Summary
Acinetobacter emerged as a significant nosocomial pathogen during the late 1970s, probably as a consequence, at least in part, of increasing use of broad-spectrum antibiotics in hospitals. Most clinically significant isolates belong to the species Acinetobacter baumannii or its close relatives, with many infections concentrated in intensive care, burns or high dependency units treating severely ill or debilitated patients. Large outbreaks can occur in such units, involving the infection or colonisation of numerous patients by specific epidemic strains of A. baumannii. Recently, a particular problem has concerned cross-infection of injured military patients repatriated from combat regions of the world (e.g. Iraq and Afghanistan). Carbapenems have previously been the treatment of choice for infected patients, but increasing reports worldwide now describe A. baumannii isolates resistant to all conventional antimicrobial regimens. Data to support therapeutic use of the limited number of new antimicrobial agents (e.g. tigecycline) with in-vitro activity against these pathogens are still very limited. Detailed advice concerning prevention and control of outbreaks caused by multidrug-resistant strains of acinetobacter is available from the UK Health Protection Agency. In addition to antibiotic prescribing policies and audit, these measures focus on reinforcing standard infection control procedures and precautions, with particular attention to thorough cleaning of patient areas to take account of the long-term survival of acinetobacter after drying and inadequate disinfection. Despite these measures, the problem continues to escalate, with many hospitals worldwide now reporting outbreaks caused by multidrug-resistant strains of acinetobacter.
Keywords
Introduction
The genus Acinetobacter has a long and convoluted taxonomic history. It was in 1911 that Beijerinck, a Dutch microbiologist working in Delft, isolated and described the first example of an organism that would now be recognised as Acinetobacter.
1
Since then, members of the genus have been classified under a variety of different names (e.g. Bacterium anitratum, Herellea vaginicola, Mima polymorpha, Moraxella lwoffi), and this confusion resulted in difficulties in establishing the epidemiology and true clinical importance of these organisms. Today, the use of molecular methods has established the identity of at least 33 different species belonging to the genus Acinetobacter, of which 18 have now been assigned formal species names (Table I). A further 28 unnamed groups have been identified that contain multiple strains, and there are also at least 21 ungrouped single strains. However, although the genus Acinetobacter comprises an ever-growing number of defined bacterial species, only a minority of these species are of clinical significance (see below).| A. calcoaceticus |
| A. baumannii |
| A. haemolyticus |
| A. junii |
| A. johnsonii |
| A. lwoffii |
| A. radioresistens |
| A. ursingii |
| A. schindleri |
| A. parvus |
| A. baylyi |
| A. bouvetii |
| A. towneri |
| A. tandoii |
| A. tjernbergiae |
| A. gerneri |
| A. beijerinckii |
| A. gyllenbergii |
a A. grimontii has recently been demonstrated to be a heterotypic synonym of A. junii, while A. venetianus currently remains as a provisional designation awaiting further investigation.
b In addition to the 18 named species listed, a further 26 unnamed groups have been identified that contain multiple strains, and there are also at least 21 ungrouped single strains that exist in culture collections.
Members of the genus Acinetobacter first began to be recognised as significant nosocomial pathogens during the early 1970s. In early in-vitro studies, most clinical isolates were susceptible to commonly used antimicrobial agents, such as ampicillin (60–70% of isolates susceptible), gentamicin (92.5%), chloramphenicol (57%) and nalidixic acid (97.8%), so that infections caused by these organisms could be treated relatively easily.
2
However, multidrug-resistant (MDR) clinical isolates of Acinetobacter spp. have been reported increasingly during the last two decades, almost certainly as a consequence of extensive use of potent broad-spectrum antimicrobial agents in hospitals throughout the world.In the clinical environment, Acinetobacter baumannii and its close relatives (genomic species 3 and 13TU), together forming the ‘A. baumannii complex’, are the genomic species of greatest clinical importance, together accounting for the vast majority of infections and hospital outbreaks involving Acinetobacter spp.
3
, 4
, 5
The members of the complex are very difficult for routine diagnostic laboratories to distinguish accurately; therefore, reports of A. baumannii in the scientific and medical literature should be assumed to include the other members of the complex unless this possibility has been specifically excluded. Many of the infections caused by these organisms occur in intensive care or high dependency units in which severely ill or debilitated patients are treated extensively with broad-spectrum antimicrobial agents. Members of the A. baumannii complex seem to have an extraordinary ability to develop resistance to even the most potent antimicrobial compounds, and are able to rapidly fill the ecological niche left vacant by the elimination of competing bacteria with broad-spectrum compounds. Genetic interchange with other bacterial species that are capable of growing at lower environmental temperatures is also possible, with significant implications for the wider spread of antibiotic resistance genes in the environment.Common misconceptions
Many misconceptions concerning acinetobacter still appear repeatedly in the scientific and medical literature. Chief among these are the statements that A. baumannii is (i) ubiquitous or highly prevalent in nature, (ii) that it can be recovered easily from soil, water and animals, and (iii) that it is a frequent skin and oropharyngeal commensal of humans. While these statements certainly apply to members of the genus Acinetobacter when considered as a whole, A. baumannii (and its close relatives of clinical importance) are not ubiquitous organisms. While it is certainly true that A. baumannii can be isolated from patients and hospital environmental sources during outbreaks, this species has no known natural habitat outside the hospital.
5
This species can be isolated only very rarely from soil, water and other environmental samples; indeed, during non-outbreak periods it is often isolated only rarely inside hospitals.In summary, three major overlapping populations of the genus Acinetobacter been identified to date: (i) MDR isolates found primarily in hospitals during outbreak situations – these isolates are capable of colonising and infecting hospitalised patients, and comprise mainly A. baumannii and its close relatives; (ii) ‘sensitive’ isolates that form part of the normal commensal skin flora of humans (25–70% of individuals) and animals, and which can also be found as part of the spoilage flora of many different foodstuffs – these isolates comprise mainly A. johnsonii, A. lwoffii and A. radioresistens; and (iii) ‘sensitive’ isolates that can be found in the environment, soil or wastewaters – these isolates comprise mainly A. calcoaceticus and A. johnsonii. The natural habitats of the many other species belonging to the genus Acinetobacter (Table I) are still poorly defined. Most species have been isolated on an occasional basis from humans, including clinical specimens, but in terms of infection control and clinical importance, concern should be reserved for the MDR isolates belonging to the A. baumannii complex. Such organisms are not ubiquitous and are generally isolated only from colonised or infected patients, or from the hospital environment during outbreaks.
Acinetobacter as a nosocomial pathogen
The main problems caused by acinetobacter in the hospital setting mostly concern critically ill patients in intensive care units (ICUs), particularly those requiring mechanical ventilation, and patients with wound or burn injuries (trauma patients). Infections associated with acinetobacter include ventilator-associated pneumonia, skin and soft-tissue infections, wound infections, urinary tract infections, secondary meningitis and bloodstream infections.
2
, 5
Such infections are caused predominantly by members of the A. baumannii complex; nosocomial infections caused by other species belonging to the genus Acinetobacter are relatively unusual and are restricted mainly to catheter-related bloodstream infections and rare outbreaks related to point-source contamination. There have also been a few reports of community-acquired infections, usually in patients with comorbidities in tropical or subtropical areas.5
Problems caused by members of the A. baumannii complex in the hospital setting are exacerbated by the high degree of resistance of these organisms to drying and disinfectants, leading to long-term persistence in the hospital environment and the occurrence of outbreaks of infection involving many patients, and the ever-increasing proportion of isolates that are MDR. Numerous studies have indicated an upward trend in MDR A. baumannii, but resistance rates can vary widely according to the individual hospital, city or country involved. Thus, in the UK, the latest available surveillance data show that resistance to carbapenems has increased from <0.5% in 1990 to 24% in 2007 (UK Health Protection Agency; unpublished data). Even allowing for the distortions caused by repeated sampling of predominant MDR epidemic strains, it is clear that A. baumannii has a remarkable ability to acquire resistance genes and to develop resistance against virtually all available antibiotic classes (see below).
The ‘reservoir’ for nosocomial infection with A. baumannii still remains uncertain, and may vary among healthcare facilities. Large numbers of A. baumannii infections have recently been reported among military casualties repatriated from war zones in Iraq and Afghanistan.
6
Based on the misconception that A. baumannii is ubiquitous in the environment, it was originally thought that such infections might have originated from contact with contaminated soil in the war zones. However, it has now become clear that the main cause was contamination of the environment of field hospitals and other healthcare facilities involved in the repatriation of military casualties.7
Potential sources of infection in the hospital environment from which these organisms have been isolated during outbreaks are numerous (Table II). Airborne transmission and patient-to-patient transmission have also been demonstrated. However, although the hands of hospital personnel, coupled with contamination of environmental surfaces and medical equipment, may play a role in the spread of A. baumannii during an outbreak, it seems likely that the infected patient forms the primary reservoir of infection, with such patients shedding extremely large numbers of A. baumannii cells into their surrounding environment. Factors facilitating the spread of A. baumannii are listed in Table III.
Table IIPotential sources from which Acinetobacter baumannii has been isolated in the hospital environment
| Hands of staff |
| Ventilators and tubing |
| Oxygen analysers |
| Bronchoscopes |
| Bed frames |
| Sinks |
| Jugs |
| Soap |
| Plastic screens |
| Bed linen, pillows and mattresses |
| Resuscitation bags |
| Blood pressure cuffs |
| Parenteral nutrition solution |
| Gloves |
| Humidifiers |
| Patients |
| Respirometers |
| Lotion dispensers |
| Rubbish bins |
| Air supply |
| Bowls |
| Hand cream |
| Bedside charts |
| Service ducts/dust |
| Computer keyboards |
| Cell phones |
Table IIIFactors facilitating the spread of Acinetobacter baumannii
| Increased length of hospital stay |
| Prior antibiotics |
| Mechanical ventilation |
| Exposure to patients colonised or infected with A. baumannii |
| Environmental contamination |
| Understaffing |
| Poor adherence of staff to hand hygiene |
Infection control measures
Once endemic in a healthcare unit, A. baumannii is extremely difficult to eradicate. Nevertheless, it is still possible to eradicate these organisms from a unit when an uncompromising approach is taken to infection control. Normal infection control measures are often insufficient to halt the transmission of MDR A. baumannii, but a range of enhanced measures that focused on controlling environmental contamination of an outbreak strain proved to be successful in eradicating A. baumannii from the ICU of a major London teaching hospital.
8
Key measures included use of a closed tracheal suction system for all patients receiving mechanical ventilation, improved hand decontamination using alcohol gels, clearer designation of responsibilities and strategies for cleaning equipment and the environment, and the use of nebulised colistin for patients with evidence of mild-to-moderate ventilator-associated pneumonia.8
Nevertheless, there are also numerous examples in which it has been necessary to implement patient isolation and/or ward closures for periods of up to four weeks in order to combat A. baumannii outbreaks.9
, 10
, 11
, 12
, 13
, 14
, 15
, 16
Detailed guidance concerning contact isolation precautions, risk factors for colonisation or infection, antibiotic prescribing policies, patient transfer procedures (internal and external), use of dedicated equipment, screening strategies, and cleaning and decontamination procedures has been made available by a Working Party of the UK Health Protection Agency (http://www.hpa.org.uk/web/HPAwebFile/HPAweb_C/1194947325341).17
To reiterate, the most important source of A. baumannii in a potential outbreak situation is the already colonised or infected patient. If an increase in the number of cases is detected, the isolates should first be identified and typed, the patients involved should be traced and isolated where possible, hygiene and infection control procedures should be re-emphasised and enhanced, antibiotic policies should be reviewed, and the unit should be cleaned thoroughly.
Epidemiology
Numerous studies have investigated the epidemiology of A. baumannii. Various patterns of spread of individual A. baumannii strains have been reported, including outbreaks caused by the same strain in multiple hospitals within a city, outbreaks in multiple cities within a country, and outbreaks in hospitals in several different countries.
18
, 19
, 20
, 21
, 22
, 23
, 24
, 25
In the UK, a survey in 1999–2001 identified 34 different A. baumannii genotypes in 46 UK hospitals.26
These genotypes belonged to 10 different clusters, with particular strains generally being characteristic of particular hospitals.26
Between 2003 and 2006, two carbapenem-resistant A. baumannii lineages (SE clone and OXA-23 clone) became prevalent in over 40 UK hospitals each, with these lineages being susceptible only to colistin and tigecycline.22
More recently, a further lineage (the Northwest strain) has become prevalent in several hospitals in the northern/midland regions of the UK.The question of whether specific carbapenem-resistant clones are spreading in European hospitals has also been examined. As part of the EU ARPAC project, 169 hospitals in 32 countries provided data concerning MDR isolates of Acinetobacter spp.
27
In total, 130 hospitals reported encountering carbapenem-resistant isolates of acinetobacter, ranging from rare sporadic isolates to an endemic/epidemic situation. Diverse clusters were identified in European hospitals by random amplified polymorphic DNA, pulsed-field gel electrophoresis and polymerase chain reaction-based sequence typing, but three major European lineages were identified. As in the UK, multiple isolates from a single hospital generally belonged to the same clone.27
Antimicrobial therapy
Table IV lists the classes of antimicrobial agents that are currently considered to have potential activity against A. baumannii. However, successive surveys have shown increasing resistance among clinical isolates, and high proportions of isolates are now resistant to most commonly used antibacterial agents, including aminopenicillins, ureidopenicillins, broad-spectrum cephalosporins, most aminoglycosides, quinolones, chloramphenicol and tetracyclines.
2
, 3
, 4
As a consequence, the emergence of MDR strains of acinetobacter, probably following the increasing use of broad-spectrum antibiotics in hospitals, has resulted in carbapenems (especially imipenem and meropenem) becoming the mainstay of treatment for acinetobacter infections. However, reports of carbapenem resistance in clinical isolates of Acinetobacter spp. are now accumulating worldwide, with some isolates being resistant to all conventional antimicrobial agents.18
, 28
, 29
, 30
It is therefore vital that therapeutic strategies optimise the use of existing antimicrobial agents and minimise the possibilities for the evolution of drug resistance.Table IVCurrently available classes of antimicrobial agents with potential activity against Acinetobacter baumannii
| Anti-pseudomonal broad-spectrum penicillins |
| Anti-pseudomonal broad-spectrum cephalosporins |
| Monobactams |
| Aminoglycosides |
| Fluoroquinolones |
| Carbapenems |
| Polymyxins |
| Sulbactam |
| Glycylcyclines |
Potential therapeutic approaches for treatment of A. baumannii infections have been considered in detail in several recent review articles.
5
, 31
, 32
, 33
, 34
The antibiotic classes listed in Table IV have potential activity against individual strains of acinetobacter, but therapy should ideally be based on the results of properly performed antimicrobial susceptibility tests. Antibiotic selection for empirical therapy is challenging and should rely, wherever possible, on institutional-level data concerning the phenotypes and genotypes of A. baumannii strains endemic in a particular hospital environment. No large prospective controlled clinical trials for the treatment of A. baumannii infections have been reported to date. Knowledge of the best therapeutic approaches is therefore based on in-vitro susceptibility data, small case series and retrospective analysis of observational studies. Of the available options (Table IV), widespread resistance means that broad-spectrum penicillins, broad-spectrum cephalosporins and monobactams cannot be recommended as suitable candidates for the empirical treatment of severe A. baumannii infections, although cefepime and cefpirome retain some potentially useful residual activity.Aminoglycosides
Resistance rates to all the clinically useful aminoglycoside antibiotics are higher in Acinetobacter spp. than in most other groups of pathogens.
3
, 35
Most aminoglycoside resistance in Acinetobacter spp. involves production of aminoglycoside-modifying enzymes, and all three classes of aminoglycoside-modifying enzymes have been found in Acinetobacter spp. Nevertheless, depending on the results of susceptibility tests, aminoglycosides, particularly amikacin, continue to show useful activity against 40–50% of strains in some centres.Fluoroquinolones
Until 1990, quinolones had reasonably good activity against A. baumannii, but resistance to these antibiotics subsequently emerged rapidly in clinical isolates. Newer fluoroquinolones, such as moxifloxacin, sometimes have increased activity in vitro against A. baumannii in comparison with older agents such as ciprofloxacin. Spence and Towner demonstrated that isolates with a single mutation in the gyrA gene at codon Ser-83 had a ciprofloxacin minimum inhibitory concentration (MIC) of 2 to >32 mg/L, but a moxifloxacin MIC of 0.25–1 mg/L.
36
All moxifloxacin-resistant (MIC >2 mg/L) clinical isolates possessed a second mutation in codon Ser-80 of the parC gene. Additional single-step mutation studies with ciprofloxacin-resistant/moxifloxacin-susceptible isolates revealed that such stable moxifloxacin-resistant mutants were difficult to generate, but that growth could occur in the presence of moxifloxacin, perhaps indicating the presence of an efflux pump that could be induced in the presence of subinhibitory concentrations of moxifloxacin.Carbapenems
As mentioned above, carbapenems (especially imipenem and meropenem) have been a mainstay of treatment for acinetobacter infections for the past decade. However, although these agents are still active against many strains, increasing numbers of clinical isolates of A. baumannii resistant to carbapenems are now being reported worldwide, reaching levels of ≥90% in some centres.
34
In northern European countries (e.g. the UK), carbapenem resistance is now reported in ∼15% of A. baumannii isolates, but levels are much higher in southern European countries (e.g. Spain, Italy, Greece).Polymyxins
Polymyxins (e.g. colistin) show bactericidal activity against A. baumannii, and resistance rates have remained relatively low. Favourable clinical responses have been reported for intravenous colistin therapy in case series of ICU patients with various types of infections, including ventilator-associated pneumonia and nosocomial meningitis.
34
Perhaps surprisingly, reports of colistin toxicity are relatively rare. Polymyxins can be administered in a nebulised form via the respiratory tract in patients with nosocomial pneumonia, and several small studies have reported clinical effectiveness.34
Some studies have indicated that colistin may be useful for treating infections caused by carbapenem-resistant isolates, but increasing use of polymyxins in critically ill patients may lead rapidly to the emergence of resistance.37
, 38
, 39
Indeed, high rates of resistance to colistin have recently been reported in A. baumannii isolates from two South Korean hospitals.40
Sulbactam
A few reports have described the successful therapeutic use of sulbactam, which has unusual intrinsic activity against Acinetobacter spp., either alone or in combination with ampicillin.
41
Urban et al. investigated the interaction of sulbactam, clavulanic acid and tazobactam with the penicillin-binding proteins (PBPs) of imipenem-resistant and -susceptible isolates of A. baumannii, and showed in competition-binding experiments that all three of these β-lactamase inhibitors bound to the PBPs of the imipenem-susceptible isolates.42
This observation may explain the in-vitro intrinsic antimicrobial properties of these agents against A. baumannii. However, as currently formulated for clinical use, sulbactam is likely to be the only one of these inhibitors to be active in vivo against A. baumannii. Recent evidence has suggested that the activity of sulbactam against A. baumannii isolates has declined significantly, perhaps in response to the increased clinical use of this compound.34
Tigecycline
Tigecycline is a member of a new class of tetracycline-related antimicrobial agents, the glycylcyclines, and was found to have good in-vitro activity against some carbapenem-resistant acinetobacter isolates in preliminary studies.
43
, 44
However, clinical experience regarding the use of tigecycline for the treatment of patients with MDR A. baumannii infections has been somewhat mixed. In the available clinical reports, tigecycline has mainly been used, often in combination regimens, to treat a small number of critically ill patients with infections such as ventilator-associated pneumonia and primary or secondary bacteraemia.45
, 46
Most patients had a good outcome, but failure of tigecycline to clear A. baumannii bacteraemia was noted in a few cases, perhaps because of suboptimal concentrations of tigecycline in blood. In-vitro studies have revealed that resistance to tigecycline can be mediated by overexpression of a multidrug efflux pump, and the emergence of resistance to tigecycline during therapy has already been reported.45
, 47
Combination therapy
Various combinations of a carbapenem with sulbactam, tobramycin, amikacin, colistin, rifampicin and aztreonam have been assessed, both in vitro and in vivo, with somewhat mixed results.
34
Other reports have described the successful use of sulbactam, which has unusual intrinsic activity against Acinetobacter spp. (see above), in combination with ampicillin, or have proposed unusual combinations of antibiotics, such as polymyxin B, imipenem and rifampicin.48
, 49
, 50
Clinical data are too few to recommend the use of specific combination regimens for the treatment of infections caused by MDR strains of A. baumannii, but combination regimens might be considered by clinicians in order to achieve synergistic activity and to maximise antimicrobial effectiveness (as well as to minimise the possibility of emergence of further resistance) in severely ill patients for whom therapeutic options are otherwise limited.Discussion
A. baumannii and its close relatives have become a major cause of hospital-acquired infections primarily because of the remarkable ability of these bacteria to survive and spread in the hospital environment and to rapidly acquire resistance determinants to a wide range of antibacterial agents. Epidemic spread of MDR strains among patients in hospitals, particularly in ICUs, has been observed frequently, with infected patients disseminating large numbers of these organisms into their environment. The problem is then compounded by the long-term survival of these organisms on numerous surfaces and inanimate objects, and by their high degree of resistance to drying, disinfectants and antibiotics. Consequently, once endemic, these organisms are extremely difficult to eradicate from a particular healthcare unit.
Other special features of the genus Acinetobacter include the fact that, perhaps by accident, it has evolved a range of its own special resistance genes (particularly carbapenemases), as well as the capacity to overexpress them in response to antibiotic challenge. It has also evolved molecular mechanisms to capture resistance genes from other organisms, and has developed a range of expression mechanisms (e.g. provision of promoters on insertion sequences) that enables ‘foreign’ resistance genes to be expressed. Consequently, antimicrobial resistance now greatly limits the available therapeutic options, especially if isolates are resistant to the carbapenem class of antimicrobial agents, which would otherwise be the agents of choice for the treatment of severe infections caused by these organisms. Knowledge of the susceptibility patterns of strains endemic in particular geographical areas is essential, but therapy of infections caused by carbapenem-resistant strains frequently requires the use of unusual drugs (e.g. colistin or sulbactam), often in novel combinations, or of drugs for which there is presently very little clinical experience (e.g. tigecycline). Anecdotes, small case series and case reports suggest that such regimens can be efficacious in individual patients, although reports of resistance to new drugs and unusual combinations are already beginning to appear.
Well-controlled clinical trials of existing and new therapies, combined with greater emphasis on the prevention of healthcare-associated A. baumannii infections, are essential in order to combat the spread of these MDR organisms. Worldwide spread of MDR lineages of A. baumannii is now being observed, although the question of whether these lineages are selected primarily on the basis of the resistance genes that they carry or because there is something special about certain lineages that confers epidemic potential currently remains unanswered.
Conflict of interest statement
None.
Funding sources
Work on acinetobacter in K.J.T.'s laboratory is supported, in part, by a grant from the Medical Research Council (grant no. RA0119).
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Article info
Publication history
Published online: May 17, 2010
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© 2009 The Hospital Infection Society. Published by Elsevier Inc. All rights reserved.
