Antimicrobe.org: Acinetobacter species
drsuryabrata@gmail.comThis is an effort to preserve some wonderful materials I used as a trainee. This website is not being updated anymore and may disappear in the future. I have no intention of infringing the copyright - if antimicrobe.org wishes me to remove the material, please get in touch with me.
Updated June, 2013
Kevin J. Towner
Author Previous Editions: Eugenie Bergogne-Berezin
Microbiology Guided Medline Search
Acinetobacter spp are aerobic Gram-negative bacilli commonly present in soil and water as free-living saprophytes. They are also common commensals of skin, throat and secretions of healthy people. The genus Acinetobacter has undergone extensive and confusing changes in taxonomic nomenclature over many years, with strains being designated previously as Bacterium anitratum, Herellea vaginicola, Mima polymorpha, Achromobacter, Micrococcus calcoaceticus, Diplococcus, B5W and Cytophaga. The use of modern molecular-based taxonomic methods has allowed the identification of at least 34 different genomic groups in the genus Acinetobacter, including 23 named species that have been validly described (Table 1), with the probability that further species will be delineated in the future.
Members of the genus Acinetobacter are aerobic Gram-negative coccobacilli, usually found in diploid formation, or chains of variable length. They are non-motile, but some strains display a 'twitching motility' associated with the presence of polar fimbriae. They are strictly aerobic and grow easily on most common microbiological isolation media, with the optimum temperature for most clinical isolates being 33 – 37°C. Growth at 41 – 44°C occurs for a few species and is a discriminating phenotypic character, while some environmental species are unable to grow above 30°C. Acinetobacter spp. are oxidase-negative, catalase-positive, indole-negative, and nitrate-negative. Some strains produce acid from D-glucose, D-ribose, D-xylose, and L-arabinose (utilized oxidatively as carbon sources). These and other phenotypic characters are incorporated in various commercial identification systems (e.g., API 20NE, VITEK, Phoenix, MicroScan WalkAway); however, while these systems are relatively accurate at identifying isolates as members of the Acinetobacter genus, putative identification of an acinetobacter isolate to the species level by current automated, semi-automated or manual commercial systems should be regarded with caution.
Acinetobacter spp. first began to be recognized as significant nosocomial pathogens during the 1970s. These early clinical isolates were not identified to an adequate species level, and it is now recognized that A. baumannii and its close relatives (genomic species 3 and 13TU, together forming the ‘A. baumannii complex’) account for the vast majority (90 – 95%) of clinically significant infections. Many of these infections involve multidrug-resistant (MDR) strains, and occur in intensive care or high-dependency units in which severely-ill or debilitated patients are treated extensively with broad-spectrum antibiotics. It should be noted that the species names A. pittii and A. nosocomialis have been proposed for genomic species 3 and 13TU, respectively (70), but these names have not yet been formally accepted. A. calcoaceticus is also genetically closely related to the A. baumannii complex, but A. calcoaceticus is a soil organism that has only very rarely been implicated in human infections. 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 by the use of modern molecular taxonomic methods. Other Acinetobacter spp., such as A. johnsonii, A. lwoffii and A. radioresistens, can often be isolated as commensals from normal human skin in both healthy people and hospital patients, but these, and other environmental Acinetobacter spp., are only implicated rarely in human infections, chiefly catheter-related bacteremia (9, 105, 106) or point source infections (10, 44, 97), are generally more susceptible to antimicrobials, and are usually considered to be of minor virulence.
Baron EJ. Acinetobacter baumanni complex
Epidemiology Guided Medline Search
Members of the genus Acinetobacter are widely distributed in nature and can be isolated from soil and fresh-water samples, as well as from humans and animals. Human carriage of Acinetobacter has been demonstrated in normal healthy individuals. Certain Acinetobacter spp., chiefly A. johnsonii, A. lwoffii and A. radioresistens, are part of the bacterial flora of the skin, where they are found predominantly in moist skin areas.
A. baumannii is the main species associated with outbreaks of nosocomial infections. It is a common misconception that A. baumannii is a ubiquitous organism that can be readily found in soil and water, and 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 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 (73). A. baumannii can only be isolated very rarely from soil, water and other environmental samples; indeed, during non-outbreak periods it is isolated only rarely inside hospitals. In an infected patient, A. baumannii colonizes the skin, oral cavity, respiratory tract, and the intestinal tract (4). During an outbreak, A. baumannii can be isolated from numerous sources in the hospital environment (Table 2), and this wide dissemination in the hospital environment results in frequent carriage of Acinetobacter by hospital staff and patients. 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 often shedding extremely large numbers of A. baumannii cells into their surrounding environment.
Severe nosocomial infections and hospital outbreaks have been attributed mainly to A. baumannii, particularly in the intensive care unit (ICU) setting, and to a lesser extent to genomic species 13 (‘A. nosocomialis’) and genomic species 3 (‘A. pittii’). Nosocomial infections caused by other named Acinetobacter spp. such as A. bereziniae, A. guillouiae, A. haemolyticus, A. johnsonii, A. junii, A. lwoffii, A. parvus, A. radioresistens, A. schindleri, A. soli and A. ursingii are rare, and are restricted mainly to catheter-related bloodstream infections (105). These latter infections usually run a benign clinical course and their associated mortality is low. Small-sized outbreaks caused by Acinetobacter spp. other than A. baumannii and its close relatives have been observed occasionally, and are often found to be related to contaminated infusion fluids such as heparin solution. There have also been a few reports of community-acquired infections, usually in patients with co-morbidities in tropical or sub-tropical areas (73).
Several studies have analyzed risk factors for colonization and infection with A. baumannii. Major surgery, major trauma, burns, premature birth, previous hospitalization, stay in an ICU, length of hospital or ICU stay, mechanical ventilation, indwelling foreign devices (e.g., intravascular catheters, urinary catheters and drainage tubes), the number of invasive procedures performed, and previous antimicrobial therapy have all been identified as risk factors predisposing to the acquisition of and infection with A. baumannii (32).
Falagas ME, Karveli EA, et al. Community-Acquired Acinetobacter Infections. Eur J Clin Microbiol Infect Dis. 2007 Dec;26:857-68.
Gabriel M. Ortiz and David Graham: Acinetobacter in military personnel
[Review Article: Brook Army Medical Center. Multidrug-Resistant Acinetobacter Extremity Infections in Soldiers. Emerg Infect Dis, Aug 2005.]
Sebeny PJ, Riddle MS, Petersen K. Acinetobacter baumannii skin and soft-tissue infection associated with war trauma.Clin Infect Dis. 2008 Aug 15;47(4):444-9.
Clinical Manifestations Guided Medline Search
The main problems caused by Acinetobacter spp. in the hospital setting mostly concern critically-ill patients in ICUs, particularly those requiring mechanical ventilation, and patients with wound or burn injuries (trauma patients). Infections associated with Acinetobacter spp. include ventilator-associated pneumonia, skin and soft-tissue infections, wound infections, urinary tract infections, peritonitis, secondary meningitis and bloodstream infections (9, 73). 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 co-morbidities in tropical or subtropical areas (73).
Nosocomial Infections. Ventilator-associated pneumonia (VAP) is the most frequent clinical manifestation of hospital-acquired A. baumannii infection, although it is sometimes difficult to distinguish upper respiratory tract colonization from true infection. Data from the National Nosocomial Surveillance System (NNIS) have revealed a substantial increase in the number of cases of A. baumannii-associated nosocomial pneumonia, with 5 – 10% of cases of ICU-acquired pneumonia in the USA being caused by A. baumannii (34). Bacteremic pneumonia carries a particular poor prognosis (86). Acinetobacter pneumonia does not differ clinically from other pneumonias caused by Gram-negative bacteria, with fever, leukocytosis, purulent sputum production and appearance of new infiltrates on radiograph or CT scan. The organism can be isolated from pulmonary procedures, including bronchial brushings or bronchoalveolar lavage (15). Acinetobacter respiratory tract infections occur predominantly in mechanically ventilated patients (13, 33, 40, 68) and elderly patients with underlying diseases (60). In large series of A. baumannii infections, pneumonias represent 26.7 – 47.9% of Acinetobacter nosocomial infections (40, 58).
A. baumannii ranks 10th among the most frequent organisms causing nosocomial bloodstream infections in the USA, being responsible for 1.3% of all monomicrobial nosocomial bloodstream infections (105). Risk factors predisposing to bacteremia are pneumonia, trauma, surgery, presence of catheters or intravenous lines, dialysis and burns (53, 60, 106). Immunosuppression or respiratory failure at admission increases the risk of bacteremia three-fold, with increased risk for nosocomial pneumonia (32). Bacteremic episodes are characterized by fever, leukocytosis and successive positive blood cultures with the same genotypic isolate of Acinetobacter (23, 51, 62, 101, 106). The prognosis is determined by the underlying condition of the patient, but A. baumannii bloodstream infection may be associated with considerable morbidity and (overall) mortality as high as 58% (17). Risk factors for a fatal outcome are severity-of-illness markers, such as septic shock at onset of infection, elevated APACHE II score, and ultimately fatal underlying disease. However, a recent study revealed that about 30% of bloodstream infections attributed to A. baumannii were actually caused by ‘A. nosocomialis’ and ‘A. pittii’, and that the organisms involved were misidentified by commercial identification systems (17). Mixed infections with other bacteria are common in cases of Acinetobacter bacteremia. It should also be noted that 10 – 15% of Acinetobacter isolates from blood cultures typically belong to species other than those included in the A. baumannii complex. Such isolates are often associated with skin contamination and should be regarded with caution unless repeat cultures are obtained.
It has long been known that A. baumannii may cause wound colonization and infection in patients with severe burns or trauma. In recent years, nosocomial A. baumannii wound infection has also been associated particularly with natural catastrophes or man-made disasters (e.g., earthquakes, floods, the tsunami catastrophe of 2004, terrorist attacks and military campaigns) when hospitals’ capacities for patient care are overloaded and standard hygiene procedures can no longer be enforced (83, 84). A. baumannii first came to wider public attention when severe wound infections, burn wound infections and osteomyelitis were reported in soldiers who had suffered major injuries during military operations in Iraq or Afghanistan, and who were then repatriated to the USA or the UK (20, 83, 84). The isolates from these infections were often MDR. Based on a widespread misinterpretation that “A. baumannii is a ubiquitous organism”, it was speculated that the organism might have been inoculated at the timeof injury, either from previously colonized skin or from contaminated dust or soil. However, it is now considered that the soldiers acquired their infecting organism during emergency care at field hospitals or following cross-transmission during their hospitalization in military hospitals (83).
A. baumannii occasionally causes urinary tract infection, often related to indwelling Foley catheters. These infections are usually benign and occur more frequently in rehabilitation centres than in ICUs (24). Overall, the incidence of urinary tract infections has decreased in recent years, probably thanks to improved care of urinary catheters.
A distinct clinical entity is cerebrospinal shunt-related meningitis in neurosurgical patients (49). Such infections include ventriculoperitoneal shunt infections (29), epidural infections, intraventricular (28) and intrathecal infections (7, 69, 71). Neonatal cases are not exceptional (69). Risk factors for acquisition of Acinetobacter meningitis include a continuous connection between ventricules, a ventriculostomy or a CSF fistula, and the external environment. In addition, the immunological condition of the patient, e.g., HIV status, and a contaminated environment are significant factors for the development of Acinetobacter neurological infections (11, 22). Community-acquired meningitis is not exceptional and may occur in patients with underlying factors such as alcoholism and diminished immune defenses (14).
Skin carriage of Acinetobacter spp. is common (4), and skin infections have been associated with decubitus ulcers, lower extremity ulcers, superinfection of eczema and onychodystrophy of the hands (8, 82). Skin infection in burn patients has also been increasingly associated with Acinetobacter spp. (37, 103).
A range of other unusual case reports involving Acinetobacter spp. have appeared in the literature, including suppurative thyroiditis, necrotizing enterocolitis, and peritonitis (8, 65, 111), as well as a case of Acinetobacter pericarditis with tamponade that occurred in a patient with systemic lupus erythematosus (54).
Community-Acquired Infections: Acinetobacter spp. have been reported occasionally as causative agents of community-acquired infections such as wound infection, urinary tract infection, otitis media, eye infections, meningitis and endocarditis. However, identification to the species level was not performed with reference methods in most of these case reports, leaving doubts about the exact species of Acinetobacter involved. In addition, Acinetobacter spp. other than A. baumannii and its close relatives are normal commensals, often colonizing the skin and mucous membranes of humans, and their isolation may therefore have been misinterpreted as being indicative of agents causing infection. Nevertheless, A. baumannii is recognized as a rare but important cause of severe community-acquired pneumonia in tropical areas of Asia and Australia. Such patients typically have severe underlying disease, such as chronic obstructive pulmonary disease, as well as diabetes mellitus or a history of excessive alcohol consumption or heavy smoking. These cases often run a fulminant clinical course with a high incidence of bacteremia and a high mortality rate of 40 – 64% (16).
Clinical Impact: A. baumannii infections mainly affect patients with severe underlying disease, and are associated with major surgery, burns or trauma, concomitant infections, high APACHE II scores, and a poor prognosis. Most studies report high overall mortality rates in patients with A. baumannii bacteremia or pneumonia. The true clinical impact of nosocomial A. baumannii infection in these patients is difficult to assess and has been a matter of continuous debate in the literature. While previously many researchers claimed that patients died with A. baumannii (i.e., from their underlying disease) rather than from A. baumannii infection, a review of matched cohort and case-control studies concluded that A. baumannii infections are associated with increased attributable mortality of 8 – 32%, but that methodological heterogeneity among the studies reviewed did not allow a meta-analysis to determine a definitive conclusion (27). Unfortunately, the clinical impact of A. baumannii is coupled with increasing resistance of A. baumannii to the major antimicrobial drugs. This is a cause for serious concern, particularly as this organism is also known for its propensity for nosocomial cross-transmission, perhaps because of its multidrug resistance and its capacity for long-term survival in the hospital environment.
Kim BN et al. Management of Meningitis due to Antibiotic-resistant Acinetobacter species.Lancet Infect Dis. 2009 Apr;9(4):245-55.
Laboratory Diagnosis Guided Medline Search
Examination of specimens taken from any site of Acinetobacter infection constitutes the reference method for isolating and identifying the infecting organism. The genus Acinetobacter comprises Gram-negative (albeit sometimes ‘Gram-variable’), non-motile, oxidase-negative, glucose non-fermenting, strictly aerobic, catalase-positive bacteria with a G+C content of 39 – 47% . The cells are ~ 1.5 mm in length, with a shape varying from coccoid to coccobacillary, depending on the growth phase. Most Acinetobacter spp. are metabolically versatile and can be grown easily on simple microbiological media, forming domed, smooth colonies of ~2 mm diameter, with some species being pigmented pale yellow or grey. The temperature range is typical of mesophylic bacteria; clinically relevant species grow optimally at ~37°C, while environmental species may prefer lower temperatures. Culture in slightly acidic mineral medium containing acetate and nitrate as carbon and nitrogen sources, respectively, or in Leeds selective medium (42) or on similar commercially available selective agars,can improve the recovery of Acinetobacter spp. from complex microbial communities, and can be used for enrichment of clinical or environmental specimens. Hemolytic activity on 5% sheep blood agar plates is observed occasionally, and hydrolysis of gelatin and urea, as well as formation of acid from glucose are also variable traits.
The above tests permit identification to the genus level, but identification of Acinetobacter spp. to the individual species level is difficult for routine microbiology laboratories. Phenotypic identification schemes are inadequate for identification of individual Acinetobacter spp. This holds true even for the commercially available automated identification systems (e.g., API 20NE, VITEK, Phoenix, MicroScan WalkAway) that are now used routinely in many clinical microbiology laboratories. Therefore, clinical and epidemiological studies in which species identification of Acinetobacter isolates is achieved only by chemotaxonomic systems should be interpreted with caution.
A. baumannii, A. calcoaceticus, genomic species 3 (‘A. pittii’) and genomic species 13TU (‘A. nosocomialis’) are closely related according to DNA-DNA hybridization studies, and can hardly be distinguished according to phenotypic or chemotaxonomic criteria. For convenience, many laboratories often group these genomic species together in the so-called ‘A. calcoaceticus – A. baumannii (Acb) complex’. From a clinical viewpoint, such grouping is undesirable as it combines the three most important species implicated in human disease (A. baumannii and genomic species 3 and 13TU) with A. calcoaceticus, which is essentially a soil organism. Considerable effort has therefore been dedicated to the development of new and user-friendly molecular techniques for precise identification of individual Acinetobacter spp., in order to better delineate their ecology, epidemiology and pathogenicity (73). In the clinical laboratory, PCR amplification of species-specific DNA regions (e.g., the blaOXA-51 carbapenemase gene intrinsic to A. baumannii) can be a valuable tool for confirmatory identification of individual pathogenic species (95). Similarly, it has proved possible to distinguish members of the Acb complex by using specific primers to amplify distinguishing regions of the gyrB gene (38, 39).
Pathogenesis Guided Medline Search
Acinetobacter was initially considered to be an organism of low virulence, but the occurrence of fulminant community-acquired Acinetobacter pneumonia (59) indicates that this organism can be of high virulence and cause invasive disease. Relative to other pathogenic Gram-negative organisms, very little is known about Acinetobacter virulence mechanisms and host responses to infection. Model systems have now been established to study A. baumannii pathogenesis, including in vitro abiotic and biotic models, and in vivo systems including invertebrate and mammalian models (72).The success of A. baumannii has so far been attributed to several factors: (i) its ability to form biofilms and resist dessication on abiotic surfaces (i.e., medical devices and environmental surfaces) (63, 94, 98, 99); (ii) its ability to adhere to, colonize and invade human epithelial cells (56, 57); (iii) its repertoire of antibiotic resistance mechanisms that can be up-regulated as required (3, 73, 76); and (iv) its ability to acquire foreign genetic material through lateral gene transfer to promote its own survival under antibiotic and host selection pressures (1, 89). Several specific potential virulence mechanisms have been identified, but despite recent advances, knowledge regarding the molecular pathogenesis and genetics of A. baumannii is still in its infancy.
SUSCEPTIBILITY IN VITRO AND IN VIVO Guided Medline SearchIn Vitro and In Vivo
Single Drug
Acinetobacter infections are often severe and difficult to treat due to high rates of resistance among clinical strains to major antibiotic classes (3, 79, 96, 100). Members of the genus Acinetobacter are characterized by their ability to rapidly develop resistance to new antibiotics. Successive surveys have shown increasing resistance among clinical isolates, and high proportions of isolates are now insusceptible to clinically achievable concentrations of most commonly used antibacterial agents, including aminopenicillins, ureidopenicillins, broad-spectrum cephalosporins, aminoglycosides, fluoroquinolones, chloramphenicol and tetracyclines. Carbapenems (especially imipenem and meropenem) have, until recently, remained effective in some geographical areas, but carbapenem resistance in clinical isolates of Acinetobacter spp. is now being reported worldwide, with some isolates being clinically insusceptible to all conventional antimicrobial agents (18, 25, 74, 76).
Combination Drugs
In vitro studies have shown that combinations of drugs can sometimes be synergic and highly bactericidal against clinical isolates of A. baumannii (19, 67, 90). Such synergic combinations include an aminoglycoside plus a β-lactam (ticarcillin, or a third-generation cephalosporin, or imipenem). For isolates highly resistant to aminoglycosides and/or fluoroquinolones, unconventional combinations have occasionally been successful in treating patients (67, 91, 107, 109). However, the existence of multiple diverse mechanisms of resistance in clinical isolates means that each strain must be tested against individual and combined antibiotics, using appropriatein vitrotechniques.
Review Article: Perez F, Hujer AM, et al. Global Challenge of Multidrug-Resistant Acinetobacter baumannii. Antimicrob Agents Chemother. 2007 Oct;51:3471-84.
Sopirala MM, et al. Synergy Testing by Etest, Microdilution Checkerboard, and Time-Kill Methods for Pan-Drug-Resistant Aceintobacter baumannii. Antimicrob Agents Chemother 2010;54:4678-4683.
ANTIMICROBIAL THERAPY Smart search Guided Medline Search
Drug of Choice
No general recommendation concerning a drug of choice or dosage regimen can be made with any degree of confidence. The spread and persistence in geographical locations of particular epidemic lineages of A. baumannii means that knowledge of the prevalent local susceptibility pattern is essential when selecting antibiotic therapy for Acinetobacter infection. It is important to emphasize that clinical isolates of A. baumannii are now frequently MDR, and that some isolates are clinically insusceptible to all conventional antimicrobial agents (18, 25, 74, 76). Infections can therefore be extremely difficult to treat successfully, with full laboratory susceptibility testing required in order to identify drugs with residual activity or potentially effective combinations. In the absence of susceptibility data, a carbapenem (usually imipenem or meropenem) has been the empiric drug of choice for treating Acinetobacter infection for the past 20 years. However, recent years have seen the emergence and worldwide spread of epidemic lineages with diminished susceptibility to carbapenems. Nevertheless, until the results of susceptibility tests are available, a carbapenem, either alone or in combination with another antibiotic class (see below), is probably still the best choice for empiric therapy of Acinetobacter infections unless local endemic strains likely to be causing an infection in a particular setting are already known to be carbapenem-resistant. 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. It is therefore strongly recommended that an infectious diseases consultant should review local antibiotic susceptibility patterns and culture results at the earliest opportunity to advise on appropriate drugs, doses and duration of therapy. In general, monotherapy is not advisable.
Bassetti M, Repetto E. Colistin and rifampicin in the treatment of multidrug-resistant Acinetobacter baumannii infections. J Antimicrob Chemother 2008 Jan 3 [Epub ahead of print]
Schafer JJ, Goff DA, et al. Early experience with tigecycline for ventilator-associated pneumonia and bacteremia caused by multidrug-resistant Acinetobacter baumanii. Pharmacotherapy 2007;27(7):980-987.
Gordon NC and Wareham DW. A Review of Clinical and Microbiological Outcomes Following Treatment of Infections Involving Multidrug-resistant Acinetobacter baumannii with Tigecycline. J Antimicrob Chemother. 2009 Jan 21. [Epub ahead of print]
Ziaka M, et al. Combined intravenous and Intraventricular Administration of Colistin Methanesulfonate in Critically Ill Patients with Central Nervous System Infection. Antimicrobial Agents and Chemotherapy 2013;57:1938-1940.
Special Infections
Pneumonia: Acinetobacter most commonly infects the respiratory tract, causing tracheobronchitis and/or pneumonia. Both community-acquired and nosocomial pneumonia are associated with striking mortality rates, and the initial choice of antimicrobial therapy can be critical. Carbapenems are usually considered to be the drugs of choice, often in combination with other antimicrobial agents (58-60). In cases of carbapenem resistance, alternative antimicrobial choices have included ampicillin/sulbactam plus an aminoglycoside (107) or intravenous colistin (33).
Meningitis: Nosocomial meningitis is a not infrequent manifestation of Acinetobacter infection (28, 29, 108). Cases of meningitis have been reported after neurosurgical procedures (108), and rare cases of community-acquired primary meningitis have also occurred (14). Acinetobacter meningitis may result from the introduction of the organism directly into the CNS following intracranial surgery or via indwelling ventriculostomy tubes or cerebrospinal fluid fistulae. Ureidopenicillin plus an aminoglycoside has been used as empiric therapy, with or without the addition of intrathecal amikacin injections (88). Successful treatment of Acinetobacter meningitis has also been reported following the use of intrathecal polymyxin E, despite numerous central nervous system side effects (7). Pefloxacin at a dosage of 800 mg twice daily has been used successfully to treat Acinetobacter meningitis, achieving a mean CSF concentration of 8.8 mg/l (85). Generally favorable results have also been obtained following treatment of cases of multiresistant A. baumannii meningitis with ampicillin/sulbactam (2 g/1g every 6 hrs or 2g/1g every 8 hours) (43, 48), although it should be noted that insusceptibility to the ampicillin/sulbactam combination is now also being reported increasingly.
Endocarditis: Empiric treatment should include broad-spectrum antibiotic therapy. In 15 cases of Acinetobacter native or prothetic valve endocarditis, 10 were cured using various antibiotic combinations, but one case was treated successfully with imipenem monotherapy (60).
Alternative Therapy
Aminoglycosides: Case reports concerning the clinical use of aminoglycosides for the treatment of Acinetobacter infections are scarce, and generally describe the use of aminoglycosides in combination with other classes of antimicrobial agents. However,depending on the results of susceptibility tests, aminoglycosides, particularly amikacin, continue to show useful in-vitro activity against up to 60% of strains in some centres, including a small proportion of carbapenem-resistant isolates (45). Case reports concerning the clinical use of aminoglycosides to treat infections in humans generally refer to cases of bacteremia or meningitis (45).
Fluoroquinolones: Historically, fluoroquinolones have had reasonably good activity against A. baumannii, but resistance to these antibiotics has emerged rapidly in clinical isolates since the 1990s. Susceptibility rates to ciprofloxacin in global collections of Acinetobacter isolates have generally been in the range of 40 – 50% (30, 96), but activity against recent MDR or carbapenem-resistant isolates of A. baumannii has been low (30, 36, 81, 96). Newer fluoroquinolones, such as moxifloxacin, sometimes have increased in vitro activity against A. baumannii when compared with older agents such as ciprofloxacin. Again, there are very few in vivo data concerning the treatment of A. baumannii infections with fluoroquinolones.
Polymyxins: Two agents of this class are currently available for clinicaluse, i.e., polymyxin B and colistin (polymyxin E). These compounds are cationic polypeptides that interact with the lipopolysaccharide molecules in the outer cell membranes of Gram-negative bacteria. Colistin itself is available in two forms, colistin sulphate for oral and topical use, and colistin sulphomethate sodium (CMS) for parenteral use, with the latter being a non-active prodrug that is used for parenteral administration because of its lower toxicity (36). Although there are few in vivo experimental studies, intravenous colistin therapy, either alone or in combinations (see below) has produced favorable clinical responses in case-series of ICU patients with various types of infections, including ventilator-associated pneumonia and nosocomial meningitis (45, 47, 73). Perhaps surprisingly, reports of colistin toxicity, particularly nephrotoxicity, are relatively rare (45).
Polymyxins can also be administered in a nebulized form via the respiratory tract, and several small studies have reported clinical effectiveness in patients with nosocomial pneumonia caused by A. baumannii (45). Unfortunately, no prospective comparative study has been performed in patients to assess the efficacy of nebulised colistin for treating infections caused by A. baumannii. Very little is known about the critical pharmacological parameters that govern dosing for maximal efficacy and minimal toxicity. In particular, patients with pre-existing renal disorders and those receiving renal replacement therapy should be treated with great caution. Of concern is the fact that increasing use of polymyxins to treat A. baumannii infections in critically-ill patients may lead rapidly to the emergence of resistance (50), and heteroresistance of A. baumannii isolates to colistin has also been described (92). These observations serve to emphasise the importance of prudent use of these compounds and the need for further detailed clinical and pharmacological studies before the use of colistin becomes widespread.
Sulbactam: In-vitro competition binding experiments have revealed that the ß-lactamase inhibitors sulbactam, clavulanic acid and tazobactam all have intrinsic activity against A. baumannii. However, as currently formulated for clinical use, in vitro data suggest that only sulbactam is likely to have in vivo activity against A. baumannii (73). In vitro susceptibilities of A. baumannii to sulbactam vary widely, according to the precise geographical region (61). As with other antibiotic classes, there have been no adequate randomised clinical trials with sulbactam. Nevertheless, favorable clinical outcomes have been reported with sulbactam, or a combination of ampicillin and sulbactam, in patients with various types of nosocomial infections caused by MDR strains of A. baumannii, including ventilator-associated pneumonia, bacteremia and nosocomial meningitis (45, 73). Overall, experience to date suggests that sulbactam can be considered as a therapeutic option for mild-to-severe A. baumannii infections. However, recent studies suggest that the antimicrobial activity of sulbactam against A. baumannii isolates has declined significantly, perhaps in response to the increased clinical use of this compound, with sulbactam resistance appearing to be common in certain geographical areas (45).
Tetracyclines: Minocycline, doxycycline and tetracycline show some in vitroactivity against a moderate proportion of A. baumanniiisolates in some geographical regions. Minocycline sometimesretains in-vitro activity against strains that are resistantto tetracycline or doxycycline (45). Several studies havesuggested that >90% of recent A. baumannii isolates retain at least some susceptibility to minocycline (2, 78). However, there are significant problems in determining minocycline susceptibilities accurately, and despite this apparent in vitro activity, there are very few clinical or experimental data to support the use of tetracyclines for the treatment of A. baumannii infections (45).
Tigecycline: Tigecycline was revealed in preliminary studies to have good in vitro activity against some carbapenem-resistant A. baumannii isolates. Clinical reports have described the use of tigecycline, often in combination regimens, to treat a small number of critically-ill patients with A. baumannii infectionssuch as ventilator-associated pneumonia and primary or secondary bacteremia (31, 35, 46, 80, 91). However, the correlation between microbiological and clinical outcomes seems to be rather poor, particularly among patients treated for respiratory tract infection (31, 35, 46). Failure of tigecycline to clear A. baumannii bacteremia has been noted in a few cases, perhaps because of sub-optimal concentrations of tigecycline in blood. The development of resistance during therapy with tigecycline has also been observed (35, 46). It therefore seems prudent to avoid the use of tigecycline as monotherapy for the empiric treatment of bloodstream infections caused by A. baumannii until a prospective study, including a comprehensive pharmacokinetic/pharmacodynamic analysis of its role, either as monotherapy or in combination with other antibiotics, has been performed.
Combination Therapy
Clinical data are too few to recommend the use of specific combination regimens for the treatment of infections caused by MDR strains of A. baumannii, but various combinations of antimicrobial agents have been used to treat individual patients, albeit with somewhat mixed results (45). Some reports have described the successful use of sulbactam, which has unusual intrinsic activity against Acinetobacter spp., in combination with ampicillin (19, 61), or have proposed unusual combinations of antibiotics, such as polymyxin B, minocycline, imipenem and rifampicin (93, 102, 110). In general, most in vitro studies that have assessed combinations of sulbactam with either carbapenems or cefepime have reported promising results (45). In vitro studies have suggested that colistin in combination with meropenem and/or sulbactam might provide good therapeutic results (55). Similarly, time-kill assays identified a synergic interaction between tigecycline and levofloxacin, amikacin, imipenem and colistin for five of seven selected isolates (77). A combination of rifampicin and colistin has been used with good results to treat critically-ill patients with pneumonia and bacteraemia caused by A. baumannii resistant to all antibiotics except colistin (6). Fluoroquinolones have also been used to treat Acinetobacter infections, particularly in combination with ceftazidime (60). Ciprofloxacin plus imipenem has yielded favorable patient outcomes in treating Acinetobacter pneumonia (15).
Overall, it seems that combination regimens might be considered by clinicians in an attempt to overcome the problem of carbapenem resistance 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. Nevertheless, nearly all of the available data refer to in vitro or in vivo animal studies. Apart from individual case reports, clinical data to support the use of specific novel combination therapies to combat infections caused by MDR and pan-resistant strains of A. baumannii are currently lacking.
Review Article: Perez F, Hujer AM, et al. Global Challenge of Multidrug-Resistant Acinetobacter baumannii. Antimicrob Agents Chemother. 2007 Oct;51:3471-84.
Kim BN et al. Management of Meningitis due to Antibiotic-resistant Acinetobacter species.Lancet Infect Dis. 2009 Apr;9(4):245-55.
ENDPOINTS FOR MONITORING THERAPY Guided Medline Search
For bacteremia, endocarditis, and meningitis, repeat cultures from blood or CSF are indicated if clinical response including defervescence does not occur. For non-sterile sites, especially wounds and the respiratory tract, immediate bacteriologic response as measured by negative cultures may not be forthcoming because of the possibility of colonization. Clinical response should take priority over bacteriologic response when assessing efficacy of therapy. If bacteriologic persistence occurs despite antibiotic therapy, and the clinical response is sub-optimal, antibiotic susceptibilities should be repeated and therapy guided by the results of this testing.
VACCINES Guided Medline Search
There are currently no vaccines for use in humans available against A. baumannii or other members of the genus Acinetobacter. These bacteria are antigenically complex and do not lend themselves easily to the production of a vaccine.
ADJUNCTIVE THERAPY Guided Medline Search
Antimicrobial therapy is generally insufficient to eradicate these organisms from the site of infection. Adjunctive therapy in ICU patients includes infection control measures and standard ICU care. Selective digestive decontamination has been advocated to prevent translocation of Acinetobacter and other intestinal colonizing flora to other infection sites, but confirmation of the efficacy of this procedure in controlled trials is lacking (87).
PREVENTION Smart searchGuided Medline Search
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 the incorporation of a range of enhanced measures, including 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 nebulized colistin for patients with evidence of mild-to-moderate ventilator-associated pneumonia has shown some evidence of success (104). 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 4 weeks in order to combat A. baumannii outbreaks (12, 21, 22, 41, 52, 64, 66, 75)
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).
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.
TABLES
Table 1. Validly Described Named Species of Acinetobacter (www.bacterio.cict.fr)
Table 2. Examples of Potential Environmental Sources of A. baumannii During Hospital Outbreaks
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Table 1. Validly Described Named Species of Acinetobacter (www.bacterio.cict.fr)
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A. calcoaceticus A. ursingii (sp.3 - A. pittii b)
A. parvus A. beijerinckii (sp.13TU - A. nosocomialisb)
A. baumannii A. soli
A. baylyi A. venetianus plus at least 9 other unnamed
A. haemolyticus A. gerneri genomic species
A. bouvetii A. radioresistens
A. junii A. bereziniae
A. tjernbergiae A. guillouiae
A. towneri A. schindleri
A. johnsonii A. gyllenbergii
A. tandoii A.grimontiia
A. lwoffii
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asynonym of A. junii; bproposed species name not yet formally accepted.
Table 2. Examples of Potential Environmental Sources of A. baumannii During Hospital Outbreaks
Patients Hands of staff
Blood pressure cuffs Parenteral nutrition solution
Gloves Humidifiers
Respirometers Lotion dispensers
Rubbish bins Air supply
Bowls Hand cream
Bedside charts Service ducts/dust
Computer keyboards Cell phones
Ventilators and tubing Oxygen analysers
Bronchoscopes Bed frames
Sinks Jugs
Soap Plastic screens
Bed linen, pillows and mattresses Resuscitation bags
Vignettes
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Review Article: Raad, I., Hanna, H. and Maki, D. Intravascular Catheter-related Infections: Advances in Diagnosis, Prevention and Management. The LANCET Infectious Diseases 2007; Vol.7, Issue 10, 645-657.
Gabriel M. Ortiz and David Graham: Acinetobacter in military personnel
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