FOCUSED REVIEWS Achromobacter Respiratory Infections Colin E. Swenson1 and Ruxana T. Sadikot1,2 1 Division of Pulmonary, Critical Care, and Sleep Medicine, College of Medicine, University of Florida, Gainesville, Florida; and 2Department of Veterans Affairs, Atlanta Veterans Affairs Medical Center and Emory University, Atlanta, Georgia

Abstract Achromobacteria are ubiquitous environmental organisms that may also become opportunistic pathogens in certain conditions, such as cystic fibrosis, hematologic and solid organ malignancies, renal failure, and certain immune deficiencies. Some members of this genus, such as xylosoxidans, cause primarily nosocomially acquired infections affecting multiple organ systems, including the respiratory tract, urinary tract, and, less commonly, the cardiovascular and central nervous systems. Despite an increasing number of published case reports and literature reviews suggesting a global increase in achromobacterial disease, most clinicians remain uncertain of the organism’s significance when clinically isolated. Moreover, effective treatment can be challenging due to

the organism’s inherent and acquired multidrug resistance patterns. We reviewed all published cases to date of non–cystic fibrosis achromobacterial lung infections to better understand the organism’s pathogenic potential and drug susceptibilities. We found that the majority of these cases were community acquired, typically presenting as pneumonias (88%), and were most frequent in individuals with hematologic and solid organ malignancies. Our findings also suggest that achromobacterial lung infections are difficult to treat, but respond well to extended-spectrum penicillins and cephalosporins, such as ticarcillin, piperacillin, and cefoperazone. Keywords: gram-negative bacteria; antimicrobial drug resistance; virulence factors; bacterial pneumonia; bronchiectasis

(Received in original form June 29, 2014; accepted in final form December 30, 2014 ) Correspondence and requests for reprints should be addressed to Colin E. Swenson, M.D., 1600 Southwest Archer Road, P.O. Box 100225, Gainesville, FL 32601. E-mail: [email protected] Ann Am Thorac Soc Vol 12, No 2, pp 252–258, Feb 2015 Copyright © 2015 by the American Thoracic Society DOI: 10.1513/AnnalsATS.201406-288FR Internet address:

Achromobacteria are ubiquitous, lactosenonfermenting, gram-negative bacilli found in aquatic environments and soil. Although classified as aerobic organisms, Achromobacter species may also thrive in anaerobic environments. The organisms have a global distribution, and may be found in both fresh and brackish bodies of water, as well as municipal and hospital water supplies. Achromobacteria may be normal gut flora in otherwise healthy subjects, and are frequently isolated from a wide range of environmental habitats (1–3). Members of the Achromobacter genus are highly motile via long, peritrichous flagella that propel the organism in a highly efficient swimming motion. The organism was first isolated and described by Yabuuchi and Oyama in 1971, reclassified to the Alcaligenes genus, and more recently placed back in the


Achromobacter genus (4, 5). Recent genomic sequencing has shown that the genus is most closely related to Bordetella than to Alcaligenes, with one study suggesting a recent common ancestor between Bordetella and Achromobacter, and proposing a shared “supergenus” status between members of both genera (6). Further complicating the phylogenic picture, there are numerous genetically distinct Achromobacter species and subspecies that have yet to be fully characterized (6, 7). Many members of the genus are nonpathogenic, and clinical respiratory isolates are not always associated with disease. However, certain species, most notably xylosoxidans and denitrificans, can cause disease in certain patient populations, such as subjects with cystic fibrosis, hematologic and solid organ malignancies,

renal failure, and immunodeficiencies (8–12). The most frequent clinical isolate is xylosoxidans, which can infect any number of organ systems, and is increasingly recognized as an important emerging nosocomial pathogen (13–19). Recent comparative genomic sequencing by Li and colleagues (6) has shown that not all members of the genus share human virulence factors, and that there are distinct genetic sequences among certain members of the xylosoxidans species that impart the ability to both colonize the human respiratory tract, and subsequently evade host defenses (20). The clinical syndromes arising from achromobacterial infection are quite diverse and beyond the scope of this article. In brief, published reports and literature reviews have demonstrated achromobacterial pneumonia, bacteremia, urinary tract

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FOCUSED REVIEWS infections, gastrointestinal infections, endocarditis, meningitis, and ophthalmic disease (17, 21–25). The vast majority of information regarding achromobacterial respiratory disease pertains to subjects with cystic fibrosis, although isolated cases of non–cystic fibrosis community and nosocomially acquired pneumonia have previously been reported (Table 1). Among patients with cystic fibrosis, Achromobacter colonization results from either acquisition from the environment or cross-contamination and horizontal transmission (1, 26, 27). Infections caused by Achromobacter are complicated by the fact that the organisms carry both intrinsic and acquired multidrug resistance (20, 22, 28–30).

Virulence Factors Although Achromobacter species are largely environmental flora that do not typically cause respiratory disease in normal subjects, they do possess intrinsic characteristics that allow survival in adverse environmental conditions that would otherwise limit distribution. Such characteristics include a large genome rich in C-G sequences, intrinsic resistance to arsenic and other toxic metals, and the ability to degrade aromatic compounds (29, 31–33). These characteristics allow Achromobacter species to survive and flourish in environments inhospitable to other organisms, and may help explain why the genus is increasingly found in the nosocomial setting. Achromobacter xylosoxidans, for instance, is frequently isolated from otherwise sterile sources, such as chlorhexidine solutions, ultrasound gel, and intravenous fluids (2, 3, 15, 23, 34). There are strain-specific virulence factors among xylosoxidans isolated from environmental versus clinical specimens, and these intraspecies genomic differences, whether intrinsic or acquired, may account for strain-specific pathogenicity among vulnerable populations (6, 35, 36). The mechanism by which achromobacteria are able to adhere, colonize, and subsequently infect the respiratory tract is unclear, but a number of shared and strain-specific virulence factors have been described. Intrinsic Genus Factors

All members of the Achromobacter genus possess peritrichous flagella that enable Focused Reviews

Table 1. Cases of Achromobacter lung disease by author and year published, clinical diagnosis, and species isolate First Author/Year

Clinical Syndrome

Holmes/1977 Pien/1978 Dworzack/1978 Saygun/1979 Igra-Siegman/1980 Welk/1982 Reverdy/1984 Puthucheary/1986 Mandell/1987 Legrand/1992 (2 cases)

Bronchitis Pneumonia, empyema Pneumonia Empyema Pneumonia, lung abscess Pneumonia Pneumonia Pneumonia, effusion Pneumonia Pneumonia Pneumonia Duggan/1996 Pneumonia De Fernandez/2001 ´ Pneumonia Gomez-Cerrezo/2003 ´ (5 cases) Pneumonia Pneumonia Pneumonia Pneumonia Pneumonia Aisenberg/2004 (6 cases) Pneumonia Pneumonia Pneumonia Pneumonia Pneumonia Pneumonia Farooq/2006 Pneumonia, hemoptysis Sancho-Chust/2010 Bronchiectasis exacerbation Claasen/2011 Pulmonary nodules Atalay/2012 Pneumonia Karanth/2012 Pneumonia Arroyo-Cozar/2012 ´ Bronchopneumonia Villamil/2013 Pneumonia Swenson/2014 Bronchopneumonia

swimming motility, contribute to potential biofilm formation, and may assist with host cell invasion (29, 37). On gram staining, an observer may see numerous motile gram-negative organisms with long, filamentous flagella that have been mistaken for fungal hyphae on silver staining (Figure 1) (38). Like other flagellated gram-negative organisms, Achromobacter species possess complex membrane-bound proteins, called secretion systems (types I–IV), for the extracellular transport of proteins and enzymes. One of the more clinically important secretion systems, type III secretion system (T3SS), is discussed subsequently in more detail (6, 29). Cell Membrane Components

Similar to other gram-negative pathogens, Achromobacter-derived LPS induces key inflammatory cytokines, such as IL-6, IL-8, and TNF (39). Likewise, Achromobacter species possess cell membrane–bound virulence factors

Isolate Xylosoxidans Xylosoxidans Xylosoxidans Xylosoxidans Xylosoxidans Xylosoxidans Xylosoxidans Xylosoxidans Xylosoxidans Xylosoxidans Xylosoxidans Xylosoxidans Xylosoxidans Xylosoxidans Xylosoxidans Xylosoxidans Xylosoxidans Xylosoxidans Xylosoxidans Xylosoxidans Xylosoxidans Xylosoxidans Xylosoxidans Xylosoxidans Xylosoxidans Xylosoxidans Xylosoxidans Denitrificans Denitrificans Xylosoxidans Xylosoxidans Xylosoxidans 1 Denitrificans

common to most other gram-negative cystic fibrosis pathogens. These factors include the O-antigen, which elicits a strong host immune response and protects the organism from adverse environmental conditions, and the Vi capsular polysaccharide, which enables surface adhesion, resistance to phagocytosis, and protection from environmental toxins and desiccation (6, 40, 41). In a similar vein, recent work by Jakobsen and colleagues (29) demonstrated the presence of the pgaABCD operon, encoding a polysaccharide involved in both cell-to-cell and cell-to-surface adhesion. Such adhesion is instrumental in the formation of biofilms, a necessary component for airway colonization, infection, and resistance of the microbe to antibiotic agents. Achromobacter species possess a T3SS, which is key to the organisms’ pathogenicity (6). The T3SS apparatus gives bacteria the ability to infect the host cell with effector proteins, as well as to evade 253


Figure 1. Grocott’s methenamine silver stain of bronchoalveolar lavage sample showing bacilli in chains (upper arrow) and filamentous aggregates (lower arrow). Achromobacter are highly motile organisms. Magnification = 403.

immune response (42, 43). Such a system is classically found in Bordetella, Yersinia, Vibrio, and Salmonella species, as well as in Pseudomonas aeruginosa. In fact, the needle tip complex of the latter organism’s T3SS has recently been shown to induce alveolar injury and an inflammatory response, even in the absence of effector proteins (44). Environmental Advantage

In terms of in vivo viability and proliferation, Achromobacter species contain genes encoding high-affinity iron chelation and phosphate transport agents, both necessary for survival in low-iron, low-phosphorous environs like the human body (45, 46). Jakobsen and colleagues (29), in their complete genomic sequencing of A. xylosoxidans, noted a gene encoding colicin V, a protein that is cytotoxic to similar bacterial strains, thus eliminating competing flora, and enabling local proliferation and potential tissue invasion. Table 2. Demographics of patients with non–cystic fibrosis Achromobacter respiratory infections Characteristics


Sex (M/F), n Age, yr, mean 6 SD Origin, n (%) Community Nosocomial Mortality, n (%)

11/6 58 6 18


14 (64) 8 (36) 4 (25)

The same authors found a gene encoding AepA, which facilitates production of cellulase and protease, both enzymes that enable mucosal invasion (29). In addition, some members of the genus produce phospholipase C, a key virulence enzyme found in P. aeruginosa, Listeria monocytogenes, and Clostridium perfringens. Phosopholipase C hydrolyzes phospholipids, a key component of alveolar surfactant, which may help to explain these organisms’ propensity to cause consolidating pneumonias (47, 48).

Denitrification Although Achromobacter are primarily aerobic organisms, clinical isolates possess a denitrification system similar to P. aeruginosa, which enables survival and proliferation in hypoxic and even anoxic environments. Jakobsen and colleagues (29) were able to demonstrate that A. xylosoxidans strain NH44784-1996, for instance, was capable of using both nitrate and nitrite as electron acceptors in anaerobic respiration. Of the genetic sequences identified, over half encoded nitrous oxide reductase, with a smaller portion involved in the reduction of nitric oxide (NO). Apart from the obvious advantage of enabling anaerobic respiration, denitrification may theoretically protect the organism from oxidative damage inflicted by the host immune defense (49). LPS and

proinflammatory cytokines, such as TNF-a and IL-1, initiated by activation of Toll-like receptors, particularly in macrophages, trigger the production of inducible NO synthase (50, 51). Inducible NO synthase induction results in extremely high levels of NO, a potent inhibitor of bacterial DNA synthesis, which enhances bacterial clearance and strengthens host immune response. NO also combines with superoxide to form peroxynitrite, a strong oxidizing agent that is part of the “oxidative burst” defense employed by macrophages. It is interesting to note that most of the Achromobacter specimens tested by Li and colleagues (6) contained genetic sequences encoding superoxide dismutases and other antioxidant enzymes that protect the organism from the reactive oxygen species typical of the host immune response.

Host Factors Achromobacter airway infections tend to occur in patients with cystic fibrosis, and colonization with A. xylosoxidans has been associated with a decline in lung function (FEV1) over time in this patient population (1, 52–54). Little is known, however, about how these infections arise in subjects without cystic fibrosis, if at all. Over the past 40 years, there have been 32 cases of respiratory Achromobacter infections reported in individuals without cystic fibrosis, where the sole clinical isolate was an Achromobacter species (Table 1). For the most part, these reports did not include information pertaining to race, ethnicity, nutritional status, occupational exposures, alcohol and drug

Table 3. Comorbidities of patients with non–cystic fibrosis Achromobacter respiratory infections Comorbidities Malignancies* Non-CF bronchiectasis† Immunodeficiencies Diabetes Mellitus Total

n 15 3 1 1 20

Definition of abbreviation: CF = cystic fibrosis. *Includes hematologic and solid organ. † Includes Mounier-Kuhn syndrome (57).

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FOCUSED REVIEWS Table 4. Radiographic characteristics of patients with non–cystic fibrosis Achromobacter respiratory infections

Radiographic Presentation Interstitial Consolidation Nodular Effusion/empyema Total




(n) 1 1 2 0 4

(n) 1 1 0 2 4

(n) 2 2 2 2 8

use, or childhood history, but did describe significant respiratory disease burden associated with the Achromobacter isolate.

Age and Sex

A total of 65% of the subjects in Table 1 were male, with a mean age of 58 years (Table 2). It is difficult to determine the significance of this male predominance in such a small sample size, but we cannot exclude sex-related risk factors, such as tobacco use and occupational exposures.


Hematologic and solid organ malignancies were by far the most common comorbidities associated with Achromobacter lung disease, comprising 75% of the 20 cases that included information on subject comorbidities (Table 3). The second most common was non–cystic fibrosis bronchiectasis (15% of cases). In perhaps the best review to date of achromobacterial lung disease in subjects with and without cystic fibrosis, Claasen and colleagues (11) found

that the most common comorbidities affecting subjects without cystic fibrosis were malignancies (solid and hematologic) and immunoglobulin deficiencies. These findings parallel earlier work on Achromobacter bacteremia, which found higher prevalence rates among immunosuppressed subjects and those with underlying malignancy (10, 19, 55). In contrast to Claassen and colleagues, we found only one definitive case of IgM deficiency among the 32 cases reviewed, and only one subject with diabetes mellitus and chronic kidney disease (16, 56). The latter finding differs significantly from other achromobacterial infections, such as bacteremia, urinary tract infection, and endocarditis, in which diabetes mellitus and chronic kidney disease were shown to be common comorbidities (17, 21–25). The vast majority of the cases in Table 1 presented as pneumonias (88%), and the radiographic descriptions are

Table 5. Percentage of isolates sensitive to antibiotic Antibiotic

% Sensitivity G-C (2003) Ais (2004) Tena (2008) Lam (2011) Ata (2012) Jac (2012) Cha (2013) Amo (2013) Tena (2014)


88 — 88 — — — — 62 11 — — 30 8 100 — 95 — 9 — 100 — — 97

— 6 8 3 92 4 96 — 23 12 — 5 5 87 44 100 97 94 8 98 — 6 100

22 55.5 0 — — 0 — — 22.2 33.3 — — 33.3 100 — — — 77.7 — — — 55.5 100

— — — 0 81.2 — — 81.2 81.2 72 — 72 63 81.2 81.2 81.2 100 81.2 27 — — — 100

— 0 — — 75 — 100 — — — — 12.5 0 87.5 50 100 — 85.7 — — 100 — 87.5

— — — — — — — — — — 52 — — 72 — 76 — — — — 44 — —

— 0 — — 66.7 — 100 — 33.3 — — 66.7 33.3 — — 100 66.7 0 — 100 — — 100

— — — — 99 — — — 51 — 95 — — 85 — 100 100 — — 100 — — 100

57.1 28.5 7.8 — 100 0 — — 21.4 7.1 — — 21.4 78.5 — — — 92.3 — — — 25 92.8

Mean 55.7 18.0 26.0 1.5 85.7 1.3 98.7 71.6 34.7 31.1 73.5 37.2 23.4 86.4 58.4 93.2 90.9 62.8 17.5 99.5 72.0 28.8 97.2

Definition of abbreviations: ACL = amoxicillin-clavulanic acid; AMK = amikacin; AMP = ampicillin; ATM = aztreonam; CAZ = ceftazidime; CFU = cefuroxime; CES = cefoperazone-sulbactam; CHL = chloramphenicol; CIP = ciprofloxacin; CTX = cefotaxime; DOR = doripenem; FEP = cefepime; GNT = gentamycin; IPM = imipenem; LVX = levofloxacin; MEM = meropenem; PIP = piperacillin; SXT = trimethroprim-sulfamethoxazole; TET = tetracycline; TIC = ticarcillin; TIG = tigecycline; TOB = tobramycin; TZP = piperacillin-tazobactam. First author names are abbreviated as follows: Ais = Aisenberg; Amo = Amoureux; Ata = Atalay; Cha = Chawla; G-C = Gomez-Cerezo; ´ Jac = Jacquier; Lam = Lambiase; Tena = Tena.

Focused Reviews


FOCUSED REVIEWS summarized in Table 4. Based on the limited data, Achromobacter pneumonias do not appear to have a “typical” radiographic appearance. Reservoirs of Infection

Although Achromobacter species are typically described as nosocomial pathogens, 14 of the 22 cases (64%) that reported these data originated from within the community (Table 2). This preponderance may be due to the sheer abundance of environmental reservoirs, as demonstrated by Amoureux and colleagues (1). These environmental Achromobacter reservoirs may be more likely to result in respiratory infections in susceptible individuals than in other types of infection.

Treatment of Achromobacter Infections and Antibiotic Resistance Perhaps no other virulence factor is more important to an organism’s pathogenicity than the ability to resist antimicrobial agents. Innate resistance of A. xylosoxidans to aminoglycosides, aztreonam, tetracyclines, and certain penicillins and cephalosporins has been documented since the genus was first described in the 1970s, but it was not until recently that the mechanisms of resistance have been described at the genomic level. Some of these genetic sequences share much in common with other cystic fibrosis pathogens, such as P. aeruginosa and Burkholderia pseudomallei, raising the likelihood of horizontal transfer of these genetic elements (57). Achromobacter clinical isolates demonstrate broad multidrug resistance, though not uniformly. Aside from b-lactamases and penicillin binding protein production, many clinical A. xylosoxidans strains contain genes encoding aminoglycoside-modifying enzymes conferring resistance to tobramycin and gentamycin (58). Other strains

have demonstrated production of carbapenemases, leading to variable sensitivities to agents, such as imipenem and meropenem (59). Table 5 lists the antibiotic susceptibility profiles of nine case series published since 2003. The two most frequently tested antibiotics were imipenem and piperacillin-tazobactam, with overall mean susceptibilities of 86.4 and 97.2%, respectively. The agents to which the clinical isolates were most susceptible were ticarcillin (99.5%), cefoperazone-sulbactam (98.7%), and piperacillin-tazobactam (97.2%). Although aztreonam and tetracycline displayed poor sensitivities overall (1.5 and 17.5%, respectively), only two of the studies included susceptibilities to these agents. Not surprisingly, clinical isolates were least sensitive to cefuroxime, amikacin, and gentamycin, as previously established. Apart from the production of enzymes and binding proteins, A. xylosoxidans employs a complex series of active efflux pumps that are only now being described (29, 57). These resistance–nodulation–cell division–type pumps, such as the AxyABM and AxyXY-OprZ, enable the cell to extrude multiple antibiotics per pump type. The AxyABM, for instance, extrudes most cephalosporins, fluoroquinolones, aztreonam, and chloramphenicol, whereas AxyXY-OprZ extrudes aminoglycosides, and can also accommodate cefepime, tetracyclines, and carbapenems, depending on the specific strain (57, 60). As noted by Bador and colleagues (57), the AxyXY-OprZ in A. xylosoxidans and the MexXY/OprM in P. aeruginosa share similar substrates, and this is in part due to the high number of shared amino acid sequences between the two transporters. The authors noted, however, that the AxyXY-OprZ, typical of the A. xylosoxidans species, conferred a much higher resistance to aminoglycosides than the MexXY-OprM in P. aeruginosa. TetA, a specialized tetracycline efflux protein found in other gram-negative pathogens, has also been

References 1 Amoureux L, Bador J, Fardeheb S, Mabille C, Couchot C, Massip C, Salignon AL, Berlie G, Varin V, Neuwirth C. Detection of Achromobacter xylosoxidans in hospital, domestic, and outdoor environmental samples and comparison with human clinical isolates. Appl Environ Microbiol 2013;79:7142–7149.


identified in the A. xylosoxidans genome (29, 61). In addition to antibiotic resistance, Jakobsen and colleagues (29) identified a number of genes in A. xylosoxidans strain NH44784-1996 that encode resistance mechanisms toward toxic metals, including mercury, arsenic, zinc, and chromium. Although other common environmental organisms-cum–cystic fibrosis pathogens employ similar mechanisms—most notably P. aeruginosa and Burkholderia cepacia—the sequenced A. xylosoxidans strain’s metal resistance subsystems far outnumbered these other organisms.

Conclusions and Future Directions Achromobacteria are environmentally ubiquitous, gram-negative bacilli that are known multidrug-resistant nosocomial and cystic fibrosis pathogens, which may also cause community-acquired respiratory disease in subjects without cystic fibrosis. Individuals with underlying malignancies and idiopathic bronchiectasis are most susceptible, and successful treatment requires parentral nonaminoglycoside antibiotics. Although there is debate about the pathogenicity of clinical isolates among immunocompetent hosts, genomic sequencing has revealed virulence factors both common to, and unique among, other gram-negative pathogens. Further studies investigating the expression of the organism’s virulence factors will help elucidate the mechanisms by which Achromobacter can lead to persistent infection and inflammation of the respiratory tract. Likewise, research into the host response to this organism, particularly at the molecular level, will better define the pathways through which disease manifests in select patients, particularly as the incidence of achromobacterial disease continues to rise. n Author disclosures are available with the text of this article at

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Focused Reviews

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AnnalsATS Volume 12 Number 2 | February 2015

Achromobacter respiratory infections.

Achromobacteria are ubiquitous environmental organisms that may also become opportunistic pathogens in certain conditions, such as cystic fibrosis, he...
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