with the emergence of acinetobacters as nosocomial pathogens, the taxonomy of the genus has been refined; 17 named species have been recognized and 15 genomic species (gen.sp.) have been delineated by DNA–DNA hybridization, but these do not yet have valid names (Table 1). The species that is most commonly involved in hospital infection is Acinetobacter baumannii , which causes a wide range of infections, including pneumonia and blood-stream infections. Numerous studies have reported the occurrence of multidrug-resistant (MDR) A. baumannii in hospitals, and at some locations pandrug-resistant strains have been identified. Currently, A. baumannii ranks among the most important nosocomial pathogens. Additionally, the number of reports of community-acquired A. baumannii infection has been steadily increasing, although overall this type of infection remains rare. Despite the numerous publications that have commented on the epidemic spread of A. baumannii, little is known about the mechanisms that have favoured the evolution of this organism to multidrug resistance and epidemicity. In this Review, we discuss the current state of knowledge of the epidemiology, antimicrobial resistance and clinical significance of acinetobacters, with an emphasis on A. baumannii. The reader is also referred to previous reviews of this organism that have been written by pioneers in the field1,2.
Identification of Acinetobacter species
In 1986, a phenotypic system for the identification of Acinetobacter species was described3, which together with a subsequent simplified version4 has proven useful for the identification of most, but not all, Acinetobacter species. In particular, Acinetobacter calcoaceticus, A. baumannii, gen.sp. 3 and gen.sp. 13TU cannot be separated well by this system4. These species are also highly similar by DNA–DNA hybridization5 and it has therefore been proposed that they should be grouped together into the so-called A. calcoaceticus–A. baumannii (Acb) complex4. From a clinical perspective this might not be appropriate, as the complex combines three of the most clinically relevant species (A. baumannii, gen.sp. 3 and gen.sp. 13TU) with an environmental species (A. calcoaceticus). It is noteworthy that the performance of commercial systems for species identification that are used in diagnostic microbiology is also unsatisfactory. Using these systems, the clinically relevant species of the Acb complex are frequently uniformly identified as A. baumannii and many other species are not identified6,7,8. These problems have led to the development of genotypic methods for Acinetobacter species identification, some of which are discussed in Box 1 (also see Fig. 1). Currently, precise species identification is not feasible in most laboratories, except for a few Acinetobacter reference laboratories. In light of the difficulties in distinguishing A. baumannii, gen.sp. 3 and gen.sp. 13TU, in this Review these species will be referred to as A. baumannii (in a broad sense) unless otherwise stated.
Epidemiology of clinical acinetobacters
The natural habitat of Acinetobacter species. Most Acinetobacter species have been found in clinical specimens (Table 1), but not all are considered to be clinically significant. One important question is where does A. baumannii come from? Furthermore, are there environmental or community reservoirs? As mentioned earlier, A. baumannii, gen.sp. 3 and gen.sp. 13TU are the most frequent species that are found in human clinical specimens5,9,10. Of these, gen.sp. 3 was the most prevalent species among clinical isolates in a Swedish study5. In 2 European studies, Acinetobacter lwoffii was the most predominant species to be found on the skin of healthy individuals, with carrier rates of 29% and 58%, whereas other Acinetobacter species, including Acinetobacter junii, Acinetobacter johnsonii, Acinetobacter radioresistens and gen.sp. 15BJ, were detected at lower frequencies11,12. The carrier rates for A. baumannii (including gen.sp. 13TU) in these studies ranged from 0.5 to 3%, whereas for gen.sp. 3 the rates ranged from 2 to 6%11,12. The faecal carriage of A. baumannii among non-hospitalized individuals in the United Kingdom and the Netherlands was 0.9%13. The most predominant species in faecal samples from the Netherlands were A. johnsonii (17.5%) and gen.sp. 11 (4%)13. A. baumannii was also recovered from the body lice of homeless people14 and it was proposed that the organisms were associated with transient bacteraemia in these individuals. In a study in Hong Kong, the carrier rates of A. baumannii, gen.sp. 3 and gen.sp. 13TU on the skin of healthy individuals were 4, 32 and 14%, respectively15. Thus, the carrier rates for gen.sp. 3 and gen.sp. 13TU in that study were strikingly higher than in the European studies. These findings indicate that, at least in Europe, the carriage of A. baumannii in the community is relatively low. Apart from its occurrence in humans, A. baumannii has also been associated with infection and epidemic spread in animals at a veterinary clinic16.
There are few available data on the environmental occurrence of A. baumannii, gen.sp. 3 and gen.sp. 13TU, but these species have been found in varying percentages in vegetables, fish, meat and soil17,18. A. baumannii has also recently been found in aquacultures of fish and shrimp farms in Southeast Asia19. However, it is not yet clear to what extent these findings are attributable to an environmental niche or to contact with humans or animals.
A. baumannii has been described as a soil organism, but without the support of appropriate references20. It was probably assumed that the wide occurrence of unspeciated acinetobacters in soil and water21 is also applicable to A. baumannii. However, in fact, there is little evidence that A. baumannii is a typical soil resident. Taken together, the existing data indicate that A. baumannii has a low prevalence in the community and that its occurrence in the environment is rare.
A. baumannii in hospitals. The most striking manifestation of A. baumannii is the endemic and epidemic occurrence of MDR strains in hospitals. The closely related gen.sp. 3 and gen.sp. 13TU might have a similar role22,23,24, and their involvement could have been underestimated as these species are phenotypically difficult to discriminate from A. baumannii. Most investigations of A. baumannii in hospitals have been ad hoc studies that were triggered by an outbreak. More in-depth studies of the prevalence of this species in hospitals, including antibiotic-resistant and antibiotic-susceptible strains, are required to better understand its true importance.
Depending on the local circumstances, and the strain in question, the pattern of an outbreak can vary. There can be a common source or multiple sources and some strains have a greater tendency for epidemic spread than others. Epidemiological typing — mostly by genotypic methods, such as amplified fragment length polymorphism (AFLP) analysis (Box 1) — is an important tool that can distinguish an outbreak strain from other, concurrent strains, and assess the sources and mode of transmission of the outbreak strain.
A scheme that depicts the dynamics of epidemic A. baumannii on a hospital ward is provided in Fig. 2. An epidemic strain is most commonly introduced by a patient who is colonized. Once on a ward, the strain can then spread to other patients and their environment. A. baumannii can survive in dry conditions25 and during outbreaks has been recovered from various sites in the patients' environment, including bed curtains, furniture and hospital equipment26. These observations, and the success that cleaning and disinfecting patients' rooms has had in halting outbreaks, emphasize the role of the hospital environment as a reservoir for A. baumannii during outbreaks. The bacteria can be spread through the air over short distances in water droplets and in scales of skin from patients who are colonized27, but the most common mode of transmission is from the hands of hospital staff. Patients who are colonized or infected by a particular A. baumannii strain can carry this strain at different body sites for periods of days to weeks28, and colonization can go unnoticed if the epidemic strain is not detected in clinical specimens2,29.
Population studies of A. baumannii. Comparative typing of epidemic strains from different hospitals has indicated that there can be spread between hospitals. For example, during a period of outbreaks in the Netherlands that involved eight hospitals, one common strain was found in three of these hospitals and another common strain was found in two others26. Similar observations of interhospital spread of MDR strains in particular geographical areas have been made in the Czech Republic30, the United Kingdom31, Portugal32 and the United States33.
Highly similar, but distinguishable, strains have been found at different locations and at different time points, without a direct epidemiological link. It is assumed that these strains represent particular lineages of descent (clones). Examples are European clones I–III34,35,36, which have been delineated by a range of genotypic typing methods, such as AFLP analysis (Box 1a; Fig. 1), ribotyping, macrorestriction analysis by pulsed-field gel electrophoresis and, most recently, multilocus sequence typing (see both MLST systems in Further information). Strains that belong to these clones are usually highly resistant to antibiotics, although within a clone there can be variation in antibiotic susceptibility. Apparently, these clones are genetically stable strains that are particularly successful in the hospital environment and evolve slowly during their spread. Whether these strains have particular virulence attributes or an enhanced ability to colonize particular patients (discussed below) remains to be established. Their wide spread might be explained by the transfer of patients between hospitals and regions over the course of time, although in many cases there is no evidence for this. It is also possible that they circulate at low rates in the community and are able to expand in hospitals under selective pressure from antibiotics. So far, their resistance to antimicrobial agents is the only known selectively advantageous trait.
Clinical impact of Acinetobacter infections
Nosocomial infections. Acinetobacters are opportunistic pathogens that have been implicated in various infections that mainly affect critically ill patients in ICUs. Hospital-acquired Acinetobacter spp. infections include: ventilator-associated pneumonia; skin and soft-tissue infections; wound infections; urinary-tract infections; secondary meningitis; and bloodstream infections. These infections are mainly attributed to A. baumannii, although gen.sp. 3 and gen.sp. 13TU have also been implicated. Nosocomial infections that are caused by other Acinetobacter species, such as A. johnsonii, A. junii, A. lwoffii, Acinetobacter parvus, A. radioresistens, Acinetobacter schindleri and Acinetobacter ursingii, are rare and are mainly restricted to catheter-related bloodstream infections8,37,38,39,40. These infections cause minimal mortality and their clinical course is usually benign, although life-threatening sepsis has been observed occasionally41. The rare outbreaks of some of these species (for example, A. junii) have been found to be related to contaminated infusion fluids41.
The risk factors that predispose individuals to the acquisition of, and infection with, A. baumannii are similar to those that have been identified for other MDR organisms. These include: host factors such as major surgery, major trauma (in particular, burn trauma) and prematurity in newborns; exposure-related factors such as a previous stay in an ICU, the length of stay in a hospital or ICU, residence in a unit in which A. baumannii is endemic and exposure to contaminated medical equipment; and factors that are related to medical treatment such as mechanical ventilation, the presence of indwelling devices (such as intravascular catheters, urinary catheters and drainage tubes), the number of invasive procedures that are performed and previous antimicrobial therapy42. Risk factors that are specific for a particular setting have also been identified, such as the hydrotherapy that is used to treat burn patients and the pulsatile lavage treatment that is used for wound débridement43,44.
The most frequent clinical manifestations of nosocomial A. baumannii infection are ventilator-associated pneumonia and bloodstream infection, both of which are associated with considerable morbidity and mortality, which can be as high as 52%45,46. Risk factors for a fatal outcome are severity-of-illness markers, an ultimately fatal underlying disease and septic shock at the onset of infection. Bacteraemic A. baumannii pneumonia has a particularly poor prognosis46. A characteristic clinical manifestation is cerebrospinal-shunt-related meningitis, caused by A. baumannii in patients who have had neurosurgery47. Wound infections have been reported mainly in patients who have severe burns or trauma, for example, soldiers who have been injured during military operations43,48. Urinary-tract infections related to indwelling urinary-tract catheters usually run a more benign clinical course and are more frequent in rehabilitation centres than in ICUs49.
The clinical impact of nosocomial A. baumannii infection has been a matter of continuing debate. Many studies report high overall mortality rates in patients that have A. baumannii bacteraemia or pneumonia45,46. However, A. baumannii mainly affects patients with severe underlying disease and a poor prognosis. It has therefore been argued that the mortality that is observed in patients with A. baumannii infections is caused by their underlying disease, rather than as a consequence of A. baumannii infection. In a case-control study, Blot and colleagues50 addressed whether A. baumannii contributes independently to mortality and concluded that A. baumannii bacteraemia is not associated with a significant increase in attributable mortality. Similar findings for A. baumannii pneumonia have been reported by Garnacho and colleagues51. By contrast, in recent reviews of matched cohort and case-control studies, Falagas and colleagues52,53 concluded that A. baumannii infection was associated with an increase in attributable mortality, ranging from 7.8 to 23%. These contradictory conclusions show that the debate on the clinical impact of A. baumannii is still ongoing.
Community-acquired infections. A. baumannii is increasingly recognized as an uncommon but important cause of community-acquired pneumonia. Most of the reported cases have been associated with underlying conditions, such as alcoholism, smoking, chronic obstructive pulmonary disease and diabetes mellitus. Community-acquired A. baumannii pneumonia appears to be a unique clinical entity that has a high incidence of bacteraemia, a fulminant clinical course and a high mortality that ranges from 40 to 64%. It has been observed almost exclusively in tropical climates, in particular in Southeast Asia and tropical Australia54,55. It is currently unclear, however, if host factors or particular virulence factors are responsible for these severe infections. Multidrug resistance in these organisms is uncommon55. Other manifestations of community-acquired A. baumannii infections are rare.
Infections associated with natural disasters and war casualties. A characteristic manifestation of nosocomial A. baumannii is wound infection that is associated with natural or man-made disasters, such as the Marmara earthquake that occurred in 1999 in Turkey, the 2002 Bali bombing and military operations48,56,57. A strikingly high number of deep-wound infections, burn-wound infections and osteomyelitis cases have been reported to be associated with repatriated casualties of the Iraq conflict48. Isolates often had multidrug resistance. Based on the common misconception that A. baumannii is ubiquitous, it has been argued that the organism might have been inoculated at the time of injury, either from previously colonized skin or from contaminated soil. However, recent data clearly indicate that contamination of the environment of field hospitals and infection transmission in health-care facilities have had a major role in the acquisition of A. baumannii58.
Epidemicity and pathogenicity
The fact that colonization with A. baumannii is more common than infection, even in susceptible patients, emphasizes that the pathogenicity of this species is generally low. However, once an infection develops, it can be severe. Studies on the epidemicity and pathogenicity factors of A. baumannii are still at an elementary stage. A number of putative mechanisms that might have a role in colonization, infection and epidemic spread are summarized in Fig. 3. Genetic, molecular and experimental studies are required to elucidate these mechanisms in more detail.
Recent DNA sequencing of a single A. baumannii strain identified 16 genomic islands that carry putative virulence genes that are associated with, for example, cell-envelope biogenesis, antibiotic resistance, autoinducer production, pilus biogenesis and lipid metabolism59. Resistance to desiccation, disinfectants25,60 and antibiotics is important for environmental survival. The extraordinary metabolic versatility3 of A. baumannii could contribute to its proliferation on a ward and in patients. Pilus-mediated biofilm formation on glass and plastics has been demonstrated61. If formed on medical devices, such as endotracheal tubes or intravascular catheters, these biofilms would probably provide a niche for the bacteria, from which they might colonize patients and give rise to respiratory-tract or bloodstream infections. Electron microscopy studies have demonstrated that pili on the surface of acinetobacters interact with human epithelial cells62. In addition, thread-like connections between these bacteria were suggestive of an early phase of biofilm formation. The pili and hydrophobic sugars in the O-side-chain moiety of lipopolysaccharide (LPS)63 might promote adherence to host cells as a first step in the colonization of patients. Quorum sensing, the presence of which has been inferred from the detection of a gene that is involved in autoinducer production59, could control the various metabolic processes, including biofilm formation.
Resistance to antibiotics, as well as the protective conditions of the skin (such as dryness, low pH, the resident normal flora and toxic lipids) and those of the mucous membranes (such as the presence of mucus, lactoferrin and lactoperoxidase and the sloughing of cells) are prerequisites for bacterial survival in a host that is receiving antibiotics. In vitro and animal experiments have identified various factors that could have a role in A. baumannii infection. For example, A. baumannii outer membrane protein A (AbOmpA, previously called Omp38) has been associated with the induction of cytotoxicity64. Iron-acquisition mechanisms65 and serum resistance66 are attributes that enable the organism to survive in the bloodstream. The LPS and lipid A of one strain, at the time named A. calcoaceticus, had biological activities in animals that were similar to those of other enterobacteria67. These included lethal toxicity, pyrogenicity and mitogenicity for mouse-spleen B cells. More recently, A. baumannii LPS was found to be the major immunostimulatory component that leads to a proinflammatory response during A. baumannii pneumonia68 in a mouse model.
Taken together, the chain of events from environmental presence to the colonization and infection of patients demonstrates the extraordinary ability of A. baumannii to adapt to variable conditions. This ability suggests that the organism must possess, in addition to other factors, effective stress-response mechanisms. Together with its resistance to antibiotics, these mechanisms might explain the success of particular A. baumannii strains in hospitals.
Antimicrobial susceptibility and treatment
Antimicrobial resistance. A. baumannii is attracting much attention owing to the increase in antimicrobial resistance and occurrence of strains that are resistant to virtually all available drugs69. This organism is generally intrinsically resistant to a number of commonly used antibiotics, including aminopenicillins, first- and second-generation cephalosporins and chloramphenicol70,71. It also has a remarkable capacity to acquire mechanisms that confer resistance to broad-spectrum β-lactams, aminoglycosides, fluoroquinolones and tetracyclines1. Numerous studies have suggested an upward trend in strains of A. baumannii that are resistant to these agents. However, because of the scarcity of large-scale surveillance studies from the 1970s to the 1990s and the difficulties in comparing local reports, such trends are difficult to quantify on a global level. Resistance rates can vary according to the country and the individual hospital, and depend on biological, epidemiological or methodical factors. For example, local susceptibility testing without correction for predominant MDR epidemic strains tends to overestimate the level of resistance72. It has also been shown that MDR isolates from geographically distant areas can be clonally related, whereas susceptible strains are genotypically heterogeneous30,34, which suggests that the problem of resistance might be associated with a limited number of successful A. baumannii lineages.
Despite the difficulties that are associated with estimating resistance trends, the potential of A. baumannii to develop resistance against virtually all available drugs is unquestionable (Table 2). Of particular concern is resistance to carbapenems — broad-spectrum β-lactams that were introduced by 1985 and that, for years, have been the most important agents for the treatment of infections caused by MDR A. baumannii. Although clinical A. baumannii isolates were shown to be invariably susceptible to these drugs in early studies70,71, hospital outbreaks caused by carbapenem-resistant strains had already been reported by the early 1990s73 and, currently, the frequency of these strains in some areas can exceed 25%74. Recently, resistance to polymyxins75 and tigecycline76 has also been described, which indicates that A. baumannii can cause infections that are fully refractory to the currently available antimicrobial armoury.
Resistance mechanisms. The resistance of A. baumannii to antimicrobial agents is mediated by all of the major resistance mechanisms that are known to occur in bacteria, including modification of target sites, enzymatic inactivation, active efflux and decreased influx of drugs (Table 2). β-lactamases are the most diverse group of enzymes that are associated with resistance, and more than 50 different enzymes, or their allelic forms, have been identified so far in A. baumannii. Aminoglycoside resistance has been attributed to at least nine distinct modifying enzymes, which can be found in different combinations in some strains77,78. Specific point mutations in the genes that encode DNA gyrase and topoisomerase IV have been correlated with resistance to fluoroquinolones79, and resistance to tetracyclines has been associated with genes that encode tetracycline-specific efflux pumps80. Most genes that encode inactivating enzymes and specific efflux pumps are present only in some strains and are associated with genetic elements such as transposons, integrons or plasmids, which suggests they were acquired by horizontal transfer. Some of these genes are also common in other bacterial genera, whereas others are predominantly associated with the genus Acinetobacter (for example, the APH(3′)-VI gene) or even with A. baumannii (for a list of genes that encode the OXA-type carbapenemases, see Table 2).
A few chromosomal resistance genes are present in most, if not all, A. baumannii strains. They are normally expressed at a low level but can be overexpressed as a result of genetic events. Chromosomal ADC-type β-lactamases can be upregulated as a consequence of the upstream insertion of an ISAba1 sequence, which provides an efficient promoter81. This insertion sequence is widespread in A. baumannii and is thought to serve as a 'moving switch' to turn on those genes with which it is juxtaposed82. ISAba1 is also thought to have a key role in some carbapenem-resistant strains by enhancing the expression of the intrinsic OXA-51-like carbapenemases83. Another chromosomal system that is typical of A. baumannii is the AdeABC efflux system84. Fully susceptible strains that contain the genes that encode AdeABC can spontaneously produce resistance mutations in the adeS or adeR genes, which regulate AdeABC expression85. Upregulation of AdeABC is so far the only mechanism that has been proven to decrease susceptibility to multiple antimicrobial classes in A. baumannii (Table 2).
The diversity of the determinants that confer resistance of A. baumannii to a particular group of antibiotics can best be illustrated by the mechanisms that are associated with carbapenem resistance86 (Table 2). These include metallo-β-lactamases (VIM-, IMP- and SIM-types), which have been reported worldwide and confer resistance to all β-lactams with the exception of monobactams. Nevertheless, the most widespread carbapenemases in A. baumannii are class D β-lactamases. In addition to the intrinsic OXA-51-like enzymes, three unrelated groups of these carbapenem-hydrolysing oxacillinases have been distinguished, which are represented by OXA-23, -24 and -58, respectively. Reduced susceptibility to carbapenems has also been associated with the modification of penicillin-binding proteins and porins or with upregulation of the AdeABC efflux system, and it has been suggested that the interplay of different mechanisms might result in high-level carbapenem resistance in A. baumannii87.
Despite the progress in the elucidation of the function and genetic basis of particular resistance mechanisms, knowledge of the genetic factors that contribute to multidrug resistance in A. baumannii is limited. Although resistance to multiple drugs can be associated with some epidemic lineages34,35, closely related MDR strains can differ greatly from each other in terms of the presence of particular resistance determinants and their combinations88. An important observation has recently been made by Fournier and colleagues20, who compared the complete genomes of MDR (AYE) and susceptible (SDF) strains of A. baumannii. Whereas the AYE strain contained an 86-kilobase (kb) genomic region, termed a resistance island (the largest identified in bacteria to date), in which 45 putative resistance genes were clustered, SDF exhibited a 20-kb genomic island at the homologous location that comprised genes that encode transposases but no resistance genes. A region that is highly similar to the 20-kb island has also been found in the genome of an A. baumannii strain that was isolated in 1951 (Ref. 59). It is conceivable that such a genomic structure could serve as a 'hot spot' that facilitates the horizontal acquisition of resistance genes20 and has had a crucial role in the development of A. baumannii multidrug resistance.
Options for treatment. Unfortunately, prospective controlled clinical trials for the treatment of A. baumannii infections have never been performed. Our knowledge of the best treatment options is therefore based on retrospective analysis of observational studies, small case series and in vitro data. Neither broad-spectrum penicillins nor cephalosporins are considered to be effective for the treatment of serious A. baumannii infections. Even if isolates are considered to be susceptible according to in vitro tests, their minimum inhibitory concentration values are usually close to the clinical breakpoint. Fluoroquinolones have remained active against sporadic A. baumannii strains but resistance is now widespread among epidemic A. baumannii strains, rendering these antimicrobial drugs no longer useful. Aminoglycosides, in particular tobramycin and amikacin, often retain their activity against resistant A. baumannii isolates; however, these compounds are rarely used alone and are more often applied in combination with other antimicrobials.
As A. baumannii is becoming increasingly resistant to carbapenems in hospitals worldwide, only a few treatment options remain. Sulbactam, a β-lactamase inhibitor that has unusual intrinsic activity against acinetobacters, has been used successfully for the treatment of MDR A. baumannii infections, such as meningitis, ventilator-associated pneumonia and catheter-related bacteraemia89,90. In most patients, sulbactam has been used in combination with ampicillin, but its usefulness is now also increasingly compromised by resistance.
In recent years, there has been a resurgence of the use of polymyxins for the treatment of MDR Gram-negative bacteria, in particular Pseudomonas aeruginosa and A. baumannii. An increasing body of evidence suggests that intravenous polymyxins can be used successfully for the treatment of ventilator-associated A. baumannii pneumonia, with less nephrotoxicity observed than had been anticipated91. Alternatively, these drugs can be applied topically by the use of an aerosol92. Resistance of A. baumannii against polymyxins is still extremely rare75. Success rates of up to 60% have been reported, but the true efficacy of these antimicrobials remains to be shown in prospective studies.
Tigecycline was the first glycylcycline antibiotic to be launched and is one of the few new antimicrobials that has activity against Gram-negative bacteria that encompass not only most Enterobacteriaceae but also — at least in vitro — MDR A. baumannii. Several studies have tested the in vitro activity of tigecycline against A. baumannii and reported good bacteriostatic activity against strains that have a wild-type susceptibility profile, as well as those that are resistant to imipenem72. However, current evidence casts doubt on the role of tigecycline as a treatment for MDR A. baumannii infection, with reports of high tigecycline resistance93 and the occurrence of an A. baumannii bloodstream infection in a patient who received tigecycline76.
Antimicrobial combination therapy appears to be a reasonable alternative for the combat of MDR A. baumannii. A considerable number of in vitro studies, and animal studies using a mouse model of pneumonia, have been carried out to analyse the effect of combination therapy94,95,96,97. Suggested combinations include imipenem and amikacin; colistin and rifampin; and imipenem, rifampin and colistin. Clinical experience with combination therapy is limited. In the light of the few agents that are currently available to treat MDR A. baumannii infections, alternative treatment strategies and agents are urgently needed. A recent study has shown that, in an animal model, the lactoferrin-derived peptide hlF(1–11) is a promising candidate for the treatment of MDR A. baumannii98. However, new antimicrobials that have activity against A. baumannii are not expected to be available within the next decade.
Conclusion and challenges
Since the 1980s, the taxonomy of the genus Acinetobacter has undergone extensive changes, with the recognition of more than 30 gen.sp. The biological significance of most species other than those of the Acb complex remains to be elucidated owing to a lack of practical identification methods. This situation is expected to improve, however, in the near future with the introduction of well-validated sequence-based identification methods.
The occurrence of MDR and pandrug-resistant A. baumannii is a growing source of concern, and the exploration of new antibiotics, including host-defence peptides, is urgently required. Apart from MDR strains, there are many antibiotic-susceptible strains of A. baumannii, but their prevalence in hospitals and the community is unknown. It is a challenge to assess whether these strains have the potential to emerge to multidrug resistance (and epidemicity) once they enter an antibiotic-rich niche, such as a hospital. Basic questions remain to be answered about the role of the upregulation of resistance genes that are already present in the genome and the contribution of acquired resistance genes, including the possibility that they are stably integrated into the chromosome. It is also possible that the MDR strains that circulate in hospitals are distinct lineages or groups of lineages within A. baumannii, as has already been shown for strains that belong to European clones I–III. The recently developed MLST systems (see both MLST systems in Further information) are important tools that can be used to investigate the prevalence of particular strains at a global scale. However, these systems are based on the similarity of housekeeping genes and the genes that confer resistance and virulence could be located on mobile elements and clustered in genomic islands that are not linked to particular sequence types. Multi-strain genome analysis will probably provide some insight into these questions.
Little is known about the bacterial mechanisms that explain the success of A. baumannii in the hospital environment. Genomics, proteomics and fitness studies are expected to be helpful approaches to clarify the remarkable adaptability of the bacteria to variable conditions and selective pressures. Furthermore, apart from general host or treatment factors, there might be intrinsic host factors, such as a particular genetic constitution or innate immune status, that make a specific host susceptible to colonization and infection. Progress is also expected in this area.
The eradication of epidemic A. baumannii from the hospital environment demands a great effort (Box 2). Some countries have managed to keep the microorganism at a sporadic level, with outbreaks occurring only occasionally. In many other countries, however, the organisms are endemic or epidemic. The combat of MDR A. baumannii (and other MDR organisms) reaches far beyond the hospital level and requires a combined strategy of decision makers and health-care officials, the challenge being to make hospitals a safer place for patients who are critically ill.
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A.N. has been supported by grant NR 8554-3 from the Internal Grant Agency of the Ministry of Health of the Czech Republic. The authors thank P. van den Broek for critical reading of the manuscript and helpful discussions and are grateful to T. van der Reijden and other members of their laboratories for their support.
Entrez Genome Project
- DNA–DNA hybridization
Determines the degree of similarity between the genomic DNA of two bacterial strains; the gold standard to assess whether organisms belong to the same species.
In this Review, refers to A. baumannii that are resistant to all available systemic anti-A. baumannii antimicrobial agents, except for polymyxins.
A population of bacterial cells in pure culture that is derived from a single colony.
The constant presence of an infectious agent in a given geographical area or hospital.
A group of bacteria that were isolated independently from different sources in time and space, but share so many identical traits that it is likely that they evolved from a common ancestor.
- Typing method
A tool that differentiates bacterial strains below the species level.
A typing method in which chromosomal DNA is digested by restriction enzymes, fragments are separated by electrophoresis and, finally, particular fragments are detected by labelled rRNA probes to generate DNA-banding patterns, which allows the differentiation of bacterial isolates.
- Macrorestriction analysis
A typing method in which chromosomal DNA is digested with rare-cutting enzymes, so creating large fragments that are separated in an alternating electric field (pulsed-field electrophoresis) according to their size.
An infection of bone or bone marrow.
- Quorum sensing
The phenomenon whereby the accumulation of signalling molecules enables a single cell to sense the number of bacteria (cell density) that are present, which allows bacteria to coordinate certain behaviours or actions.
- Strict isolation
Rigorous separation to prevent highly contagious or virulent agents that can spread both by air and contact.
- Contact isolation
The separation of colonized or infected individuals from others to prevent, or limit, the direct or indirect transmission of diseases that are spread primarily by close or direct contact.
- Minimum inhibitory concentration
The lowest concentration of an antibiotic that inhibits visible growth of the organism.
- Clinical breakpoint
A discriminatory antimicrobial concentration that is used to interpret the results of susceptibility testing and to define bacterial populations as susceptible, intermediate or resistant based on the likelihood of therapeutic success.
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Dijkshoorn, L., Nemec, A. & Seifert, H. An increasing threat in hospitals: multidrug-resistant Acinetobacter baumannii. Nat Rev Microbiol 5, 939–951 (2007). https://doi.org/10.1038/nrmicro1789
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