SEARCH

SEARCH BY CITATION

Keywords:

  • Acinetobacter;
  • antimicrobial resistance;
  • carbapenems;
  • Europe;
  • review;
  • surveillance

Abstract

  1. Top of page
  2. Abstract
  3. Search strategy and selection criteria
  4. The acinetobacter genus and clinically important species
  5. Nosocomial infections caused by acinetobacter spp.
  6. Epidemiology of acinetobacter spp.
  7. Clonal spread of epidemic strains
  8. The emergence of resistance
  9. Β-Lactams
  10. Aminoglycosides
  11. Quinolones
  12. Other antibiotics
  13. Genetics of resistance
  14. Treatment options for carbapenem-resistant acinetobacter spp.
  15. Conclusions
  16. Acknowledgements
  17. References

Bacteria of the genus Acinetobacter are ubiquitous in nature. These organisms were invariably susceptible to many antibiotics in the 1970s. Since that time, acinetobacters have emerged as multiresistant opportunistic nosocomial pathogens. The taxonomy of the genus Acinetobacter underwent extensive revision in the mid-1980s, and at least 32 named and unnamed species have now been described. Of these, Acinetobacter baumannii and the closely related unnamed genomic species 3 and 13 sensu Tjernberg and Ursing (13TU) are the most relevant clinically. Multiresistant strains of these species causing bacteraemia, pneumonia, meningitis, urinary tract infections and surgical wound infections have been isolated from hospitalised patients worldwide. This review provides an overview of the antimicrobial susceptibilities of Acinetobacter spp. in Europe, as well as the main mechanisms of antimicrobial resistance, and summarises the remaining treatment options for multiresistant Acinetobacter infections.


Search strategy and selection criteria

  1. Top of page
  2. Abstract
  3. Search strategy and selection criteria
  4. The acinetobacter genus and clinically important species
  5. Nosocomial infections caused by acinetobacter spp.
  6. Epidemiology of acinetobacter spp.
  7. Clonal spread of epidemic strains
  8. The emergence of resistance
  9. Β-Lactams
  10. Aminoglycosides
  11. Quinolones
  12. Other antibiotics
  13. Genetics of resistance
  14. Treatment options for carbapenem-resistant acinetobacter spp.
  15. Conclusions
  16. Acknowledgements
  17. References

Data for this review were obtained through searches of Medline and Pubmed, from references cited in relevant articles, through searches of abstracts and posters presented at different national and international meetings, from the worldwide web, and from surveillance studies, associated with the introduction of new agents, conducted by the pharmaceutical industry. Search terms used were ‘Acinetobacter’, ‘antimicrobial resistance’, ‘antibiotics’, ‘carbapenems’, ‘aminoglycosides’, ‘quinolones’ and ‘treatment’. Only studies published in English, French, German or Dutch were reviewed. The first phase of the literature search resulted in the identification of > 3500 references, but initial review of the abstracts revealed that many articles were duplicated across the different search strategies. After exclusion of duplicate references, 2158 studies published between 1963 and 2003 remained. Of these, 267 were downloaded for detailed review.

The acinetobacter genus and clinically important species

  1. Top of page
  2. Abstract
  3. Search strategy and selection criteria
  4. The acinetobacter genus and clinically important species
  5. Nosocomial infections caused by acinetobacter spp.
  6. Epidemiology of acinetobacter spp.
  7. Clonal spread of epidemic strains
  8. The emergence of resistance
  9. Β-Lactams
  10. Aminoglycosides
  11. Quinolones
  12. Other antibiotics
  13. Genetics of resistance
  14. Treatment options for carbapenem-resistant acinetobacter spp.
  15. Conclusions
  16. Acknowledgements
  17. References

Acinetobacter spp. are glucose-non-fermentative, non-fastidious, strictly aerobic Gram-negative coccobacilli, usually occurring in diploid formation, or in chains of variable length. They are non-motile, catalase-positive and oxidase-negative [1]. Since 1986, the taxonomy of the genus Acinetobacter has undergone extensive revision. The original single species named Acinetobacter calcoaceticus has been abandoned, and at least 32 genomic species have now been proposed, of which 17 have been assigned species names. Correct identification of acinetobacters to the species level by the use of phenotypic methods is problematic [2,3]. In particular, discrimination between Acinetobacter baumannii and the genetically closely related unnamed genomic species 3 and 13 sensu Tjernberg and Ursing (13TU) is difficult. Genotypic methods, such as amplified ribosomal DNA restriction analysis [4] and analysis of whole genome fingerprints obtained by selective amplification of restriction fragments [5,6], have been useful for precise species identification when tested against libraries of well-validated strains, but these methods are not currently suitable for use in routine clinical diagnostic microbiology laboratories.

Studies using well-validated identification methods have shown clearly that most clinical isolates are strains of A. baumannii[7], and that this species, and to a lesser extent the closely related unnamed genomic species 3 and 13TU, are responsible for most infections and hospital outbreaks involving Acinetobacter spp. [3,4,6,8–11]. Other species, such as Acinetobacter junii, have been implicated only occasionally in outbreaks of nosocomial infection [3].

It is worth emphasising that the species names mentioned in the present review are those used by the authors of the original papers, and should be considered with some caution, given the problems of phenotypic identification in most of the studies reviewed. In articles published before the mid-1980s, the taxonomic status of the organisms is even more obscure, since, at that time, the genus Acinetobacter included only one all-encompassing species. Because of these considerations, acinetobacters are denoted as Acinetobacter spp. in the current review if their taxonomic status at the species level is uncertain.

Nosocomial infections caused by acinetobacter spp.

  1. Top of page
  2. Abstract
  3. Search strategy and selection criteria
  4. The acinetobacter genus and clinically important species
  5. Nosocomial infections caused by acinetobacter spp.
  6. Epidemiology of acinetobacter spp.
  7. Clonal spread of epidemic strains
  8. The emergence of resistance
  9. Β-Lactams
  10. Aminoglycosides
  11. Quinolones
  12. Other antibiotics
  13. Genetics of resistance
  14. Treatment options for carbapenem-resistant acinetobacter spp.
  15. Conclusions
  16. Acknowledgements
  17. References

Acinetobacter spp. are recognised as important opportunistic pathogens mainly in immunocompromised patients [12]. Their contribution to nosocomial infection has increased over the past three decades, and many outbreaks of hospital infection involving acinetobacters have been reported worldwide. According to data from the National Nosocomial Infections Surveillance system, Acinetobacter spp. were isolated in 1% of all nosocomial infections from 1990 to 1992 [13]. However, the true frequency of nosocomial infection caused by Acinetobacter spp. is difficult to assess because isolation of Acinetobacter spp. in clinical specimens may reflect colonisation rather than infection [14].

Although prevalent in nature and regarded generally as commensals of human skin and the human respiratory tract, acinetobacters have also been implicated as the cause of serious infectious diseases such as pneumonia, urinary tract infection, endocarditis, wound infection, meningitis and septicaemia, involving mostly patients with impaired host defences [12]. Acinetobacter spp. have emerged as particularly important organisms in intensive care units (ICUs), and this is probably related, at least in part, to the increasingly invasive diagnostic and therapeutic procedures used in hospital ICUs in recent years [12]. Risk factors for acquisition of Acinetobacter spp. include hospitalisation, poor general medical status of patients, mechanical ventilation, cardiovascular or respiratory failure, previous infection or antimicrobial therapy, and the presence of central venous or urinary catheters [15].

Epidemiology of acinetobacter spp.

  1. Top of page
  2. Abstract
  3. Search strategy and selection criteria
  4. The acinetobacter genus and clinically important species
  5. Nosocomial infections caused by acinetobacter spp.
  6. Epidemiology of acinetobacter spp.
  7. Clonal spread of epidemic strains
  8. The emergence of resistance
  9. Β-Lactams
  10. Aminoglycosides
  11. Quinolones
  12. Other antibiotics
  13. Genetics of resistance
  14. Treatment options for carbapenem-resistant acinetobacter spp.
  15. Conclusions
  16. Acknowledgements
  17. References

Acinetobacters are ubiquitous in nature; they can be recovered easily from soil or water, and have also been found frequently in animal and human hosts [16]. Several studies during the 1960s and 1970s reported isolation of these organisms from the skin of healthy individuals at rates of 0.8–20% for glucose-acidifying acinetobacters (Herellea vaginicola c.q. Acinetobacter anitratus), and 0–33.6% for glucose-non-acidifying acinetobacters (Mima polymorpha c.q. Acinetobacter lwoffii) [17–20]. Skin colonisation of patients plays an important role in the subsequent contamination of the hands of hospital staff during contacts, thereby contributing to the spread of the organisms [21]. High colonisation rates of the skin, throat, respiratory system or digestive tract, of various degrees of importance, have been documented in several outbreaks. However, general conclusions on the clinical significance of skin and mucosal Acinetobacter carriage are difficult to draw if the organisms are not identified correctly to the species level.

The epidemiology of Acinetobacter at the local institutional level can be investigated without reference to the taxonomy if the organisms are typed using appropriate methods. Cell-envelope protein profiling has shown that multiple body sites of patients can be colonised with clinically relevant strains for days to weeks, even if the organisms were not detected in clinical specimens of patients [22,23]. Two recent studies in Germany and the UK, using accurate identification methods, have reported carriage of acinetobacters on the body surface in patients and/or healthy individuals [24,25]. Overall colonisation rates for Acinetobacter spp. were > 40% for volunteers, and 75% for patients, when multiple body sites were sampled. Interestingly, A. baumannii and the unnamed genomic species 13TU, which predominate in hospital infections, were rarely isolated in the German study, while the unnamed genomic species 3 represented 11% of the total number of isolates, but was not detected in the UK study. In a similar study in Hong Kong [26], A. baumannii and spp. 3 and 13TU had a relatively high prevalence, both in patients and in healthy individuals, with a surprising level of > 35% for sp. 3 in community individuals and student nurses.

The reservoirs from which epidemic strains are imported into hospitals have not yet been elucidated. A recent study in New York, which compared A. baumannii strains from patients in two hospitals with isolates from the hands of community members, showed that strains in the community were distinct from those in the hospitals [27]. The authors concluded that the reservoir for epidemic strains was in the hospital itself.

Clonal spread of epidemic strains

  1. Top of page
  2. Abstract
  3. Search strategy and selection criteria
  4. The acinetobacter genus and clinically important species
  5. Nosocomial infections caused by acinetobacter spp.
  6. Epidemiology of acinetobacter spp.
  7. Clonal spread of epidemic strains
  8. The emergence of resistance
  9. Β-Lactams
  10. Aminoglycosides
  11. Quinolones
  12. Other antibiotics
  13. Genetics of resistance
  14. Treatment options for carbapenem-resistant acinetobacter spp.
  15. Conclusions
  16. Acknowledgements
  17. References

A study comparing outbreak and non-outbreak A. baumannii isolates allowed delineation of two groups of genetically highly related, multiresistant strains among outbreak isolates from different northwestern European cities [4]. It was hypothesised that these groups represented two clonal lineages, the occurrence of which has since been reported also in the Czech Republic [10]. A third clone of widespread multiresistant strains from hospitals in other European countries was described by van Dessel et al.[28]. Most recently, the spread of another A. baumannii clone among 24 hospitals in the London (UK) region has been detected (J. Turton et al., unpublished results). The possible relatedness of the above clones to an amikacin-resistant strain that has spread among eight hospitals in Spain has not yet been investigated [29]. Overall, the findings from these studies indicate that several clones are responsible for many outbreaks in Europe.

The emergence of resistance

  1. Top of page
  2. Abstract
  3. Search strategy and selection criteria
  4. The acinetobacter genus and clinically important species
  5. Nosocomial infections caused by acinetobacter spp.
  6. Epidemiology of acinetobacter spp.
  7. Clonal spread of epidemic strains
  8. The emergence of resistance
  9. Β-Lactams
  10. Aminoglycosides
  11. Quinolones
  12. Other antibiotics
  13. Genetics of resistance
  14. Treatment options for carbapenem-resistant acinetobacter spp.
  15. Conclusions
  16. Acknowledgements
  17. References

Acinetobacter spp. have become resistant to almost all antimicrobial agents that are currently available, including the aminoglycosides, quinolones and broad-spectrum β-lactams. Most strains are resistant to cephalosporins, while resistance to carbapenems is being reported increasingly [30,31]. Important differences in antimicrobial susceptibility exist between A. baumannii and other species in the genus, with A. baumannii being the most resistant species [32–34]. Difficulty in eradicating these bacteria has allowed them to colonise niches left vacant following the eradication of more susceptible microbes.

This review provides an overview of the evolution of the susceptibilities of Acinetobacter spp. to the different antimicrobial classes. However, it should be stressed that comparison of susceptibility rates between studies is rendered difficult, not only because of variations in local epidemiology, antibiotic selection pressure and patient populations, but also because of differences in study protocols. Thirty-one studies concerning the antimicrobial surveillance of Acinetobacter spp. in Europe were identified. An overview of these studies is given in Table 1. Duplicates were excluded and internal quality control through the use of standard control strains was performed in most of the studies. One study used the breakpoints recommended by the British Society for Antimicrobial Chemotherapy (BSAC), another did not specify the breakpoints used, and the remaining studies used the breakpoints recommended by the National Committee for Clinical Laboratory Standards. The identification methods used for the Acinetobacter strains were heterogeneous; however, as mentioned above, species identification using a correct method is an important factor to be taken into account when comparing different studies.

Table 1.  Summary of surveillance papers reviewed
AuthorsCountrySettingType of isolates or hospital departmentIsolation periodMethodBreakpointsExternal quality assuranceInternal quality controlExclusion of duplicatesStrain identificationNo. of isolates testedAntimicrobial agents tested (no.)
  1. NCCLS, National Committee for Clinical Laboratory Standards.

Aksaray et al.[85]Turkey8 hospitalsICU1997EtestNCCLSNot mentionedYesNoAcinetobacter spp.164Amikacin, amoxycillin–clavulanate, cefepime, cefodizime, cefotaxime, ceftazidime, ceftriaxone, cefuroxime, ciprofloxacin, gentamicin, imipenem, piperacillin–tazobactam (12)
Betriu et al.[80]Spain12 medical centresClinical isolates2001Agar dilutionNCCLSNot mentionedYesYesA. baumannii 64Ampicillin–sulbactam, cefepime, gentamicin, imipenem, levofloxacin, piperacillin–tazobactam, polymyxin B, sulbactam, tigecycline (9)
Buirma et al.[66]Netherlands8 hospitalsICU or medium-care surgical unit1990Broth microdilutionNCCLSNot mentionedYesNoAcinetobacter spp. 11Amikacin, ampicillin, amoxycillin–clavulanate, aztreonam, cefazolin, cefotaxime, ceftazidime, ceftriaxone, cefuroxime, ciprofloxacin, gentamicin, imipenem, mezlocillin, piperacillin, ticarcillin–clavulanate, tobramycin (16)
Fluit et al.[93] (SENTRY)14 European countries25 university hospitalsBlood isolates1997–1999Broth microdilutionNCCLSNot mentionedYesYesAcinetobacter spp.247Amikacin, amoxycillin–clavulanate, ampicillin, aztreonam, cefazolin, cefepime, cefoxitin, ceftazidime, ceftriaxone, cefuroxime, ciprofloxacin, gatifloxacin, gentamicin, imipenem, levofloxacin, meropenem, ofloxacin, piperacillin, piperacillin–tazobactam, sparfloxacin, tetracycline, ticarcillin, ticarcillin–clavulanate, tobramycin, trovafloxacin (25)
Garcia-Arata et al.[76]SpainTeaching hospitalClinical isolates1990–1994Agar dilutionNCCLSNot mentionedYesYesA. calcoaceticus–A. baumannii complex177Amikacin amoxycillin–clavulanate, ampicillin, ampicillin–sulbactam, ceftazidime, gentamicin, imipenem, meropenem, ofloxacin, piperacillin, piperacillin–tazobactam, sulbactam, ticarcillin, tobramycin (14)
Glupczynski et al.[67]Belgium18 hospitalsICU1994–1995EtestNCCLSNot mentionedYesYesAcinetobacter spp. 23Amikacin, amoxycillin–clavulanate, aztreonam, ceftazidime, ceftriaxone, cefuroxime, ciprofloxacin, gentamicin, imipenem, piperacillin, piperacillin–tazobactam, ticarcillin–clavulanate (12)
Glupczynski et al.[71]Belgium26 hospitalsICU1996–1997 and 1998–1999EtestNCCLSNot mentionedYesYesAcinetobacter spp.65 (1996–1997); 34 (1998–1999)Amoxycillin–clavulanate, aztreonam, ceftazidime, ceftriaxone, cefuroxime, ciprofloxacin, gentamicin, imipenem, piperacillin, piperacillin–tazobactam (10)
Günseren et al.[84]Turkey8 hospitalsICU1996EtestNCCLSNot mentionedYesNoAcinetobacter spp. 80Amikacin, amoxycillin–clavulanate, cefepime, cefodizime, cefotaxime, ceftazidime, ceftazidime–clavulanate, ceftriaxone, cefuroxime, ciprofloxacin, gentamicin, imipenem, piperacillin–tazobactam (13)
Hanberger et al.[68]Belgium, France, Portugal, Spain, Sweden118 hospitalsICU1994–1995EtestNCCLSNot mentionedYesYesAcinetobacter spp. 29Amikacin, ceftazidime, ceftriaxone, ciprofloxacin, gentamicin, imipenem, piperacillin, piperacillin–tazobactam (8)
Henwood et al.[72]UK54 diagnostic laboratoriesClinical isolates2000Agar dilution and Etest (confirmation)BSACNot mentionedNot mentionedYesA. baumannii complex and other genomic groups595Amikacin, cefotaxime, ceftazidime, ciprofloxacin, colistin, gentamicin, imipenem, meropenem, minocycline, piperacillin, piperacillin–tazobactam, rifampicin, sulbactam, tetracycline, tigecycline (15)
Hoban et al.[111]16 European countries61 laboratoriesClinical isolates1997–1999Broth microdilutionNCCLSNot mentionedYesYesA. baumannii368Ciprofloxacin, gemifloxacin, levofloxacin, ofloxacin (4)
Hostacka and Klokocnikova [89]SlovakiaHospitalClinical isolatesNot specifiedBroth microdilutionNot specifiedNot mentionedNot mentionedNot mentionedA. baumannii, A. lwoffii, A. calcoaceticus, A. haemolyticus 50Amikacin, ampicillin, ampicillin–sulbactam, cefotaxime, ceftazidime, cefuroxime, ciprofloxacin, co-trimoxazole, gentamicin, meropenem, netilmicin, piperacillin, piperacillin–tazobactam (13)
Jarlier et al.[75]France39 teaching hospitalsICU1991Broth microdilutionNCCLSNot mentionedYesYesA. baumannii268Aztreonam, cefotaxime, ceftazidime, ciprofloxacin, gentamicin, imipenem, piperacillin, tobramycin (8)
Jones et al. [94] (SENTRY)12 European countries20 university hospitalsSkin and soft tissue infections1997Broth microdilutionNCCLSNot mentionedYesYesAcinetobacter spp. 41Amikacin, amoxycillin–clavulanate, ampicillin-amoxycillin, aztreonam, cefazolin, cefepime, cefotaxime–ceftriaxone, cefoxitin, ceftazidime, cefuroxime, ciprofloxacin, gatifloxacin, gentamicin, imipenem, levofloxacin, meropenem, ofloxacin, piperacillin, piperacillin–tazobactam, sparfloxacin, tetracycline, ticarcillin, ticarcillin–clavulanate, tobramycin, trimethoprim– sulphamethoxazole, trovafloxacin (26)
Kocazeybek [87]Turkey4 hospitalsSurgical ICU1999Broth microdilution and EtestNCCLSNot mentionedYesNoA. baumannii 32Amikacin, amoxycillin–clavulanate, ampicillin, ampicillin–sulbactam, aztreonam, cefazolin, cefoperazone, cefotaxime, cefotetan, ceftazidime, ceftriaxone, cefuroxime, ciprofloxacin, gentamicin, imipenem, piperacillin, tetracycline, ticarcillin, ticarcillin-clavulanate, tobramycin, trimethoprim-sulphamethoxazole (21)
Maniatis et al. [83]Greece9 tertiary care hospitalsICU1998Broth microdilutionNCCLSNot mentionedYesYesA. baumannii121Amikacin, ampicillin–sulbactam, aztreonam, ceftazidime, ciprofloxacin, gentamicin, imipenem, netilmicin, piperacillin, ticarcillin–clavulanate, tobramycin (11)
Martín- Lozano et al. [79]SpainUniversity hospitalBlood isolates/ bacteraemia1997–1999Broth microdilution and Etest (colistin)NCCLSNot mentionedNot mentionedYesA. baumannii109Amikacin, ampicillin, ampicillin–sulbactam, aztreonam, cefotaxime, ceftazidime, ciprofloxacin, colistin, gentamicin, imipenem, tetracycline, trimethoprim– sulphamethoxazole (12)
Naaber et al. [91]EstoniaUniversity hospitalICU1995 and 1998Disk diffusionNCCLSNot mentionedNot mentionedYesAcinetobacter spp.Not specified, only %Amikacin, aztreonam, cefepime, ceftazidime, ciprofloxacin, gentamicin, imipenem (7)
Patzer et al. [90]PolandHospitalICU1997–2000Agar dilutionNCCLSNot mentionedNot mentionedYesAcinetobacter spp.  32Cefepime, cefotaxime, ceftazidime, ciprofloxacin, gentamicin, imipenem, meropenem, piperacillin–tazobactam, tobramycin (9)
Pfaller et al. [86]Turkey9 university hospitalsClinical isolates1997EtestNCCLSNot mentionedYesNot mentionedAcinetobacter spp.  80Aztreonam, cefepime, cefoperazone–sulbactam, cefotaxime, ceftazidime, imipenem, ticarcillin–clavulanate (7)
Ruiz et al. [77]SpainUniversity hospitalClinical isolates1991–1996Broth microdilutionNCCLSNot mentionedYesYesA. calcoaceticus–A. baumannii complex1532Amikacin, ampicillin, ampicillin–sulbactam, aztreonam, cefotaxime, ceftazidime, ciprofloxacin, gentamicin, imipenem, ofloxacin, piperacillin, tetracycline, ticarcillin, trimethoprim–sulphamethoxazole, tobramycin (15)
Schmitz et al. [110] (SENTRY)12 European countries20 university hospitalsBlood isolates, pneumonia, wound, and urinary tract infections1997–1998Broth microdilutionNCCLSNot mentionedYesYesAcinetobacter spp. 279Ciprofloxacin, gatifloxacin, levofloxacin, ofloxacin, sparfloxacin, trovafloxacin (6)
Schmitz et al. [101] (SENTRY)12 European countries20 university hospitalsBlood isolates, pneumonia, wound, and urinary tract infections1997–1998Broth microdilutionNCCLSNot mentionedYesYesAcinetobacter spp. 279Amikacin, gentamicin, tobramycin (3)
Seifert et al. [32]Germany11 hospitalsBlood cultures, central venous catheters, cerebrospinal fluidPeriod of 18 monthsBroth microdilutionNCCLSNot mentionedYesNot mentionedA. baumannii, A. haemolyticus, A. johnsonni, A. junii A. lwoffii and other Acinetobacter spp. 180Amikacin, amoxycillin-clavulanate, ampicillin, aztreonam, cefazolin, cefotaxime, cefoxitin, ceftazidime, ceftriaxone, cefuroxime, ciprofloxacin, gentamicin, imipenem, mezlocillin, piperacillin, tobramycin (16)
Shah et al. [65]Germany10 hospitalsICU1990Broth microdilutionNCCLSNot mentionedYesYesAcinetobacter spp.  23Amikacin, ampicillin, amoxycillin–clavulanate, aztreonam, cefazolin, cefotaxime, ceftazidime, ceftriaxone, cefuroxime, ciprofloxacin, gentamicin, imipenem, mezlocillin, piperacillin, ticarcillin–clavulanate, tobramycin (16)
Stratchounski et al. [92]Russia10 hospitalsICU1995–1996EtestNCCLSYesYesYesAcinetobacter spp. 77Amikacin, amoxycillin–clavulanate, cefotaxime, ceftazidime, ceftriaxone, cefuroxime, ciprofloxacin, co-trimoxazole, gentamicin, imipenem, piperacillin, piperacillin–tazobactam (12)
Tambic et al. [88]Croatia22 microbiology laboratoriesClinical isolates1999Disk diffusionNCCLSYesYesYesAcinetobacter spp.Not specified, only %Amikacin, ampicillin–sulbactam, imipenem, netilmicin (4 + several other antibiotics that are not specified)
Turner et al. [74] (MYSTIC)12 European countries37 hospital centresMajority ICU1997–2000Agar dilutionNCCLSNot mentionedYesNot mentionedA. baumannii, A. calcoaceticus var. lwoffii and other Acinetobacter spp. 635Ceftazidime, ciprofloxacin, imipenem, meropenem, piperacillin–tazobactam, tobramycin (6)
Verbist [69]Belgium16 hospitalsICU1990Broth microdilutionNCCLSNot mentionedYesNoAcinetobacter spp. 70Amikacin, ampicillin, amoxycillin–clavulanate, aztreonam, cefazolin, cefotaxime, ceftazidime, ceftriaxone, cefuroxime, ciprofloxacin, gentamicin, imipenem, mezlocillin, piperacillin, ticarcillin–clavulanate, tobramycin (16)
Verbist and Glupczynski [70]Belgium28 hospitalsClinical isolates1992EtestNCCLSNot mentionedYesYesAcinetobacter spp.111Aztreonam, cefepime, cefotaxime, ceftazidime, imipenem (5)
Vila et al. [34]Spain3 hospitalsClinical isolatesNot specifiedAgar dilutionNCCLSNot mentionedNot mentionedNot mentionedA. baumannii 54Amikacin, amoxycillin, amoxycillin–clavulanate, ampicillin, ampicillin–sulbactam, aztreonam, cefotaxime, ceftazidime, ceftizoxime, ceftriaxone, ciprofloxacin, chloramphenicol, doxycycline, enoxacin, gentamicin, imipenem, isepamicin, netilmicin, norfloxacin, ofloxacin, piperacillin, ticarcillin, ticarcillin–clavulanate, tobramycin, trimethoprim– sulphamethoxazole (25)

Β-Lactams

  1. Top of page
  2. Abstract
  3. Search strategy and selection criteria
  4. The acinetobacter genus and clinically important species
  5. Nosocomial infections caused by acinetobacter spp.
  6. Epidemiology of acinetobacter spp.
  7. Clonal spread of epidemic strains
  8. The emergence of resistance
  9. Β-Lactams
  10. Aminoglycosides
  11. Quinolones
  12. Other antibiotics
  13. Genetics of resistance
  14. Treatment options for carbapenem-resistant acinetobacter spp.
  15. Conclusions
  16. Acknowledgements
  17. References

Acinetobacter is resistant to most β-lactam antibiotics, particularly penicillins and cephalosporins, especially in ICU patients [32–35]. Ceftazidime, piperacillin and carbapenems are among the β-lactam antibiotics most active against A. baumannii.

The main mechanism of resistance to β-lactam antibiotics in Acinetobacter spp. is the production of β-lactamases encoded either by the chromosome or by plasmids [36]. In addition, the low permeability of the outer-membrane of Acinetobacter, resulting from the small outer-membrane pore size and/or limited porin production [37], as well as alterations in the affinity of penicillin-binding proteins (PBPs), have been implicated in the resistance of Acinetobacter to these antibiotics. Danes et al.[38] described the distribution of β-lactamases in a collection of epidemiologically unrelated A. baumannii clinical isolates. The results suggested that over-expression of the chromosomal cephalosporinase AmpC could play an important role in resistance to β-lactam antibiotics.

Resistance to ampicillin, carboxypenicillin and ureidopenicillin has been attributed to the production of TEM-1 [34,39], TEM-2 [40], OXA-21 [38,41] or OXA-37 [42]β-lactamase. Most of the TEM and SHV types of extended-spectrum β-lactamases have not yet been detected in A. baumannii. The non-TEM, non-SHV extended-spectrum β-lactamases PER-1 and VEB-1 are the only extended-spectrum β-lactamases reported to date in A. baumannii. PER-1 has been detected in Turkish and French isolates [43–45]. An epidemiological survey performed in Turkey in 1996 identified the spread of PER-1-positive A. baumannii isolates [44], and infections with these isolates positive for PER-1 have been associated with a higher risk of mortality [45]. Isolates of A. baumannii producing VEB-1 were associated with a French outbreak in 2001 [46].

Carbapenems have become the preferred treatment for serious Acinetobacter infections in many centres, and have retained better activity than other antimicrobial agents; however, the number of reports of carbapenem resistance is growing steadily and is a cause for concern. In the last few years, carbapenem-resistant Acinetobacter isolates have been reported worldwide [47,48]. In northern Europe, carbapenem-resistant strains of A. baumannii have been mostly sporadic, but in some southern European countries, including parts of Spain, they are endemic [49,50]. In 2001, the International Network for the Study and Prevention of Emerging Antimicrobial Resistance (INSPEAR) defined the emergence of carbapenem resistance in Acinetobacter as a ‘global sentinel event’, warranting prompt epidemiological and microbiological interventions [51].

Several mechanisms of carbapenem resistance have been described in A. baumannii, including loss of outer-membrane proteins [52] and altered PBPs [53]. In addition, isolates of A. baumannii can acquire carbapenemases, including class B metallo-β-lactamases [54,55] and class A and D β-lactamases [56–59]. A combination of several mechanisms may be present in the same isolate, as has been described in other Gram-negative bacteria [49]. In general, the prevalence of carbapenemases is still relatively limited compared to the prevalence of other β-lactamases [60].

The first known A. baumannii isolate with a carbapenem-hydrolysing β-lactamase was collected in 1985 in Scotland, and was initially designated ARI-1 (subsequently renamed OXA-23) [30]. This enzyme hydrolyses imipenem and also confers resistance to penicillins, but not to second- and third-generation cephalosporins. A later study of this isolate identified a plasmid location for the OXA-23 gene [61]. Acinetobacter isolates producing carbapenemases have now been reported from at least 12 countries, including Belgium, France, Italy, Spain and the UK [56]. Some of these carbapenemases are IMP- or VIM-type metallo-β-lactamases belonging to class B [55,62,63], but most carbapenem-resistant acinetobacters produce zinc-independent β-lactamases of class D [56]. Sequenced carbapenemases from acinetobacters of this latter class include OXA-23 (ARI-1) [59], OXA-24 [57], OXA-25, OXA-26, OXA-27 [56] and OXA-40 [64]. The OXA-type β-lactamases all have relatively weak activity against carbapenems.

In a study from Germany in the early 1990s, imipenem was found to be the most active agent against A. baumannii. All 180 Acinetobacter spp. isolates tested were fully susceptible to imipenem. Amoxycillin–clavulanate showed moderate activity, whereas ampicillin, broad-spectrum penicillins and cephalosporins were less active. Similarly, in another report dating from 1991, 23 Acinetobacter spp. isolates were obtained from ICU patients in ten German hospitals. Ceftazidime and imipenem were the most active β-lactam antibiotics, with 96% of the isolates remaining susceptible. Susceptibilities to piperacillin and cefotaxime were 65% and 61%, respectively [65]. All 11 Acinetobacter spp. strains isolated in 1990 from patients in eight Dutch hospitals were susceptible to imipenem, and ten (91%) of the strains were susceptible to ceftazidime, ceftriaxone and amoxycillin–clavulanate [66].

Acinetobacter spp. collected between June 1994 and June 1995 from ICUs in five European countries showed susceptibilities to ceftazidime of 82% in Belgium, 30% in France, 19% in Portugal, 24% in Spain and 100% in Sweden. Susceptibilities to imipenem were 88% in Belgium, 91% in France, 95% in Portugal, 84% in Spain and 81% in Sweden [67,68]. In 1990, 70 Acinetobacter spp. from ICU patients in 16 Belgian hospitals showed susceptibilities to imipenem, ceftazidime and ceftriaxone of 93%, 86% and 74%, respectively [69].

Between September and October 1992, 111 Acinetobacter spp. were collected in 28 Belgian hospitals. Ceftazidime was the most active agent (78% susceptible), followed by cefepime (74%), cefotaxime (66%), piperacillin (56%) and aztreonam (47%) [70]. During 1996–1997 and 1998–1999, 41 and 11 Acinetobacter spp., respectively, were collected in the ICUs of Belgian hospitals. Imipenem (90% and 89%) and ceftazidime (80% and 100%) were the most active agents. Some important changes in resistance rates took place between both collections. However, the small number of isolates, as well as the lack of complete identification to the species level for most isolates, precluded any comparison between both collection periods [71].

In the UK, 13 (2.2%) of 595 Acinetobacter spp. isolated during 2000 from routine clinical specimens at 54 sentinel laboratories were carbapenem-resistant (BSAC breakpoint, MIC ≥ 8 mg/L) [72]. An allele of blaIMP was detected in one of these isolates, but the other 12 isolates either had carbapenemase-independent resistance, or undetectable carbapenemase activity combined with other resistance mechanisms. Routine surveillance data obtained in 2001 from England and Wales similarly showed only 1% resistance to imipenem in bacteraemia isolates of Acinetobacter spp. [73]. These results are in sharp contrast to those of the MYSTIC (Meropenem Yearly Susceptibility Test Information Collection) study reported below [74]; however, only isolates of A. baumannii were investigated in the MYSTIC study.

Of 268 A. baumannii isolates from French teaching hospitals in 1991, 21% were susceptible to piperacillin and cefotaxime, 20% to aztreonam, 71% to ceftazidime, and 100% to imipenem [75]. Similar results were reported with 177 A. calcoaceticus–A. baumannii complex strains isolated in 1990–1994 from patients admitted to a Spanish teaching hospital. Imipenem and meropenem (99% susceptibility) were the most active agents tested, with 97% of isolates being susceptible to ampicillin–sulbactam. Only 25% of the isolates were susceptible to ceftazidime [76].

In a Spanish study published in 1993, almost all 54 A. baumannii isolates tested were resistant to both ampicillin and amoxycillin. Addition of the β-lactamase inhibitor sulbactam increased the percentage of strains susceptible to ampicillin to 52%, while the addition of clavulanic acid to amoxycillin or ticarcillin did not significantly change the percentage of susceptible strains. However, the enhanced activity in the presence of sulbactam may be attributable to the activity of sulbactam alone. More than 50% of the isolates were resistant to piperacillin, cefotaxime, ticarcillin and ceftazidime [34].

Other Spanish studies have also documented significant levels of resistance. In one study, ceftazidime resistance increased from 57.4% in 1991 to 86.8% in 1996, while imipenem resistance increased from 1.3% to 80.0%[77]. In another study, seven (21%) of 34 multiresistant clinical isolates recovered during 1990–1995 were resistant to imipenem [78]. In a third study during the period 1997–1999, isolates from patients with nosocomial A. baumannii bacteraemia were studied. Of 109 isolates, 71% were resistant to cefotaxime, 66% to ceftazidime, and 34% to imipenem [79]. In a fourth study, of 64 A. baumannii isolates obtained from 12 Spanish medical centres in 2001, 37.5% were resistant to cefepime, and 28.1% to imipenem [80]. Finally, in a hospital in Seville, all A. baumannii isolates in blood were susceptible to imipenem in 1991, whereas 50% were resistant to imipenem in 2000 [81].

In Greece, all A. baumannii isolates in the Greek WHONET study in 1996 were fully susceptible to imipenem (http://mednet.gr/whonet) [82]. During a 4-month period from January to April 1998, 121 clinical isolates of A. baumannii were collected from patients hospitalised in the ICUs of nine Greek tertiary care hospitals. High rates of resistance to β-lactam antibiotics, such as aztreonam (93.4%) and ceftazidime (95.9%), were detected, but imipenem-resistant acinetobacters were not isolated. However, after the study period, a few imipenem-resistant acinetobacters emerged in a large Greek hospital that had participated in the study [83].

In Turkey, a surveillance study in 1996 of Gram-negative bacteria isolated from ICUs in eight hospitals found that 5% of 80 Acinetobacter spp. isolates were susceptible to cefotaxime and ceftriaxone, 7.5% to ceftazidime, 11.2% to cefepime, and 71.2% to imipenem [84]. When the study was repeated in 1997, no antibacterial agent other than imipenem was effective against Acinetobacter spp., and of the 164 isolates investigated, only 49.3% were susceptible to imipenem [85]. Also in Turkey, a multicentre evaluation in 1997 of seven broad-spectrum β-lactams found that the 80 Acinetobacter spp. isolates investigated were generally not susceptible to ceftazidime, cefotaxime, aztreonam or ticarcillin–clavulanate (range 17.2–29.3% susceptible), but were more susceptible to both imipenem (85.0%) and cefoperazone–sulbactam (73.8%) [86], although the latter finding could be caused by the intrinsic activity of sulbactam against Acinetobacter spp.

A third Turkish study in 1999 of 32 A. baumannii isolates from the ICUs of four different hospitals found that 5.6% were susceptible to cefotaxime, 3.1% to ceftriaxone, 20.6% to ceftazidime, and 100% to imipenem [87].

In Croatia, imipenem resistance rates of Acinetobacter spp. in 1999 varied between 0% and 8% in 22 Croatian microbiology laboratories representing the major geographical regions of the country, with 18% of isolates resistant to ampicillin–sulbactam [88]. In a Slovakian study published in 2002, 46 (92%) of 50 clinical Acinetobacter spp. isolates (A. baumannii, A. lwoffii, A. calcoaceticus, A. haemolyticus) were resistant to ampicillin, 90% to cefuroxime, 58% to piperacillin, 50% to cefotaxime, 42% to ceftazidime, 38% to piperacillin–tazobactam, and 16% to ampicillin–sulbactam. None of the isolates was resistant to meropenem [89].

In Poland, all 32 isolates investigated during 1997–2000 remained susceptible to imipenem and meropenem (MIC90 0.5-2 mg/L) [90], while a 1995 study in the ICUs of an Estonian university hospital found that 56% of Acinetobacter spp. isolates were susceptible to ceftazidime, decreasing to 43% in 1998. In 1998, 47% of isolates remained susceptible to cefepime, with a small increase in susceptibility to imipenem from 93% in 1995 to 99% in 1998 [91]. In ten Russian hospitals between September 1995 and May 1996, 77 Acinetobacter spp. strains isolated from ICU patients showed high resistance rates to β-lactam antibiotics, ranging between 73% and 96%. Imipenem was the most active agent, with all isolates remaining susceptible [92].

In the 1997–1998 European arm of the SENTRY antimicrobial surveillance programme, imipenem and meropenem were the most active drugs against Acinetobacter spp. isolated from blood, with 80.2% and 78.1%, respectively, of the 247 Acinetobacter spp. isolates remaining susceptible. Of the cephalosporins tested, ceftazidime and cefepime were the most active, although only 51.4% and 62.8%, respectively, of the isolates remained susceptible to these agents [93]. In 1997, the antimicrobial susceptibilities of 41 Acinetobacter spp. isolates associated with skin and soft tissue infections were determined in the SENTRY study. Imipenem was the most active β-lactam compound tested, with 90.2% of the isolates being susceptible. Susceptibilities to meropenem, ceftazidime and cefepime were 85.4%, 41.5% and 48.8%, respectively [94].

Among the 490 A. baumannii isolates from patients with serious infections in 37 European hospitals participating in the 1997–2000 MYSTIC programme, the two carbapenems showed the greatest clinically useful activity. Susceptibilities of A. baumannii to meropenem were very high (97–100%) in all countries except Italy (70%), Turkey (66%) and the UK (77%). A similar pattern was seen for imipenem (93–100%), except for Italy (78%), Turkey (62%) and the UK (78%). The 51 isolates of A. calcoaceticus var. lwoffii were more susceptible than A. baumannii. Susceptibilities of A. calcoaceticus var. lwoffii to meropenem and imipenem were 100% in all countries except Turkey, where there was 87% susceptibility to meropenem, and 73% susceptibility to imipenem. For the 94 isolates of other Acinetobacter spp., high (91–100%) susceptibilities to meropenem and imipenem were seen in all countries that obtained isolates from this group, except Italy (88%) and Turkey (27%) [74].

Data from the 1999–2000 ESAR (European Surveillance of Antibiotic Resistance) study showed no resistance of Acinetobacter to carbapenems in Scotland (0/1316 isolates), 1.51% resistance in Germany (6/398 isolates), 0.4% resistance in Slovakia (10/250 isolates), and 0.56% resistance in Poland (3/535 isolates) (http://www.esbic.de/esbic/esar/results2001/esar-body116htm).

Aminoglycosides

  1. Top of page
  2. Abstract
  3. Search strategy and selection criteria
  4. The acinetobacter genus and clinically important species
  5. Nosocomial infections caused by acinetobacter spp.
  6. Epidemiology of acinetobacter spp.
  7. Clonal spread of epidemic strains
  8. The emergence of resistance
  9. Β-Lactams
  10. Aminoglycosides
  11. Quinolones
  12. Other antibiotics
  13. Genetics of resistance
  14. Treatment options for carbapenem-resistant acinetobacter spp.
  15. Conclusions
  16. Acknowledgements
  17. References

Aminoglycosides are used widely for the treatment of Acinetobacter infections, but increasing numbers of highly resistant strains have been reported since the late 1970s.

The most frequent cause of resistance to aminoglycosides in Acinetobacter spp. is the modification of hydroxyl or amino groups of the antibiotic by aminoglycoside-modifying enzymes. All three types of aminoglycoside-modifying enzymes (acetylases, adenylases and phosphotransferases) have been detected in clinical isolates of Acinetobacter spp. [40,95]. However, geographical variations have been observed. For example, the gene for AAC(3)-Ia was found frequently in isolates of Acinetobacter spp. from Belgium (36 of 45 strains) [96], but in only two of 54 strains from Spain [34]. Various adenylating enzymes have been described in Acinetobacter spp. In Spain, 15% of the 54 clinical A. baumannii isolates studied contained ANT(3′′)9, which modifies streptomycin and spectinomycin [34]. The phosphotransferase found most frequently in Acinetobacter spp. is APH(3′)VI. In 1990, Lambert et al.[97] described the dissemination of the aph6 gene in France, and APH(3′)VI was detected in 15 of the 54 clinical A. baumannii isolates studied in Spain [34]. In addition, it was demonstrated that the spread of amikacin resistance in A. baumannii isolated in Spain was associated with an epidemic strain carrying the aph(3′)-VIa gene [29]. A. haemolyticus and related species are intrinsically resistant to aminoglycosides through synthesis of the chromosomally encoded specific N-acetyltransferase AAC(6′) [98, 99]. Other mechanisms of resistance to aminoglycosides in Acinetobacter spp. include alterations of the target ribosomal protein, and ineffective transportation of the antibiotic to the interior of bacteria [34]. In 2001, Magnet et al.[100] described a resistance-nodulation-cell division-type efflux pump involved in aminoglycoside resistance in a multiresistant A. baumannii isolate from a patient with urinary tract infection. This efflux pump was also shown to affect the level of susceptibility to other drugs, including fluoroquinolones, tetracyclines, chloramphenicol and trimethoprim.

Resistance to aminoglycosides is relatively common in clinical isolates of Acinetobacter spp. In a study performed in Germany in 1990, only 57% of 23 isolates from ICU patients were susceptible to gentamicin, and 78% were susceptible to tobramycin [65]. In The Netherlands, 11 Acinetobacter spp. isolated in 1990 from patients of eight hospitals were all susceptible to amikacin, with 72% susceptible to tobramycin, and 45% to gentamicin [66]. In 1994–1995, the percentages of gentamicin-susceptible Acinetobacter spp. isolates from ICU patients were 82% in Belgium, 34% in France, 36% in Portugal, 19% in Spain and 100% in Sweden. For amikacin, the figures were 85% in Belgium, 64% in France, 90% in Portugal and 49% in Spain [67,68].

Of 70 Acinetobacter spp. isolated in 1990 from Belgian ICU patients, 57% were susceptible to amikacin, 49% to tobramycin and 43% to gentamicin [69]. Between 1996 and 1999, 83% of 41 Acinetobacter spp. isolates from ICUs of Belgian hospitals in 1996–1997 were susceptible to gentamicin, compared with 56% of 11 isolates in 1998–1999 [71]. A French study in 1991 found that 19% and 28%, respectively, of 268 A. baumannii isolates from ICU patients were susceptible to gentamicin and tobramycin [75].

In a Spanish study during the early 1990s, 50% of 54 A. baumannii isolates tested were susceptible to tobramycin, 33% to gentamicin, 66% to netilmicin, and 72% to amikacin and isepamicin [34]. Of 177 A. calcoaceticus–A. baumanni complex isolates from patients admitted to a Spanish teaching hospital between 1990 and 1994, 94% were susceptible to amikacin [76]. Between 1991 and 1996, an increase in aminoglycoside resistance among clinical isolates of Acinetobacter spp. was noticed in Spain, rising from 33.0% to 71.8% for tobramycin, and from 21.0% to 83.7% for amikacin [77].

The Greek System for Surveillance of Antimicrobial Resistance reported in 1996 that 41.5% and 75.6%, respectively, of A. baumannii ICU isolates were resistant to netilmicin and gentamicin, while resistance rates of 51.6% and 58.4%, respectively, were reported in hospital wards (http://mednet.gr/whonet) [82]. In 1998, 121 A. baumannii isolates from ICU patients of nine hospitals in Greece showed resistance levels of 87.6% and 56.2%, respectively, to gentamicin and netilmicin, while amikacin retained activity against 70.2% of the isolates [83].

In Turkey, only 8.7% of 80 isolates from ICUs in 1996 were susceptible to gentamicin and only 29.1% to amikacin [84]. In 1997, of 164 isolates of Acinetobacter spp., 17.1% were susceptible to gentamicin and 34.8% to amikacin [85]. Of 32 A. baumannii isolates from Turkish ICUs in 1999, 62.5% were susceptible to amikacin and 15.6% to gentamicin [87]. In Croatia in 1999, 25% of isolates were resistant to amikacin and 26% to netilmicin [88], while in a Slovakian study of 2002, 58% of 50 Acinetobacter spp. isolates (A. baumannii, A. lwoffii, A. calcoaceticus, A. haemolyticus) were resistant to gentamicin, 44% to amikacin and 24% to netilmicin [89]. In Estonia, 27% of isolates of Acinetobacter spp. from ICUs were susceptible to gentamicin in 1995, decreasing to 19% in 1998, while susceptibility to amikacin decreased from 95% in 1995 to 60% in 1998 [91]. In Russia, 91% of 77 Acinetobacter spp. isolates in 1995–1996 were resistant to gentamicin, while only 7% were resistant to amikacin [92].

In the 1997–1998 European SENTRY study, tobramycin showed the greatest activity of the tested aminoglycosides against Acinetobacter spp., with 60.2% of 279 strains susceptible. Susceptibilities to amikacin and gentamicin were 58.1% and 43.4%, respectively [101]. Of 247 Acinetobacter spp. isolates from blood cultures, 62.4% were susceptible to tobramycin, 59.1% to amikacin and 48.6% to gentamicin [93]. During a 3-month period in 1997, 41 Acinetobacter spp. isolates associated with skin and soft tissue infections were isolated in 20 European hospitals. Susceptibilities to amikacin, gentamicin and tobramycin were 46.3%, 34.2% and 43.9%, respectively [94].

Quinolones

  1. Top of page
  2. Abstract
  3. Search strategy and selection criteria
  4. The acinetobacter genus and clinically important species
  5. Nosocomial infections caused by acinetobacter spp.
  6. Epidemiology of acinetobacter spp.
  7. Clonal spread of epidemic strains
  8. The emergence of resistance
  9. Β-Lactams
  10. Aminoglycosides
  11. Quinolones
  12. Other antibiotics
  13. Genetics of resistance
  14. Treatment options for carbapenem-resistant acinetobacter spp.
  15. Conclusions
  16. Acknowledgements
  17. References

Until 1988, quinolones had good activity against Acinetobacter strains [102] compared to expanded-spectrum cephalosporins and aminoglycosides. However, resistance to these antibiotics has emerged rapidly in clinical isolates [32–34]. Resistance of A. baumannii to the fluoroquinolones has been attributed to changes in the structure of DNA gyrase or topoisomerase IV, caused by mutations in the gyrA or parC genes, respectively, which lower the affinity of the drug for the enzyme–DNA complex [103–106]. A second mechanism of resistance involves mutations of chromosomally-encoded drug-influx and -efflux systems that determine intracellular drug accumulation [103,105,107]. These mutations result either in reduced production of specific outer-membrane proteins which mediate quinolone influx, or over-expression of some efflux system(s), leading to active drug expulsion. Two studies suggesting the involvement of efflux pumps in the acquisition of resistance to quinolones in A. baumannii have been published [108,109].

In Germany, 96% of Acinetobacter spp. isolates from ICU patients were susceptible to ciprofloxacin [65], and all 11 Acinetobacter spp. isolated in 1990 from patients of eight Dutch hospitals were susceptible to ciprofloxacin [66]. In 1994–1995, susceptibilities to ciprofloxacin in isolates from ICU patients were 82% in Belgium, 22% in France, 25% in Portugal, 19% in Spain and 81% in Sweden [67, 68]. In Belgium, 51% of the 70 Acinetobacter spp. isolates from ICU patients in 1990 were susceptible to ciprofloxacin [69], while 76% of the 41 Acinetobacter spp. isolated in 1997 from Belgian ICUs were susceptible to ciprofloxacin, compared with 56% of the 11 isolates in 1999 [71]. Of the 268 A. baumannii isolated from the ICUs of 39 French teaching hospitals in 1991, 18% were susceptible to ciprofloxacin [75].

In Spain, Vila et al.[34] found ciprofloxacin (70%) and ofloxacin (72%) to be more active against clinical isolates of A. baumannii than norfloxacin (18%), but in a separate study, ciprofloxacin resistance in clinical isolates of Acinetobacter increased in Spain from 54.4% in 1991 to 90.4% in 1996 [77].

In 1996 in Greece, 76.6% of the A. baumannii isolates from wards, and 92.4% of the ICU isolates, were resistant to ciprofloxacin (http://mednet.gr/whonet) [82]. Of 121 A. baumannii isolates collected in 1998 from Greek ICUs, 92.6% were resistant to ciprofloxacin [83]. In 1996 in Turkey, 26.4% of Acinetobacter spp. isolates from ICUs were susceptible to ciprofloxacin [84] compared with 32.9% in 1997 [85], while a separate study in 1999 found that 31.3% of 32 A. baumannii isolates from ICUs were susceptible to ciprofloxacin [87].

In a Slovakian study published in 2002, 68% of the 50 tested Acinetobacter spp. isolates (A. baumannii, A. lwoffii, A. calcoaceticus, A. haemolyticus) were resistant to ciprofloxacin [89], while 81.3% of 32 Acinetobacter spp. isolates collected from children in a Polish ICU between 1997 and 2000 were susceptible to ciprofloxacin [90]. In 1995, 67% of Acinetobacter spp. isolates from Estonian ICUs were susceptible to ciprofloxacin, decreasing to 33% in 1998 [91]. Of 77 Acinetobacter spp. strains isolated in Russia from patients with ICU-acquired infections, 53% were resistant to ciprofloxacin [92].

Of the 279 clinical Acinetobacter spp. isolates from 20 European university hospitals participating in the 1997–1998 SENTRY study, 45.2%, 46.6% and 47.3% were susceptible to ciprofloxacin, ofloxacin and levofloxacin, respectively. Gatifloxacin and trovafloxacin showed the best in-vitro activities against Acinetobacter spp. [110]. Quinolones showed poor activity against Acinetobacter spp. from blood cultures. Only 50.6%, 52.6% and 54.7% of the 247 isolates showed in-vitro susceptibility to ciprofloxacin, ofloxacin and levofloxacin, respectively. Similar resistance rates were seen throughout the different European centres [93]. Of the 41 Acinetobacter spp. isolates associated with skin and soft tissue infections, 41.5%, 46.3% and 48.8% were susceptible to ciprofloxacin, ofloxacin and levofloxacin, respectively [94].

Between 1997 and 1999, 368 A. baumannii isolates were collected from 16 European countries. Susceptibilities to gemifloxacin, ciprofloxacin, levofloxacin and ofloxacin were 53.8%, 49.7%, 61.7% and 51.4%, respectively. The isolates of A. anitratus, A. calcoaceticus, A. haemolyticus and A. lwoffii investigated were less resistant than those of A. baumannii[111].

Other antibiotics

  1. Top of page
  2. Abstract
  3. Search strategy and selection criteria
  4. The acinetobacter genus and clinically important species
  5. Nosocomial infections caused by acinetobacter spp.
  6. Epidemiology of acinetobacter spp.
  7. Clonal spread of epidemic strains
  8. The emergence of resistance
  9. Β-Lactams
  10. Aminoglycosides
  11. Quinolones
  12. Other antibiotics
  13. Genetics of resistance
  14. Treatment options for carbapenem-resistant acinetobacter spp.
  15. Conclusions
  16. Acknowledgements
  17. References

A. baumannii has a high degree of resistance to both chloramphenicol and trimethoprim–sulphamethoxazole, but little is known about the genetic basis of resistance to these compounds in these bacteria. Devaud et al.[40] found that chloramphenicol resistance involves the synthesis of chloramphenicol acetyltransferase I (CAT1). The CAT1 gene has been associated with both chromosomal and plasmid DNA in a clinical Acinetobacter isolate, suggesting that the CAT1 gene might be transposon-encoded, thereby improving its survival potential by being located in both replicons [112]. However, in another study, CAT1 activity was not detected, suggesting that resistance could result from a change in permeability to the antibiotic or a mutation in the target protein [34]. Similarly, Goldstein et al.[39] studied a multiresistant strain of A. calcoaceticus var. anitratus and found that resistance to chloramphenicol was not associated with CAT production. In a Spanish study published in 1993, all 54 A. baumanni isolates tested were resistant to chloramphenicol [34]. In other bacteria, resistance to sulphonamides is normally caused by the acquisition of plasmids encoding resistant versions of the target protein, dihydropteroate synthase. Similarly, high-level trimethoprim resistance is generally caused by the acquisition of plasmid DNA carrying a dhfr gene encoding a dihydrofolate reductase with low affinity for trimethoprim [113]. No specific studies on mechanisms of resistance to these antibiotics in Acinetobacter spp. have been published.

A Spanish study on the evolution of resistance among clinical isolates of Acinetobacter found that 41.1% and 88.9% of isolates were resistant to trimethoprim-sulphamethoxazole in 1991 and 1996, respectively [77]. Of 109 isolates in Spain between 1997 and 1999 from patients with nosocomial A. baumannii bacteraemia, 85% were resistant to trimethoprim-sulphamethoxazole [79]. In a Spanish study published in 1993, 63% of 54 A. baumannii isolates tested were susceptible to trimethoprim–sulphamethoxazole [34]. In 1999, 43.8% of 32 A. baumannii isolates from the ICUs of four different hospitals in Turkey were susceptible to trimethoprim–sulphamethoxazole [87], while in a Slovakian study published in 2002, 58% of 50 Acinetobacter spp. isolates (A. baumannii, A. lwoffii, A. calcoaceticus, A. haemolyticus) were resistant to trimethoprim–sulphamethoxazole [89]. Of the 77 Acinetobacter spp. isolates from patients with ICU-acquired infections in ten Russian hospitals, 88% were resistant to trimethoprim–sulphamethoxazole [92].

Tetracycline acts by binding to the 30S ribosomal subunit, resulting in the inhibition of protein synthesis [114]. Tetracycline-resistant bacteria generally express one of two different resistance mechanisms: an efflux pump or a ribosomal protection system. Different tetracycline resistance determinant classes have been recognised and classified, with classes A–E being detected most frequently among Gram-negative bacteria. As most tetracycline resistance genes have been found on plasmids or transposons, acquisition of resistance is generally assumed to be mediated mainly by gene transfer [115]. Guardabassi et al.[116] found the TetA and TetB determinants in clinical and aquatic strains of A. baumannii. A transposon containing the tetA determinant was characterised partially by Ribera et al.[117], who also detected the presence of the TetM determinant in a clinical isolate of A. baumannii[118].

Different publications have reported excellent activity of doxycycline or minocycline, but not tetracycline, against Acinetobacter spp. [34,119]. This may result from the fact that TetA, the major tetracycline resistance determinant, confers resistance to tetracycline, but not to minocycline. In a Spanish study of the early 1990s, 98% of 54 A. baumannii isolates tested were susceptible to doxycycline [34]. Of 109 A. baumannii isolates tested in Spain between 1997 and 1999, 85% were resistant to tetracycline [79]. Tigecycline, a new glycylcycline, was evaluated in the UK with 595 Acinetobacter spp. isolated during 2000 from routine clinical specimens at 54 sentinel laboratories. Tigecycline was found to be less active than minocycline, but both agents overcame most tetracycline resistance [72]. In the 1997–1998 SENTRY study, 247 Acinetobacter spp. were isolated from blood cultures, of which 51% were susceptible to tetracycline [93]. Of 41 Acinetobacter spp. isolates in 1997 that were associated with skin and soft tissue infections, 43.9% were susceptible to tetracycline [94].

Genetics of resistance

  1. Top of page
  2. Abstract
  3. Search strategy and selection criteria
  4. The acinetobacter genus and clinically important species
  5. Nosocomial infections caused by acinetobacter spp.
  6. Epidemiology of acinetobacter spp.
  7. Clonal spread of epidemic strains
  8. The emergence of resistance
  9. Β-Lactams
  10. Aminoglycosides
  11. Quinolones
  12. Other antibiotics
  13. Genetics of resistance
  14. Treatment options for carbapenem-resistant acinetobacter spp.
  15. Conclusions
  16. Acknowledgements
  17. References

Acinetobacter is a genus that appears to have a propensity to develop antibiotic resistance extremely rapidly, perhaps as a consequence of its long-term evolutionary exposure to antibiotic-producing organisms in soil [12]. Furthermore, Acinetobacter spp., and A. baumannii in particular, are intrinsically resistant to many of the antimicrobial agents used most commonly [120].

A major contributing factor in the emergence of resistant Acinetobacter spp. is the acquisition and transfer of antibiotic resistance on plasmids, transposons and integrons. Several studies have reported that > 80% of Acinetobacter spp. isolates carry multiple indigenous plasmids of various molecular sizes [121,122], although another report found plasmids in only 28% of the clinical isolates of A. baumannii analysed [123]. In a recent Dutch study, plasmids were detected in 42% (20/48) of Acinetobacter isolates [124].

Transposons probably play an important role, in conjunction with integrons [125], in ensuring that particular novel genes can become established in a new gene pool. Different studies have reported chromosomally-located transposons carrying multiple antibiotic resistance genes in clinical isolates of Acinetobacter spp. [126].

The presence of integrons in Acinetobacter spp. has been well-described, as has their relatively high frequency of carriage in epidemic strains [124,127]. Three main classes of integrons have been described. Class 1 integrons (mostly associated with the sul1 gene) include the gene encoding the Int1 integrase (intI1). Class 2 integrons (related to transposon Tn7 and its close relatives) have a defective intI gene (intI2*) with partial homology to intI1. Class 3 integrons encode the IntI3 integrase, showing 60.9% homology with the amino-acid sequence of the IntI1 integrase [128]. Most investigators have found predominantly class 1 integrons in Acinetobacter spp. [124,129,130]. However, Gonzalez et al.[131] found predominantly class 2 integrons in A. baumannii isolates from Chilean hospitals. Possibly, the isolates from the latter study were more genetically related. Among A. baumannii integrons, a high prevalence of genes encoding aminoglycoside-modifying enzymes and β-lactamases have been found [41,129,130,132]. Seward and Towner [129] found similar integrons in genotypically distinct Acinetobacter spp. isolates from different locations worldwide. This is in agreement with the findings of Gombac et al.[127], who found that integron structures with the same variable region can be retrieved from genotypically distinguishable strains, and with the findings of Ribera et al.[133], who demonstrated that non-related A. baumannii isolates from different geographical areas are able to acquire common integrons.

Characterisation of integron structure in epidemiologically unrelated strains of A. baumannii suggests, based on integron structure similarity, that inter-species transfer may have occurred from Enterobacteriaceae [127]. Similarly, in a Spanish study, the integrons carried genes that were identical or closely related to genes found previously in integrons from organisms such as Pseudomonas aeruginosa, suggesting the potential transfer of genetic material between A. baumannii and P. aeruginosa[134]. On the other hand, related strains possessing unrelated integrons have also been found [134].

Treatment options for carbapenem-resistant acinetobacter spp.

  1. Top of page
  2. Abstract
  3. Search strategy and selection criteria
  4. The acinetobacter genus and clinically important species
  5. Nosocomial infections caused by acinetobacter spp.
  6. Epidemiology of acinetobacter spp.
  7. Clonal spread of epidemic strains
  8. The emergence of resistance
  9. Β-Lactams
  10. Aminoglycosides
  11. Quinolones
  12. Other antibiotics
  13. Genetics of resistance
  14. Treatment options for carbapenem-resistant acinetobacter spp.
  15. Conclusions
  16. Acknowledgements
  17. References

Very few of the major antibiotics are now reliably effective for the treatment of severe nosocomial Acinetobacter infections, particularly in patients confined to ICUs. Until recently, the recommended drugs for therapy were extended-spectrum penicillins, broad-spectrum cephalosporins or carbapenems, combined with an aminoglycoside [12]. However, increasing resistance to these antimicrobial agents necessitates a critical appraisal of the remaining antibiotic treatment options.

Sulbactam is a synthetic β-lactam molecule, with structural, chemical and pharmacokinetic properties similar to those of the aminopenicillins. A feature that distinguishes sulbactam from other available β-lactamase inhibitors is its direct antimicrobial activity against Bacteroides fragilis and Acinetobacter spp., organisms against which most cephalosporins display little or no activity [135]. Binding of sulbactam to PBP2 of these organisms results in intrinsic antibacterial activity [136].

Most studies have investigated only the ampicillin–sulbactam combination, since sulbactam alone is not available commercially in many countries. In 1993, ampicillin–sulbactam was used for the treatment of ten patients with infections caused by imipenem-resistant A. calcoaceticus, nine of whom improved clinically [137]. In 1996, a prospective observational study followed 79 patients with A. baumannii bacteraemia. Ampicillin–sulbactam was used in eight patients, with a cure rate of 88%[138]. In 1997, a series of patients with multiresistant A. baumannii meningitis who were treated with ampicillin–sulbactam was reported. Eight cases of nosocomial meningitis were treated with ampicillin–sulbactam 2 g + 1 g every 6 h (seven patients) or 2 g + 1 g every 8 h (one patient). All isolates were resistant to gentamicin, ceftazidime and ciprofloxacin, while seven of eight were imipenem-resistant. Six patients were cured, while two died of meningitis [139]. Corbella et al.[140] treated 42 patients with non-life-threatening multiresistant A. baumannii infections, including seven bacteraemias, with sulbactam alone and in combination with ampicillin (1 g every 8 h); 39 improved or were cured with no major adverse effects. In this study, killing curves showed that sulbactam was bacteriostatic, and no synergy was observed between ampicillin and sulbactam. The authors suggested a role for sulbactam in non-life-threatening infections caused by A. baumannii. A retrospective analysis (1987–1999) compared treatment outcomes of 48 patients with A. baumannii bacteraemia treated with imipenem–cilastatin or ampicillin–sulbactam for ≥ 72 h. Ampicillin–sulbactam was at least as effective as imipenem–cilastatin and was a cost-effective alternative for treatment [141].

Unfortunately, emergence of resistance to sulbactam has been noted in imipenem-resistant strains of A. baumannii, leaving the polymyxins (colistimethate and polymyxin B) as the only treatment alternative [142]. Colistin is rapidly bactericidal and exerts its effects by acting as a cationic detergent, causing disruption of the integrity of the bacterial cell membrane, with leakage of intracellular contents and cell death [143]. Resistance to colistin has been postulated to occur via decreased affinity of lipopolysaccharides for colistin [143]. Colistin was used in the 1960s and 1970s, but was abandoned because of adverse side effects, including nephrotoxicity, neuromuscular blockade and neurotoxicity [144], and because of the emergence of newer and safer antimicrobials. Levin et al.[144] reported the outcomes following treatment with colistin of 60 nosocomial infections caused by multiresistant A. baumannii and P. aeruginosa. There was a good outcome for 35 (58%) patients, while three patients died within the first 48 h of treatment. The poorest results were observed in cases of pneumonia, where only five (25%) of 20 patients had a good outcome. The main adverse effect of treatment was renal failure (27% in patients with initial normal renal function, and 58% in patients with initial abnormal renal function); nevertheless, colistin can be recommended for the treatment of severe infections caused by multiresistant A. baumannii. In 2002, Jimenez-Mejias et al.[145] reported a case of meningitis caused by multiresistant A. baumannii which was treated successfully with intravenous colistin sulphomethate sodium (5 mg/kg/day). Colistin penetrated the cerebrospinal fluid at one-quarter the serum levels without adverse effects. In 1994, Go et al.[146] reported a nosocomial outbreak of infections caused by imipenem-resistant A. baumannii in a New York hospital. Infection and colonisation were eliminated by intensive infection control measures, and wound irrigation with polymyxin B.

Conclusions

  1. Top of page
  2. Abstract
  3. Search strategy and selection criteria
  4. The acinetobacter genus and clinically important species
  5. Nosocomial infections caused by acinetobacter spp.
  6. Epidemiology of acinetobacter spp.
  7. Clonal spread of epidemic strains
  8. The emergence of resistance
  9. Β-Lactams
  10. Aminoglycosides
  11. Quinolones
  12. Other antibiotics
  13. Genetics of resistance
  14. Treatment options for carbapenem-resistant acinetobacter spp.
  15. Conclusions
  16. Acknowledgements
  17. References

Acinetobacter spp. are important nosocomial pathogens, capable of rapid adaptation to the hospital environment. There is no doubt that these organisms will pose continuing problems, which is disturbing because of the extent of their antibiotic resistance profiles. Although antimicrobial resistance of Acinetobacter spp. appears to be increasing across Europe, it is difficult to estimate accurately the extent of this emerging problem, in part because the published susceptibility data are based on different methods, and also because of population bias and clonal variation. A reference method for susceptibility testing and MIC breakpoints should be established to better monitor trends of resistance. Surveillance of antimicrobial resistance, the study of resistance mechanisms, the development of new drugs, and the prevention of the spread of multiresistant strains, are all important measures required to control the impact of these multiresistant bacteria.

References

  1. Top of page
  2. Abstract
  3. Search strategy and selection criteria
  4. The acinetobacter genus and clinically important species
  5. Nosocomial infections caused by acinetobacter spp.
  6. Epidemiology of acinetobacter spp.
  7. Clonal spread of epidemic strains
  8. The emergence of resistance
  9. Β-Lactams
  10. Aminoglycosides
  11. Quinolones
  12. Other antibiotics
  13. Genetics of resistance
  14. Treatment options for carbapenem-resistant acinetobacter spp.
  15. Conclusions
  16. Acknowledgements
  17. References
  • 1
    Von Graevenitz A. Acinetobacter, Alcaligenes, Moraxella, and other nonfermentative Gram-negative bacteria. In: MurrayPR, BaronJE, PfallerMA, TenoverFC, YolkenRH, eds. Manual of clinical microbiology.Washington DC: ASM Press, 1995; 520532.
  • 2
    Gerner-Smidt P, Tjernberg I, Ursing J. Reliability of phenotypic tests for identification of Acinetobacter species. J Clin Microbiol 1991; 29: 277282.
  • 3
    Bernards AT, De Beaufort AJ, Dijkshoorn L, Van Boven CP. Outbreak of septicaemia in neonates caused by Acinetobacter junii investigated by amplified ribosomal DNA restriction analysis (ARDRA) and four typing methods. J Hosp Infect 1997; 35: 129140.
  • 4
    Dijkshoorn L, Aucken H, Gerner-Smidt P et al. Comparison of outbreak and nonoutbreak Acinetobacter baumannii strains by genotypic and phenotypic methods. J Clin Microbiol 1996; 34: 15191525.
  • 5
    Nemec A, De Baere T, Tjernberg I, Vaneechoutte M, Van Der Reijden TJ, Dijkshoorn L. Acinetobacter ursingii sp. nov. & Acinetobacter schindleri sp. nov., isolated from human clinical specimens. Int J Syst Evol Microbiol 2001; 51: 18911899.
  • 6
    Nemec A, Dijkshoorn L, Cleenwerck I et al. Acinetobacter parvus sp. nov., a small-colony-forming species isolated from human clinical specimens. Int J Syst Evol Microbiol 2003; 53: 15631567.
  • 7
    Seifert H, Baginski R, Schulze A, Pulverer G. The distribution of Acinetobacter species in clinical culture materials. Zentralbl Bakteriol 1993; 279: 544552.
  • 8
    Dijkshoorn L, Aucken HM, Gerner-Smidt P, Kaufmann ME, Ursing J, Pitt TL. Correlation of typing methods for Acinetobacter isolates from hospital outbreaks. J Clin Microbiol 1993; 31: 702705.
  • 9
    Horrevorts A, Bergman K, Kollee L, Breuker I, Tjernberg I, Dijkshoorn L. Clinical and epidemiological investigations of Acinetobacter genomospecies 3 in a neonatal intensive care unit. J Clin Microbiol 1995; 33: 15671572.
  • 10
    Nemec A, Janda L, Melter O, Dijkshoorn L. Genotypic and phenotypic similarity of multiresistant Acinetobacter baumannii isolates in the Czech Republic. J Med Microbiol 1999; 48: 287296.
  • 11
    Van Dessel H, Kamp-Hopmans TE, Fluit AC et al. Outbreak of a susceptible strain of Acinetobacter species 13 (sensu Tjernberg and Ursing) in an adult neurosurgical intensive care unit. J Hosp Infect 2002; 51: 8995.
  • 12
    Bergogne-Berezin E, Towner KJ. Acinetobacter spp. as nosocomial pathogens: microbiological, clinical, and epidemiological features. Clin Microbiol Rev 1996; 9: 148165.
  • 13
    Emori TG, Gaynes RP. An overview of nosocomial infections, including the role of the microbiology laboratory. Clin Microbiol Rev 1993; 6: 428442.
  • 14
    Struelens MJ, Carlier E, Maes N, Serruys E, Quint WG, Van Belkum A. Nosocomial colonization and infection with multiresistant Acinetobacter baumannii: outbreak delineation using DNA macrorestriction analysis and PCR-fingerprinting. J Hosp Infect 1993; 25: 1532.
  • 15
    Husni RN, Goldstein LS, Arroliga AC et al. Risk factors for an outbreak of multi-drug-resistant Acinetobacter nosocomial pneumonia among intubated patients. Chest 1999; 115: 13781382.
  • 16
    Henriksen SD. Moraxella, Neisseria, Branhamella and Acinetobacter. Annu Rev Microbiol 1976; 30: 6383.
  • 17
    Al Khoja MS, Darrell JH. The skin as the source of Acinetobacter and Moraxella species occurring in blood cultures. J Clin Pathol 1979; 32: 497499.
  • 18
    Rosenthal SL. Sources of Pseudomonas and Acinetobacter species found in human culture materials. Am J Clin Pathol 1974; 62: 807811.
  • 19
    Somerville DA, Noble WC. A note on the gram negative bacilli of human skin. Rev Eur Etud Clin Biol 1970; 15: 669671.
  • 20
    Taplin D, Zaias N. The human skin as a source of Mima–Herellea infections. JAMA 1963; 186: 952955.
  • 21
    Getchell-White SI, Donowitz LG, Groschel DH. The inanimate environment of an intensive care unit as a potential source of nosocomial bacteria: evidence for long survival of Acinetobacter calcoaceticus. Infect Control Hosp Epidemiol 1989; 10: 402407.
  • 22
    Dijkshoorn L, Van Vianen W, Degener JE, Michel MF. Typing of Acinetobacter calcoaceticus strains isolated from hospital patients by cell envelope protein profiles. Epidemiol Infect 1987; 99: 659667.
  • 23
    Dijkshoorn L, Wubbels JL, Beunders AJ, Degener JE, Boks AL, Michel MF. Use of protein profiles to identify Acinetobacter calcoaceticus in a respiratory care unit. J Clin Pathol 1989; 42: 853857.
  • 24
    Berlau J, Aucken H, Malnick H, Pitt T. Distribution of Acinetobacter species on skin of healthy humans. Eur J Clin Microbiol Infect Dis 1999; 18: 179183.
  • 25
    Seifert H, Dijkshoorn L, Gerner-Smidt P, Pelzer N, Tjernberg I, Vaneechoutte M. Distribution of Acinetobacter species on human skin: comparison of phenotypic and genotypic identification methods. J Clin Microbiol 1997; 35: 28192825.
  • 26
    Chu YW, Leung CM, Houang ET et al. Skin carriage of acinetobacters in Hong Kong. J Clin Microbiol 1999; 37: 29622967.
  • 27
    Zeana C, Larson E, Sahni J, Bayuga SJ, Wu F, Della-Latta P. The epidemiology of multidrug-resistant Acinetobacter baumannii: does the community represent a reservoir? Infect Control Hosp Epidemiol 2003; 24: 275279.
  • 28
    Van Dessel H, Dijkshoorn L, Van Der Reijden T et al. Identification of a new geographically widespread multiresistant Acinetobacter baumannii clone from European hospitals. Res Microbiol 2004; 155: 105112.
  • 29
    Vila J, Ruiz J, Navia M et al. Spread of amikacin resistance in Acinetobacter baumannii strains isolated in Spain due to an epidemic strain. J Clin Microbiol 1999; 37: 758761.
  • 30
    Paton RH, Miles RS, Hood J, Amyes SGB. ARI-1: β-lactamase-mediated imipenem resistance in Acinetobacter baumannii. Int J Antimicrob Agents 1993; 2: 8188.
  • 31
    Lyytikainen O, Koljalg S, Harma M, Vuopio-Varkila J. Outbreak caused by two multi-resistant Acinetobacter baumannii clones in a burns unit: emergence of resistance to imipenem. J Hosp Infect 1995; 31: 4154.
  • 32
    Seifert H, Baginski R, Schulze A, Pulverer G. Antimicrobial susceptibility of Acinetobacter species. Antimicrob Agents Chemother 1993; 37: 750753.
  • 33
    Traub WH, Spohr M. Antimicrobial drug susceptibility of clinical isolates of Acinetobacter species (A. baumannii, A. haemolyticus, genospecies 3, and genospecies 6). Antimicrob Agents Chemother 1989; 33: 16171619.
  • 34
    Vila J, Marcos A, Marco F et al. In vitro antimicrobial production of β-lactamases, aminoglycoside-modifying enzymes, and chloramphenicol acetyltransferase by and susceptibility of clinical isolates of Acinetobacter baumannii. Antimicrob Agents Chemother 1993; 37: 138141.
  • 35
    Shi ZY, Liu PY, Lau Y, Lin Y, Hu BS, Shir J-M. Antimicrobial susceptibility of clinical isolates of Acinetobacter baumannii. Diagn Microbiol Infect Dis 1996; 24: 8185.
  • 36
    Amyes SGB, Young HK. Mechanisms of antibiotic resistance in Acinetobacter spp.—genetics of resistance. In: Bergogne-BerezinE, Joly-GuillouML, TownerKJ, eds. Acinetobacter: microbiology, epidemiology, infections, management. New York, NY: CRC Press, 1996; 185223.
  • 37
    Sato K, Nakae T. Outer membrane permeability of Acinetobacter calcoaceticus and its implication in antibiotic resistance. J Antimicrob Chemother 1991; 28: 3545.
  • 38
    Danes C, Navia MM, Ruiz J et al. Distribution of β-lactamases in Acinetobacter baumannii clinical isolates and the effect of Syn 2190 (AmpC inhibitor) on the MICs of different β-lactam antibiotics. J Antimicrob Chemother 2002; 50: 261264.
  • 39
    Goldstein FW, Labigne-Roussel A, Gerbaud G, Carlier C, Collatz E, Courvalin P. Transferable plasmid-mediated antibiotic resistance in Acinetobacter. Plasmid 1983; 10: 138147.
  • 40
    Devaud M, Kayser FH, Bachi B. Transposon-mediated multiple antibiotic resistance in Acinetobacter strains. Antimicrob Agents Chemother 1982; 22: 323329.
  • 41
    Vila J, Navia M, Ruiz J, Casals C. Cloning and nucleotide sequence analysis of a gene encoding an OXA-derived β-lactamase in Acinetobacter baumannii. Antimicrob Agents Chemother 1997; 41: 27572759.
  • 42
    Navia MM, Ruiz J, Vila J. Characterization of an integron carrying a new class D β-lactamase (OXA-37) in Acinetobacter baumannii. Microb Drug Resist 2002; 8: 261265.
  • 43
    Poirel L, Karim A, Mercat A et al. Extended-spectrum β-lactamase-producing strain of Acinetobacter baumannii isolated from a patient in France. J Antimicrob Chemother 1999; 43: 157158.
  • 44
    Vahaboglu H, Ozturk R, Aygun G et al. Widespread detection of PER-1-type extended-spectrum β-lactamases among nosocomial Acinetobacter and Pseudomonas aeruginosa isolates in Turkey: a nationwide multicenter study. Antimicrob Agents Chemother 1997; 41: 22652269.
  • 45
    Vahaboglu H, Coskunkan F, Tansel O et al. Clinical importance of extended-spectrum β-lactamase (PER-1-type)-producing Acinetobacter spp. and Pseudomonas aeruginosa strains. J Med Microbiol 2001; 50: 642645.
  • 46
    Poirel L, Menuteau O, Agoli N, Cattoen C, Nordmann P. Outbreak of extended-spectrum β-lactamase VEB-1-producing isolates of Acinetobacter baumannii in a French hospital. J Clin Microbiol 2003; 41: 35423547.
  • 47
    Afzal-Shah M, Livermore DM. Worldwide emergence of carbapenem-resistant Acinetobacter spp. J Antimicrob Chemother 1998; 41: 576577.
  • 48
    Da Silva GJ, Leitao GJ, Peixe L. Emergence of carbapenem-hydrolyzing enzymes in Acinetobacter baumannii clinical isolates. J Clin Microbiol 1999; 37: 21092110.
  • 49
    Bou G, Cervero G, Dominguez MA, Quereda C, Martinez-Beltran J. Characterization of a nosocomial outbreak caused by a multiresistant Acinetobacter baumannii strain with a carbapenem-hydrolyzing enzyme: high-level carbapenem resistance in A. baumannii is not due solely to the presence of β-lactamases. J Clin Microbiol 2000; 38: 32993305.
  • 50
    Corbella X, Montero A, Pujol M et al. Emergence and rapid spread of carbapenem resistance during a large and sustained hospital outbreak of multiresistant Acinetobacter baumannii. J Clin Microbiol 2000; 38: 40864095.
  • 51
    Richet HM, Mohammed J, McDonald LC, Jarvis WR. Building communication networks: international network for the study and prevention of emerging antimicrobial resistance. Emerg Infect Dis 2001; 7: 319322.
  • 52
    Clark RB. Imipenem resistance among Acinetobacter baumannii: association with reduced expression of a 33–36 kDa outer membrane protein. J Antimicrob Chemother 1996; 38: 245251.
  • 53
    Gehrlein M, Leying H, Cullmann W, Wendt S, Opferkuch W. Imipenem resistance in Acinetobacter baumanii is due to altered penicillin-binding proteins. Chemotherapy 1991; 37: 405412.
  • 54
    Chu YW, Afzal-Shah M, Houang ET et al. IMP-4, a novel metallo-β-lactamase from nosocomial Acinetobacter spp. collected in Hong Kong between 1994 and 1998. Antimicrob Agents Chemother 2001; 45: 710714.
  • 55
    Riccio ML, Franceschini N, Boschi L et al. Characterization of the metallo-β-lactamase determinant of Acinetobacter baumannii AC-54/97 reveals the existence of bla (IMP) allelic variants carried by gene cassettes of different phylogeny. Antimicrob Agents Chemother 2000; 44: 12291235.
  • 56
    Afzal-Shah M, Woodford N, Livermore DM. Characterization of OXA-25, OXA-26, and OXA-27, molecular class D β-lactamases associated with carbapenem resistance in clinical isolates of Acinetobacter baumannii. Antimicrob Agents Chemother 2001; 45: 583588.
  • 57
    Bou G, Oliver A, Martinez-Beltran J. OXA-24, a novel class D β-lactamase with carbapenemase activity in an Acinetobacter baumannii clinical strain. Antimicrob Agents Chemother 2000; 44: 15561561.
  • 58
    Brown S, Bantar C, Young HK, Amyes SG. Limitation of Acinetobacter baumannii treatment by plasmid-mediated carbapenemase ARI-2. Lancet 1998; 351: 186187.
  • 59
    Donald HM, Scaife W, Amyes SG, Young HK. Sequence analysis of ARI-1, a novel OXA β-lactamase, responsible for imipenem resistance in Acinetobacter baumannii 6B92. Antimicrob Agents Chemother 2000; 44: 196199.
  • 60
    Bush K. Metallo-β-lactamases: a class apart. Clin Infect Dis 1998; 27(suppl 1): S48S53.
  • 61
    Scaife W, Young HK, Paton RH, Amyes SG. Transferable imipenem-resistance in Acinetobacter species from a clinical source. J Antimicrob Chemother 1995; 36: 585586.
  • 62
    Cornaglia G, Riccio ML, Mazzariol A, Lauretti L, Fontana R, Rossolini GM. Appearance of IMP-1 metallo-β-lactamase in Europe. Lancet 1999; 353: 899900.
  • 63
    Tysall L, Stockdale MW, Chadwick PR et al. IMP-1 carbapenemase detected in an Acinetobacter clinical isolate from the UK. J Antimicrob Chemother 2002; 49: 217218.
  • 64
    Lopez-Otsoa F, Gallego L, Towner KJ, Tysall L, Woodford N, Livermore DM. Endemic carbapenem resistance associated with OXA-40 carbapenemase among Acinetobacter baumannii isolates from a hospital in northern Spain. J Clin Microbiol 2002; 40: 47414743.
  • 65
    Shah PM, Asanger R, Kahan FM. Incidence of multi-resistance in gram-negative aerobes from intensive care units of 10 German hospitals. Scand J Infect Dis 1991; 78(suppl): 2234.
  • 66
    Buirma RJ, Horrevorts AM, Wagenvoort JH. Incidence of multi-resistant gram-negative isolates in eight Dutch hospitals. The 1990 Dutch Surveillance Study. Scand J Infect Dis 1991; 78(suppl): 3544.
  • 67
    Glupczynski Y, Delmee M, Goossens H, Struelens M. A multicentre survey of antimicrobial resistance in gram-negative isolates from Belgian intensive care units in 1994–1995. Belgian Multicenter ICU Study Group. Acta Clin Belg 1998; 53: 2838.
  • 68
    Hanberger H, Garcia-Rodriguez JA, Gobernado M, Goossens H, Nilsson LE, Struelens MJ. Antibiotic susceptibility among aerobic gram-negative bacilli in intensive care units in 5 European countries. French and Portuguese ICU Study Groups. JAMA 1999; 281: 6771.
  • 69
    Verbist L. Incidence of multi-resistance in gram-negative bacterial isolates from intensive care units in Belgium: a surveillance study. Scand J Infect Dis 1991; 78(suppl): 4553.
  • 70
    Verbist L, Glupczynski Y. Belgian multicentre study on the in vitro activity of cefepime against gram-negative bacilli. Acta Clin Belg 1996; 51: 2835.
  • 71
    Glupczynski Y, Delmee M, Goossens H, Struelens M. Distribution and prevalence of antimicrobial resistance among gram-negative isolates in intensive care units (ICU) in Belgian hospitals between 1996 and 1999. Acta Clin Belg 2001; 56: 297306.
  • 72
    Henwood CJ, Gatward T, Warner M et al. Antibiotic resistance among clinical isolates of Acinetobacter in the UK, and in vitro evaluation of tigecycline (GAR-936). J Antimicrob Chemother 2002; 49: 479487.
  • 73
    Anonymous. Acinetobacter spp. & Enterococcus spp. bacteraemia: England and Wales, 2001. CDR Weekly 2002; 12: 18.
  • 74
    Turner PJ, Greenhalgh JM. The activity of meropenem and comparators against Acinetobacter strains isolated from European hospitals, 1997–2000. Clin Microbiol Infect 2003; 9: 563567.
  • 75
    Jarlier V, Fosse T, Philippon A. Antibiotic susceptibility in aerobic gram-negative bacilli isolated in intensive care units in 39 French teaching hospitals (ICU study). Intens Care Med 1996; 22: 10571065.
  • 76
    Garcia-Arata MI, Alarcon T, Lopez-Brea M. Emergence of resistant isolates of Acinetobacter calcoaceticusA. baumannii complex in a Spanish hospital over a five-year period. Eur J Clin Microbiol Infect Dis 1996; 15: 512515.
  • 77
    Ruiz J, Nunez ML, Perez J, Simarro E, Martinez-Campos L, Gomez J. Evolution of resistance among clinical isolates of Acinetobacter over a 6-year period. Eur J Clin Microbiol Infect Dis 1999; 18: 292295.
  • 78
    Martinez-Martinez L, Rodriguez G, Pascual A, Suarez AI, Perea EJ. In-vitro activity of antimicrobial agent combinations against multiresistant Acinetobacter baumannii. J Antimicrob Chemother 1996; 38: 11071108.
  • 79
    Martin-Lozano D, Cisneros JM, Becerril B et al. Comparison of a repetitive extragenic palindromic sequence-based PCR method and clinical and microbiological methods for determining strain sources in cases of nosocomial Acinetobacter baumannii bacteremia. J Clin Microbiol 2002; 40: 45714575.
  • 80
    Betriu C, Rodriguez-Avial I, Sanchez BA, Gomez M, Alvarez J, Picazo JJ. In vitro activities of tigecycline (GAR-936) against recently isolated clinical bacteria in Spain. Antimicrob Agents Chemother 2002; 46: 892895.
  • 81
    Cisneros JM, Rodriguez-Bano J. Nosocomial bacteremia due to Acinetobacter baumannii: epidemiology, clinical features and treatment. Clin Microbiol Infect 2002; 8: 687693.
  • 82
    Vatopoulos AC, Kalapothaki V, Legakis NJ. An electronic network for the surveillance of antimicrobial resistance in bacterial nosocomial isolates in Greece. The Greek Network for the Surveillance of Antimicrobial Resistance. Bull WHO 1999; 77: 595601.
  • 83
    Maniatis AN, Pournaras S, Orkopoulou S, Tassios PT, Legakis NJ. Multiresistant Acinetobacter baumannii isolates in intensive care units in Greece. Clin Microbiol Infect 2003; 9: 547553.
  • 84
    Günseren F, Mamikoglu L, Oztürk S et al. A surveillance study of antimicrobial resistance of gram-negative bacteria isolated from intensive care units in eight hospitals in Turkey. J Antimicrob Chemother 1999; 43: 373378.
  • 85
    Aksaray S, Dokuzoğuz B, Güvener E et al. Surveillance of antimicrobial resistance among gram-negative isolates from intensive care units in eight hospitals in Turkey. J Antimicrob Chemother 2000; 45: 695699.
  • 86
    Pfaller MA, Korten V, Jones RN, Doern GV. Multicenter evaluation of the antimicrobial activity for seven broad-spectrum β-lactams in Turkey using the Etest method. Turkish Antimicrobial Resistance Study Group. Diagn Microbiol Infect Dis 1999; 35: 6573.
  • 87
    Kocazeybek BS. Antimicrobial resistance surveillance of gram-negative bacteria isolated from intensive care units of four different hospitals in Turkey. Evaluation of the prevalence of extended-spectrum and inducible β-lactamases using different E-test strips and direct induction methods. Chemotherapy 2001; 47: 396408.
  • 88
    Tambic AA, Tambic T, Kalenic S, Jankovic V. Surveillance for antimicrobial resistance in Croatia. Emerg Infect Dis 2002; 8: 1418.
  • 89
    Hostacka A, Klokocnikova L. Characteristics of clinical Acinetobacter spp. strains. Folia Microbiol (Praha) 2002; 47: 579582.
  • 90
    Patzer J, Dzierzanowska D, Turner P. Susceptibility patterns of Gram-negative bacteria from a Polish intensive care unit, 1997–2000. Int J Antimicrob Agents 2002; 19: 431434.
  • 91
    Naaber P, Koljalg S, Maimets M. Antibiotic usage and resistance—trends in Estonian university hospitals. Int J Antimicrob Agents 2000; 16: 309315.
  • 92
    Stratchounski LS, Kozlov RS, Rechedko GK, Stetsiouk OU, Chavrikova EP. Antimicrobial resistance patterns among aerobic Gram-negative bacilli isolated from patients in intensive care units: results of a multicenter study in Russia. Clin Microbiol Infect 1998; 4: 497507.
  • 93
    Fluit AC, Jones ME, Schmitz FJ, Acar J, Gupta R, Verhoef J. Antimicrobial susceptibility and frequency of occurrence of clinical blood isolates in Europe from the SENTRY antimicrobial surveillance program, 1997 and 1998. Clin Infect Dis 2000; 30: 454460.
  • 94
    Jones ME, Schmitz FJ, Fluit AC, Acar J, Gupta R, Verhoef J. Frequency of occurrence and antimicrobial susceptibility of bacterial pathogens associated with skin and soft tissue infections during 1997 from an International Surveillance Programme. SENTRY Participants Group. Eur J Clin Microbiol Infect Dis 1999; 18: 403408.
  • 95
    Murray BE, Moellering RC. Evidence of plasmid-mediated production of aminoglycoside-modifying enzymes not previously described in Acinetobacter. Antimicrob Agents Chemother 1980; 17: 3036.
  • 96
    Shaw KJ, Hare RS, Sabatelli FJ et al. Correlation between aminoglycoside resistance profiles and DNA hybridization of clinical isolates. Antimicrob Agents Chemother 1991; 35: 22532261.
  • 97
    Lambert T, Gerbaud G, Bouvet P, Vieu JF, Courvalin P. Dissemination of amikacin resistance gene aphA6 in Acinetobacter spp. Antimicrob Agents Chemother 1990; 34: 12441248.
  • 98
    Lambert T, Gerbaud G, Galimand M, Courvalin P. Characterization of Acinetobacter haemolyticusaac (6)-Ig gene encoding an aminoglycoside 6′-N-acetyltransferase which modifies amikacin. Antimicrob Agents Chemother 1993; 37: 20932100.
  • 99
    Rudant E, Bouvet P, Courvalin P, Lambert T. Phylogenetic analysis of proteolytic Acinetobacter strains based on the sequence of genes encoding aminoglycoside 6′-N-acetyltransferases. Syst Appl Microbiol 1999; 22: 5967.
  • 100
    Magnet S, Courvalin P, Lambert T. Resistance-nodulation-cell division-type efflux pump involved in aminoglycoside resistance in Acinetobacter baumannii strain BM4454. Antimicrob Agents Chemother 2001; 45: 33753380.
  • 101
    Schmitz FJ, Verhoef J, Fluit AC. Prevalence of aminoglycoside resistance in 20 European university hospitals participating in the European SENTRY Antimicrobial Surveillance Programme. Eur J Clin Microbiol Infect Dis 1999; 18: 414421.
  • 102
    Higgins PG, Coleman K, Amyes SG. Bactericidal and bacteriostatic activity of gemifloxacin against Acinetobacter spp. in vitro. J Antimicrob Chemother 2000; 45(suppl 1): 7177.
  • 103
    Drlica K, Zhao X. DNA gyrase, topoisomerase IV, and the 4-quinolones. Microbiol Mol Biol Rev 1997; 61: 377392.
  • 104
    Vila J, Ruiz J, Goni P, Marcos A, Jimenez De Anta MT. Mutation in the gyrA gene of quinolone-resistant clinical isolates of Acinetobacter baumannii. Antimicrob Agents Chemother 1995; 39: 12011203.
  • 105
    Piddock LJ. Mechanisms of resistance to fluoroquinolones: state-of-the-art 1992–1994. Drugs 1995; 49(suppl 2): 2935.
  • 106
    Vila J, Ruiz J, Goni P, Jimenez De Anta MT. Quinolone-resistance mutations in the topoisomerase IV parC gene of Acinetobacter baumannii. J Antimicrob Chemother 1997; 39: 757762.
  • 107
    Blondeau JM. Expanded activity and utility of the new fluoroquinolones: a review. Clin Ther 1999; 21: 340.
  • 108
    Ribera A, Ruiz J, Jiminez de Anta MT, Vila J. Effect of an efflux pump inhibitor on the MIC of nalidixic acid for Acinetobacter baumannii and Stenotrophomonas maltophilia clinical isolates. J Antimicrob Chemother 2002; 49: 697698.
  • 109
    Vila J, Ribera A, Marco F et al. Activity of clinafloxacin, compared with six other quinolones, against Acinetobacter baumannii clinical isolates. J Antimicrob Chemother 2002; 49: 471477.
  • 110
    Schmitz FJ, Verhoef J, Fluit AC. Comparative activities of six different fluoroquinolones against 9,682 clinical bacterial isolates from 20 European university hospitals participating in the European SENTRY surveillance programme. The SENTRY participants group. Int J Antimicrob Agents 1999; 12: 311317.
  • 111
    Hoban DJ, Bouchillon SK, Johnson JL et al. Comparative in vitro potency of gemifloxacin and fluoroquinolones against recent European clinical isolates from a global surveillance study. Eur J Clin Microbiol Infect Dis 2001; 20: 814819.
  • 112
    Elisha BG, Steyn LM. The use of molecular techniques for the location and characterisation of antibiotic resistance genes in clinical isolates of Acinetobacter. In: TownerKJ, Bergogne-BerezinE, FewsonCA, eds. The biology of Acinetobacter. New York: Plenum Publishing, 1991; 133148.
  • 113
    Huovinen P, Sundstrom L, Swedberg G, Skold O. Trimethoprim and sulfonamide resistance. Antimicrob Agents Chemother 1995; 39: 279289.
  • 114
    Chopra I, Roberts M. Tetracycline antibiotics: mode of action, applications, molecular biology, and epidemiology of bacterial resistance. Microbiol Mol Biol Rev 2001; 65: 232260.
  • 115
    Roberts MC. Tetracycline resistance determinants: mechanisms of action, regulation of expression, genetic mobility, and distribution. FEMS Microbiol Rev 1996; 19: 124.
  • 116
    Guardabassi L, Dijkshoorn L, Collard JM, Olsen JE, Dalsgaard A. Distribution and in-vitro transfer of tetracycline resistance determinants in clinical and aquatic Acinetobacter strains. J Med Microbiol 2000; 49: 929936.
  • 117
    Ribera A, Roca I, Ruiz J, Gibert I, Vila J. Partial characterization of a transposon containing the tet(A) determinant in a clinical isolate of Acinetobacter baumannii. J Antimicrob Chemother 2003; 52: 477480.
  • 118
    Ribera A, Ruiz J, Vila J. Presence of the Tet M determinant in a clinical isolate of Acinetobacter baumannii. Antimicrob Agents Chemother 2003; 47: 23102312.
  • 119
    Obana Y, Nishino T, Tanino T. In-vitro and in-vivo activities of antimicrobial agents against Acinetobacter calcoaceticus. J Antimicrob Chemother 1985; 15: 441448.
  • 120
    Lortholary O, Fagon JY, Hoi AB et al. Nosocomial acquisition of multiresistant Acinetobacter baumannii: risk factors and prognosis. Clin Infect Dis 1995; 20: 790796.
  • 121
    Gerner-Smidt P. Frequency of plasmids in strains of Acinetobacter calcoaceticus. J Hosp Infect 1989; 14: 2328.
  • 122
    Seifert H, Schulze A, Baginski R, Pulverer G. Plasmid DNA fingerprinting of Acinetobacter species other than Acinetobacter baumannii. J Clin Microbiol 1994; 32: 8286.
  • 123
    Marcos MA, Jimenez De Anta MT, Vila J. Correlation of six methods for typing nosocomial isolates of Acinetobacter baumannii. J Med Microbiol 1995; 42: 328335.
  • 124
    Koeleman JG, Stoof J, Van Der Bijl MW, Vandenbroucke-Grauls CM, Savelkoul PH. Identification of epidemic strains of Acinetobacter baumannii by integrase gene PCR. J Clin Microbiol 2001; 39: 813.
  • 125
    Collis CM, Grammaticopoulos G, Briton J, Stokes HW, Hall RM. Site-specific insertion of gene cassettes into integrons. Mol Microbiol 1993; 9: 4152.
  • 126
    Towner KJ. Plasmid and transposon behaviour in Acinetobacter. In: TownerKJ, Bergogne-BerezinE, FewsonCA, eds. The biology of Acinetobacter. New York: Plenum Publishing, 1991; 149167.
  • 127
    Gombac F, Riccio ML, Rossolini GM et al. Molecular characterization of integrons in epidemiologically unrelated clinical isolates of Acinetobacter baumannii from Italian hospitals reveals a limited diversity of gene cassette arrays. Antimicrob Agents Chemother 2002; 46: 36653668.
  • 128
    Rowe-Magnus DA, Mazel D. Resistance gene capture. Curr Opin Microbiol 1999; 2: 483488.
  • 129
    Seward RJ, Towner KJ. Detection of integrons in worldwide nosocomial isolates of Acinetobacter spp. Clin Microbiol Infect 1999; 5: 308318.
  • 130
    Ploy MC, Denis F, Courvalin P, Lambert T. Molecular characterization of integrons in Acinetobacter baumannii: description of a hybrid class 2 integron. Antimicrob Agents Chemother 2000; 44: 26842688.
  • 131
    Gonzalez G, Sossa K, Bello H, Dominguez M, Mella S, Zemelman R. Presence of integrons in isolates of different biotypes of Acinetobacter baumannii from Chilean hospitals. FEMS Microbiol Lett 1998; 161: 125128.
  • 132
    Gallego L, Towner KJ. Carriage of class 1 integrons and antibiotic resistance in clinical isolates of Acinetobacter baumannii from northern Spain. J Med Microbiol 2001; 50: 7177.
  • 133
    Ribera A, Vila J, Fernandez-Cuenca F et al. Type 1 integrons in epidemiologically unrelated Acinetobacter baumannii isolates collected at Spanish hospitals. Antimicrob Agents Chemother 2004; 48: 364365.
  • 134
    Ruiz J, Navia MM, Casals C, Sierra JM, Jimenez De Anta MT, Vila J. Integron-mediated antibiotic multiresistance in Acinetobacter baumannii clinical isolates from Spain. Clin Microbiol Infect 2003; 9: 907911.
  • 135
    Williams JD. β-Lactamase inhibition and in vitro activity of sulbactam and sulbactam/cefoperazone. Clin Infect Dis 1997; 24: 494497.
  • 136
    Noguchi JK, Gill MA. Sulbactam: a β-lactamase inhibitor. Clin Pharm 1988; 7: 3751.
  • 137
    Urban C, Go E, Mariano N et al. Effect of sulbactam on infections caused by imipenem-resistant Acinetobacter calcoaceticus biotype anitratus. J Infect Dis 1993; 167: 448451.
  • 138
    Cisneros JM, Reyes MJ, Pachon J et al. Bacteremia due to Acinetobacter baumannii: epidemiology, clinical findings, and prognostic features. Clin Infect Dis 1996; 22: 10261032.
  • 139
    Jimenez-Mejias ME, Pachon J, Becerril B, Palomino-Nicas J, Rodriguez-Cobacho A, Revuelta M. Treatment of multidrug-resistant Acinetobacter baumannii meningitis with ampicillin/sulbactam. Clin Infect Dis 1997; 24: 932935.
  • 140
    Corbella X, Ariza J, Ardanuy C et al. Efficacy of sulbactam alone and in combination with ampicillin in nosocomial infections caused by multiresistant Acinetobacter baumannii. J Antimicrob Chemother 1998; 42: 793802.
  • 141
    Jellison TK, Mckinnon PS, Rybak MJ. Epidemiology, resistance, and outcomes of Acinetobacter baumannii bacteremia treated with imipenem–cilastatin or ampicillin–sulbactam. Pharmacotherapy 2001; 21: 142148.
  • 142
    Wood CA, Reboli AC. Infections caused by imipenem-resistant Acinetobacter calcoaceticus biotype anitratus. J Infect Dis 1993; 168: 16021603.
  • 143
    Catchpole CR, Andrews JM, Brenwald N, Wise R. A reassessment of the in-vitro activity of colistin sulphomethate sodium. J Antimicrob Chemother 1997; 39: 255260.
  • 144
    Levin AS, Barone AA, Penco J et al. Intravenous colistin as therapy for nosocomial infections caused by multidrug-resistant Pseudomonas aeruginosa and Acinetobacter baumannii. Clin Infect Dis 1999; 28: 10081011.
  • 145
    Jimenez-Mejias ME, Pichardo-Guerrero C, Marquez-Rivas FJ, Martin-Lozano D, Prados T, Pachon J. Cerebrospinal fluid penetration and pharmacokinetic/pharmacodynamic parameters of intravenously administered colistin in a case of multidrug-resistant Acinetobacter baumannii meningitis. Eur J Clin Microbiol Infect Dis 2002; 21: 212214.
  • 146
    Go ES, Urban C, Burns J et al. Clinical and molecular epidemiology of acinetobacter infections sensitive only to polymyxin B and sulbactam. Lancet 1994; 344: 13291332.