Acinetobacter baumannii-calcoaceticus complex (ABC) organisms are aerobic gram-negative coccobacillary rods with a natural reservoir in soil and water sources around the world. Clinically, ABC organisms cause health care-associated infections, such as ventilator-associated pneumonias, urinary tract infections, surgical wound infections, and bloodstream infections. These bacteria are also well-known causes of health care-associated outbreaks, particularly in intensive care units and among immunocompromised patients.1 Over the past decade, the challenge of managing infections caused by ABC organisms has been complicated by an increase in antimicrobial resistance, especially multidrug resistance, with some strains now resistant to all or almost all commonly used antimicrobial agents.
ABC species have emerged as health care-associated pathogens, in part, because they are resilient bacteria with a diverse natural habitat. Not only can they survive in moist environments, but they can also survive for weeks on dry surfaces2,3; these organisms can live for an average of 20 days at a relative humidity of 31%.4 Outbreak investigations have demonstrated that environmental contamination with ABC can be widespread and serve as sources of infection.5-7 In addition, ABC organisms can colonize the human skin,8 throat,9 and respiratory tract. Thus, in health care facilities, these bacteria can contaminate the environment and spread between colonized or infected patients directly from hospital equipment or via the hands of health care workers,10,11 especially when there are lapses in infection control practices.
Aside from their capacity to survive in the hospital environment, ABC organisms have a remarkable ability to develop antimicrobial resistance. These bacteria possess a variety of intrinsic resistance mechanisms that can be expressed constitutively or in response to antimicrobial pressure. Changes in outer membrane proteins can reduce the access of antimicrobial agents to penicillin-binding proteins in the cell membrane of the bacteria. Mutations in topoisomerase genes can provide fluoroquinolone resistance. Efflux pumps can expel various classes of antimicrobial agents including β-lactams, quinolones, tetracyclines, and aminoglycosides. ABC organisms also have several types of aminoglycoside-modifying enzymes (acetylating, adenylating, and phosphorylating). Although various β-lactamases have been described in ABC, the AmpC cephalosporinases are common to most, if not all, strains.12 In certain circumstances, production of this cephalosporinase is up-regulated and confers resistance to ceftazidime and other third-generation cephalosporins.13 Another intrinsic β-lactamase, whose genes have been identified in all ABC isolates, is an oxacillinase (specifically, OXA-69).14 This oxacillinase has carbapenemase properties, although, in many circumstances, its expression is low.
In addition to these myriad intrinsic resistance mechanisms, ABC organisms also have the ability to acquire resistance genes. These bacteria can readily acquire resistance from mobile genetic elements such as plasmids,15 transposons,16 and integrons.17 In particular, plasmids that carry class I or class II integrons likely play an important role in the accumulation of antimicrobial resistance, and these genetic elements are often acquired through contact with other bacteria that inhabit similar environments.18-20 For example, a recent study by Fournier et al identified a 86-kb resistance "island" in an ABC isolate recovered from France that contained 45 resistance genes, most of which were likely acquired from other gram-negative bacteria.21
An analysis of susceptibility data for ABC organisms reported to the Centers for Disease Control and Prevention's National Nosocomial Infection Surveillance System between 1995 and 2004 confirmed a nationwide increase in resistance among these pathogens.22 In this analysis, there was a significant increase in the percentage of isolates that were tested against and nonsusceptible to all antimicrobial agents in 4 major classes of antimicrobials: fluoroquinolones (50%-73% nonsusceptible), aminoglycosides (19%-31% nonsusceptible), β-lactams (39%-66% nonsusceptible), and carbapenems (9%-39% nonsusceptible). The dramatic rise in carbapenem resistance is of particular concern, given that this class of agents is often viewed as the "last line of defense" in treating highly resistant ABC. ABC strains have a variety of mechanisms at their disposal to specifically resist carbapenems including porin loss, increased expression of efflux pumps, modification of penicillin binding proteins, upregulation of intrinsic carbapenem-hydrolyzing oxacillinases, and acquisition of carbapenem-hydrolysing class D β-lactamases (eg, OXA-23, OXA-24, or OXA-58) or metallo-β-lactamases.23
Of even greater concern is the fact that the accumulation of resistance determinants in some ABC isolates has led to resistance to multiple classes of antimicrobial agents, sometimes referred to as "multidrug-resistance." Unfortunately, there are currently no standard definitions for multidrug resistance, which creates confusion over the use of this term. Indeed, a recent review pointed out that the term "multidrug-resistance" has been variously applied to ABC isolates resistant to multiple agents within a single class of antimicrobial agents and to isolates resistant to all currently available classes of antimicrobial agents.24 Further complicating this issue has been the introduction of the term "pan drug-resistance," which was introduced to try and distinguish highly resistant isolates. However, there are no uniform definitions for this term either, which has resulted, predictably, in a broad spectrum of applications.
From a patient care perspective, uniform definitions of multidrug resistance may not be so important because resistance to any drug class can meaningfully impact treatment options. However, from an epidemiologic perspective, consensus definitions would help in the analysis and reporting of studies on multidrug-resistant ABC. Paterson25 recently suggested that multidrug resistance in gram-negative organisms be defined as diminished susceptibility to greater than 1 of the following antimicrobial classes: antipseudomonal cephalosporins, antipseudomonal carbapenems, β-lactam-β-lactamase inhibitor combinations, antipseudomonal fluoroquinolones, and aminoglycosides. "Panresistance" was proposed to refer to isolates with diminished susceptibility to all of the following: antipseudomonal cephalosporins, antipseudomonal carbapenems, piperacillin/tazobactam, and quinolones. Finally, he proposed the use of the term "extreme drug resistance" to refer to isolates that are nonsusceptible to all available antimicrobial agents including polymixins.26
We adopted a slightly modified version of this approach in the aforementioned analysis of National Nosocomial Infection Surveillance System data on ABC where multidrug resistance was defined as diminished susceptibility to all tested agents (that could have activity against ABC) within 3 of the 4 major classes (fluoroquinolones, aminoglycosides, β-lactams, and carbapenems) of antimicrobial agents, and extensive drug resistance was defined as diminished susceptibility to all agents in all 4 classes. Using these definitions, the percentage of all multidrug-resistance isolates increased significantly from 14% in 1995 to 26% in 2004, and extensive drug resistance increased significantly from 5% to 17% during the same time period.22
Multidrug and extensive drug-resistant isolates of ABC leave clinicians with few treatment options. Further complicating this situation is the absence of any truly novel antimicrobial agents with activity against ABC. Although the slow pace of all antimicrobial development has been appropriately highlighted as a major public health threat by the Infectious Diseases Society of America,27 there has been progress in the battle against resistant gram-positive organisms, with the release of some antimicrobial agents that have unique targets as well as other new drugs in the pipeline. Compare this with the situation for ABC, where no agents with unique targets have been approved for some time and no others seem to be on the immediate horizon. The release of tigecycline in 2005 did provide one new therapeutic option, but this agent does not have a novel target, and clinical resistance in ABC has already been reported.28,29
It is against this backdrop that we can best appreciate the importance of the article in this issue of Infectious Diseases in Clinical Practice in which Griffith et al30 describe the successful use of oral minocycline to treat 8 patients with carbapenem-resistant ABC infections at Brooke Army Medical Center. Although the study is small, the results are encouraging and the investigation itself is noteworthy. Given the lack of novel agents to treat highly resistant strains of ABC, we must examine or, in some cases, reexamine, potentially new uses of older agents. Recent years have seen a resurgence in the use of colistin in the management of infections caused by highly resistant ABC strains, an agent that had been abandoned for many years due to concerns about toxicity. Although the toxicity of colistin remains higher than most other antimicrobial agents, recent reports have provided encouraging data to suggest that complications such as nephrotoxicity and neurotoxicity occur less frequently than previously reported.31,32 Likewise, other small studies have examined the efficacy of various other antimicrobial agents, either alone or in combinations, to treat infections caused by highly resistant ABC.33,34 The study by Griffith et al,30 provides further evidence of the need for more research directed at the use of existing antibiotics to treat resistant ABC. What are needed now are much larger retrospective studies that would set the stage for prospective investigations.
In the meantime, we must concentrate our efforts on multifaceted strategies to prevent and control multidrug-resistant ABC infections. Fortunately, a variety of strategies have a long history of success in this area, and most of these measures are readily available in health care facilities. Evidenced-based strategies to prevent the transmission of ABC and other multidrug-resistant organisms are summarized in the Healthcare Infection Control Practices Advisory Committee document "Management of Multidrug-resistant Organisms in Healthcare Settings, 2006" (MDRO Guidelines).35 For ABC, control efforts will need to pay particular attention to careful environmental cleaning and disinfection, given the importance of this reservoir for ABC. One especially appealing characteristic of the approaches outlined in the MDRO Guidelines is that they can be effective against all multidrug-resistant microorganisms.
Unfortunately, there is nothing to suggest that antimicrobial resistance in ABC will diminish spontaneously. Instead, tackling this public health problem will require a concerted effort directed not only at controlling transmission within health care facilities but also at increasing research and development of antibacterial agents to treat infections due to highly resistant ABC.
1. Villegas MV, Hartstein AI. Acinetobacter
outbreaks, 1977-2000. Infect Control Hosp Epidemiol
2. Getchell-White SI, Donowitz LG, Gröschel 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
3. Jawad A, Seifert H, Snelling AM, et al. Survival of Acinetobacter baumannii
on dry surfaces: comparison of outbreak and sporadic isolates. J Clin Microbiol
4. Jawad A, Heritage J, Snelling AM, et al. Influence of relative humidity and suspending menstrua on survival of Acinetobacter
spp. on dry surfaces. J Clin Microbiol.
5. Sherertz RJ, Sullivan ML. An outbreak of infections with Acinetobacter calcoaceticus
in burn patients: contamination of patients' mattresses. J Infect Dis
6. Weernink A, Severin WP, Tjernberg I, et al. Pillows, an unexpected source of Acinetobacter
. J Hosp Infect
7. Scott P, Deye G, Srinivasan A, et al. An outbreak of multidrug-resistant Acinetobacter baumannii-calcoaceticus
complex infection in the US military health care system associated with military operations in Iraq. Clin Infect Dis
8. Seifert H, Dijkshoorn L, Gerner-Smidt P, et al. Distribution of Acinetobacter
species on human skin: comparison of phenotypic and genotypic identification methods. J Clin Microbiol
9. Anstey NM, Currie BJ, Hassell M, et al. Community-acquired bacteremic Acinetobacter
pneumonia in tropical Australia is caused by diverse strains of Acinetobacter baumannii
, with carriage in the throat in at-risk groups. J Clin Microbiol
10. Buxton AE, Anderson RL, Werdegar D, et al. Nosocomial respiratory tract infection and colonization with Acinetobacter calcoaceticus
. Am J Med
11. Villegas MV, Hartstein AI. Acinetobacter outbreaks, 1977-2000. Infect Control Hosp Epidemiol
12. Bonomo RA, Szabo D. Mechanisms of multidrug resistance in Acinetobacter
species and Pseudomonas aeruginosa
. Clin Infect Dis
. 2006;43(suppl 2):S49-S56.
13. Heritier C, Poirel L, Nordmann P. Cephalosporinase over-expression resulting from insertion of ISAba1 in Acinetobacter baumannii
. Clin Microbiol Infect
14. Héritier C, Poirel L, Fournier PE, et al. Characterization of the naturally occurring oxacillinase of Acinetobacter baumannii
. Antimicrob Agents Chemother
15. Seifert H, Boullion B, Schulze A, et al. Plasmid DNA profiles of Acinetobacter baumannii
: clinical application in a complex endemic setting. Infect Control Hosp Epidemiol
16. Devaud M, Kayser FH, Bächi B. Transposon-mediated multiple antibiotic resistance in Acinetobacter
strains. Antimicrob Agents Chemother
17. Segal H, Thomas R, Gay Elisha B. Characterization of class 1 integron resistance gene cassettes and the identification of a novel IS-like element in Acinetobacter baumannii
18. 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
19. Poirel L, Menuteau O, Agoli N, et al. Outbreak of extended-spectrum beta-lactamase VEB-1-producing isolates of Acinetobacter baumannii
in a French hospital. J Clin Microbiol
20. Ruiz J, Navia MM, Casals C, et al. Integron-mediated antibiotic multiresistance in Acinetobacter baumannii
clinical isolates from Spain. Clin Microbiol Infect
21. Fournier PE, Vallenet D, Barbe V, et al. Comparative genomics of multidrug resistance in Acinetobacter baumannii
. PLoS Genet
22. Gaynes R, Edwards JR. Overview of nosocomial infections caused by gram-negative bacilli. Clin Infect Dis
23. Poirel L, Nordmann P. Carbapenem resistance in Acinetobacter baumannii
: mechanisms and epidemiology. Clin Microbiol Infect
24. Falagas ME, Koletsi PK, Bliziotis IA. The diversity of definitions of multidrug-resistant (MDR) and pandrug-resistant (PDR) Acinetobacter baumannii
and Pseudomonas aeruginosa
. J Med Microbiol
25. Paterson DL. The epidemiological profile of infections with multidrug-resistant Pseudomonas aeruginosa
species. Clin Infect Dis
. 2006;43(suppl 2):S43-S48.
26. Paterson DL, Doi Y. A step closer to extreme drug resistance (XDR) in gram-negative bacilli. Clin Infect Dis
27. Talbot GH, Bradley J, Edwards JE Jr, et al. Bad bugs need drugs: an update on the development pipeline from the Antimicrobial Availability Task Force of the Infectious Diseases Society of America. Clin Infect Dis
28. Peleg AY, Potoski BA, Rea R, et al. Acinetobacter baumannii
bloodstream infection while receiving tigecycline: a cautionary report. J Antimicrob Chemother
29. Reid GE, Grim SA, Aldeza CA, et al. Rapid development of Acinetobacter baumannii
resistance to tigecycline. Pharmacotherapy
30. Griffith ME, Yun HC, Horvath LL, et al. Minocycline therapy for traumatic wound infections caused by the multidrug-resistant Acinetobacter baumannii-Acinobacter calcoaceticus
complex. Infect Dis Clin Pract.
31. Falagas ME, Kasiakou SK. Colistin: the revival of polymyxins for the management of multidrug-resistant gram-negative bacterial infections. Clin Infect Dis
32. Ouderkirk JP, Nord JA, Turett GS, et al. Polymyxin B nephrotoxicity and efficacy against nosocomial infections caused by multiresistant gram-negative bacteria. Antimicrob Agents Chemother
33. Holloway KP, Rouphael NG, Wells JB, et al. Polymyxin B and doxycycline use in patients with multidrug-resistant Acinetobacter baumannii
infections in the intensive care unit. Ann Pharmacother
34. Rahal JJ. Novel antibiotic combinations against infections with almost completely resistant Pseudomonas aeruginosa
species. Clin Infect Dis
. 2006;43(suppl 2):S95-S99.