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: www.atsjournals.org
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
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)
ACL AMK AMP ATM CAZ CFU CES CHL CIP CTX DOR FEP GNT IPM LVX MEM PIP SXT TET TIC TIG TOB TZP
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 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 www.atsjournals.org.
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AnnalsATS Volume 12 Number 2 | February 2015
FOCUSED REVIEWS 4 Yabuuchi E, Oyama A. Achromobacter xylosoxidans n. sp. from human ear discharge. Jpn J Microbiol 1971;15:477–481. 5 Yabuuchi E. Twenty-seven years with the nomenclature of Achromobacter xylosoxidans [in Japanese]. Rinsho Biseibutshu Jinsoku Shindan Kenkyukai Shi 1999;10:1–12. 6 Li X, Hu Y, Gong J, Zhang L, Wang G. Comparative genome characterization of Achromobacter members reveals potential genetic determinants facilitating the adaptation to a pathogenic lifestyle. Appl Microbiol Biotechnol 2013;97: 6413–6425. 7 Vandamme P, Moore ER, Cnockaert M, Peeters C, Svensson-Stadler L, Houf K, Spilker T, LiPuma JJ. Classiﬁcation of Achromobacter genogroups 2, 5, 7 and 14 as Achromobacter insuavis sp. nov., Achromobacter aegrifaciens sp. nov., Achromobacter anxifer sp. nov. and Achromobacter dolens sp. nov., respectively. Syst Appl Microbiol 2013;36:474–482. 8 Almuzara M, Limansky A, Ballerini V, Galanternik L, Famiglietti A, Vay C. In vitro susceptibility of Achromobacter spp. isolates: comparison of disk diffusion, Etest and agar dilution methods. Int J Antimicrob Agents 2010;35:68–71. 9 Ridderberg W, Wang M, Nørskov-Lauritsen N. Multilocus sequence analysis of isolates of Achromobacter from patients with cystic ﬁbrosis reveals infecting species other than Achromobacter xylosoxidans. J Clin Microbiol 2012;50:2688–2694. 10 Aisenberg G, Rolston KV, Safdar A. Bacteremia caused by Achromobacter and Alcaligenes species in 46 patients with cancer (1989–2003). Cancer 2004;101:2134–2140. 11 Claassen SL, Reese JM, Mysliwiec V, Mahlen SD. Achromobacter xylosoxidans infection presenting as a pulmonary nodule mimicking cancer. J Clin Microbiol 2011;49:2751–2754. 12 Legrand C, Anaissie E. Bacteremia due to Achromobacter xylosoxidans in patients with cancer. Clin Infect Dis 1992;14:479–484. 13 Adam P, Czapiewski P, Colak S, Kosmidis P, Tousseyn T, Sagaert X, Boudova L, Okoń K, Morresi-Hauf A, Agostinelli C, et al. Prevalence of Achromobacter xylosoxidans in pulmonary mucosa-associated lymphoid tissue lymphoma in different regions of Europe. Br J Haematol 2013. 14 Asano K, Tada S, Matsumoto T, Miyase S, Kamio T, Sakurai K, Iida M. A novel bacterium Achromobacter xylosoxidans as a cause of liver abscess: three case reports. J Hepatol 2005;43:362–365. 15 Behrens-Muller B, Conway J, Yoder J, Conover CS. Investigation and control of an outbreak of Achromobacter xylosoxidans bacteremia. Infect Control Hosp Epidemiol 2012;33:180–184. 16 Chandrasekar PH, Arathoon E, Levine DP. Infections due to Achromobacter xylosoxidans: case report and review of the literature. Infection 1986;14:279–282. 17 Derber C, Elam K, Forbes BA, Bearman G. Achromobacter species endocarditis: a case report and literature review. Can J Infect Dis Med Microbiol 2011;22:e17–e20. 18 Gahrn-Hansen B, Alstrup P, Dessau R, Fuursted K, Knudsen A, Olsen H, Oxhøj H, Petersen AR, Siboni A, Siboni K. Outbreak of infection with Achromobacter xylosoxidans from contaminated intravascular pressure transducers. J Hosp Infect 1988;12:1–6. 19 G omez-Cerezo ´ J, Suarez ´ I, R ´ıos JJ, Peña P, Garc´ıa de Miguel MJ, de Jose´ M, Monteagudo O, Linares P, Barbado-Cano A, V azquez ´ JJ. Achromobacter xylosoxidans bacteremia: a 10-year analysis of 54 cases. Eur J Clin Microbiol Infect Dis 2003;22: 360–363. 20 Traglia GM, Almuzara M, Merkier AK, Adams C, Galanternik L, Vay C, Centron ´ D, Ram´ırez MS. Achromobacter xylosoxidans: an emerging pathogen carrying different elements involved in horizontal genetic transfer. Curr Microbiol 2012;65:673–678. 21 Puthucheary SD, Ngeow YF. Infections with Achromobacter xylosoxidans. Singapore Med J 1986;27:58–62. 22 Reddy AK, Garg P, Shah V, Gopinathan U. Clinical, microbiological proﬁle and treatment outcome of ocular infections caused by Achromobacter xylosoxidans. Cornea 2009;28:1100–1103. 23 Tena D, Carranza R, Barbera´ JR, Valdezate S, Garrancho JM, Arranz M, Saez-Nieto ´ JA. Outbreak of long-term intravascular catheter-related bacteremia due to Achromobacter xylosoxidans subspecies xylosoxidans in a hemodialysis unit. Eur J Clin Microbiol Infect Dis 2005;24:727–732.
24 Tena D, Gonzalez-Praetorius ´ A, Perez-Balsalobre ´ M, Sancho O, Bisquert J. Urinary tract infection due to Achromobacter xylosoxidans: report of 9 cases. Scand J Infect Dis 2008;40: 84–87. 25 Tena D, Mart´ınez NM, Losa C, Sol´ıs S. Skin and soft tissue infection caused by Achromobacter xylosoxidans: report of 14 cases. Scand J Infect Dis 2013. ´ Mart´ınez MT, Garc´ıa G, Otero JR, 26 Barrado L, Brañas P, Orellana MA, Chaves F. Molecular characterization of Achromobacter isolates from cystic ﬁbrosis and non–cystic ﬁbrosis patients in Madrid, Spain. J Clin Microbiol 2013;51:1927–1930. 27 Spilker T, Vandamme P, Lipuma JJ. Identiﬁcation and distribution of Achromobacter species in cystic ﬁbrosis. J Cyst Fibros 2013;12: 298–301. 28 Gahrn-Hansen B, Siboni K. Studies on ampicillin resistance in Achromobacter xylosoxidans: brief report. APMIS 1988;96: 185–187. 29 Jakobsen TH, Hansen MA, Jensen PØ, Hansen L, Riber L, Cockburn A, Kolpen M, Rønne Hansen C, Ridderberg W, Eickhardt S, et al. Complete genome sequence of the cystic ﬁbrosis pathogen Achromobacter xylosoxidans NH44784-1996 complies with important pathogenic phenotypes. PLoS ONE 2013;8:e68484. 30 Nicolosi D, Nicolosi VM, Cappellani A, Nicoletti G, Blandino G. Antibiotic susceptibility proﬁles of uncommon bacterial species causing severe infections in Italy. J Chemother 2009;21:253–260. 31 Felgate H, Giannopoulos G, Sullivan MJ, Gates AJ, Clarke TA, Baggs E, Rowley G, Richardson DJ. The impact of copper, nitrate and carbon status on the emission of nitrous oxide by two species of bacteria with biochemically distinct denitriﬁcation pathways. Environ Microbiol 2012;14:1788–1800. 32 Hassanshahian M, Ahmadinejad M, Tebyanian H, Kariminik A. Isolation and characterization of alkane degrading bacteria from petroleum reservoir waste water in Iran (Kerman and Tehran provenances). Mar Pollut Bull 2013;73:300–305. 33 Majumder A, Bhattacharyya K, Bhattacharyya S, Kole SC. Arsenictolerant, arsenite-oxidising bacterial strains in the contaminated soils of West Bengal, India. Sci Total Environ 2013;463-464: 1006–1014. ´ıa A, Bordes34 Molina-Cabrillana J, Santana-Reyes C, Gonzalez-Garc ´ Ben´ıtez A, Horcajada I. Outbreak of Achromobacter xylosoxidans pseudobacteremia in a neonatal care unit related to contaminated chlorhexidine solution. Eur J Clin Microbiol Infect Dis 2007;26: 435–437. 35 Wiatr M, Morawska A, Składzień J, Kedzierska J. Alcaligenes xylosoxidans—a pathogen of chronic ear infection [in Polish]. Otolaryngol Pol 2005;59:277–280. 36 Qin X, Razia Y, Johnson JR, Stapp JR, Boster DR, Tsosie T, Smith DL, Braden CR, Gay K, Angulo FJ, et al. Ciproﬂoxacin-resistant gramnegative bacilli in the fecal microﬂora of children. Antimicrob Agents Chemother 2006;50:3325–3329. 37 LiPuma JJ, Rathinavelu S, Foster BK, Keoleian JC, Makidon PE, Kalikin LM, Baker JR Jr. In vitro activities of a novel nanoemulsion against Burkholderia and other multidrug-resistant cystic ﬁbrosis– associated bacterial species. Antimicrob Agents Chemother 2009; 53:249–255. 38 Swenson C, Sadikot R. Community acquired Achromobacter bronchopneumonia. Poster session presented at: Infectious Disease Case Reports of the ATS International Conference, May 16–21, 2014, San Diego, California. 39 Hutchison ML, Bonell EC, Poxton IR, Govan JR. Endotoxic activity of lipopolysaccharides isolated from emergent potential cystic ﬁbrosis pathogens. FEMS Immunol Med Microbiol 2000;27:73–77. 40 Rietschel ET, Kirikae T, Schade FU, Mamat U, Schmidt G, Loppnow H, Ulmer AJ, Zahringer ¨ U, Seydel U, Di Padova F, et al. Bacterial endotoxin: molecular relationships of structure to activity and function. FASEB J 1994;8:217–225. 41 Roberts IS. The biochemistry and genetics of capsular polysaccharide production in bacteria. Annu Rev Microbiol 1996;50:285–315. 42 Marshall NC, Finlay BB. Targeting the type III secretion system to treat bacterial infections. Expert Opin Ther Targets 2013. 43 Nicholson TL, Brockmeier SL, Loving CL, Register KB, Kehrli ME, Shore SM. The Bordetella bronchiseptica type III secretion system is
required for persistence and disease severity but not transmission in swine. Infect Immun 2013. Audia JP, Lindsey AS, Housley NA, Ochoa CR, Zhou C, Toba M, Oka M, Annamdevula NS, Fitzgerald MS, Frank DW, et al. In the absence of effector proteins, the Pseudomonas aeruginosa type three secretion system needle tip complex contributes to lung injury and systemic inﬂammatory responses. PLoS ONE 2013;8:e81792. Iwasaki H, Yoshimura T, Suzuki S, Shidara S. Spectral properties of Achromobacter xylosoxidans cytochromes c9 and their NO complexes. Biochim Biophys Acta 1991;1058:79–82. Tian F, Ding Y, Zhu H, Yao L, Du B. Genetic diversity of siderophoreproducing bacteria of tobacco rhizosphere. Braz J Microbiol 2009; 40:276–284. Ivanov A, Kostadinova S. Phosphatidylcholine-speciﬁc phospholipase C from Achromobacter xylosoxidans. Acta Microbiol Bulg 1993;29:3–8. Kostadinova S, Ivanov A, Kamberov E. Puriﬁcation and some properties of phospholipase C from Achromobacter xylosoxidans. J Chromatogr A 1991;568:315–324. Green SJ, Scheller LF, Marletta MA, Seguin MC, Klotz FW, Slayter M, Nelson BJ, Nacy CA. Nitric oxide: cytokine-regulation of nitric oxide in host resistance to intracellular pathogens. Immunol Lett 1994;43: 87–94. Kadowaki S, Chikumi H, Yamamoto H, Yoneda K, Yamasaki A, Sato K, Shimizu E. Down-regulation of inducible nitric oxide synthase by lysophosphatidic acid in human respiratory epithelial cells. Mol Cell Biochem 2004;262:51–59. Mizel SB, Honko AN, Moors MA, Smith PS, West AP. Induction of macrophage nitric oxide production by gram-negative ﬂagellin involves signaling via heteromeric Toll-like receptor 5/Toll-like receptor 4 complexes. J Immunol 2003;170:6217–6223. Ridderberg W, Bendstrup KE, Olesen HV, Jensen-Fangel S, NørskovLauritsen N. Marked increase in incidence of Achromobacter xylosoxidans infections caused by sporadic acquisition from the environment. J Cyst Fibros 2011;10:466–469.
53 Ciofu O, Hansen CR, Høiby N. Respiratory bacterial infections in cystic ﬁbrosis. Curr Opin Pulm Med 2013;19:251–258. 54 Lambiase A, Catania MR, Del Pezzo M, Rossano F, Terlizzi V, Sepe A, Raia V. Achromobacter xylosoxidans respiratory tract infection in cystic ﬁbrosis patients. Eur J Clin Microbiol Infect Dis 2011;30: 973–980. 55 Hernandez ´ JA, Martino R, Pericas R, Sureda A, Brunet S, DomingoAlbos ´ A. Achromobacter xylosoxidans bacteremia in patients with hematologic malignancies. Haematologica 1998;83:284–285. 56 Dworzack DL, Murray CM, Hodges GR, Barnes WG. Communityacquired bacteremic Achromobacter xylosoxidans type IIIa pneumonia in a patient with idiopathic IgM deﬁciency. Am J Clin Pathol 1978;70:712–717. 57 Bador J, Amoureux L, Blanc E, Neuwirth C. Innate aminoglycoside resistance of Achromobacter xylosoxidans is due to AxyXY-OprZ, an RND-type multidrug efﬂux pump. Antimicrob Agents Chemother 2013;57:603–605. 58 Poole K. Aminoglycoside resistance in Pseudomonas aeruginosa. Antimicrob Agents Chemother 2005;49:479–487. 59 Iyobe S, Kusadokoro H, Takahashi A, Yomoda S, Okubo T, Nakamura A, O’Hara K. Detection of a variant metallo-beta-lactamase, IMP-10, from two unrelated strains of Pseudomonas aeruginosa and an Alcaligenes xylosoxidans strain. Antimicrob Agents Chemother 2002; 46:2014–2016. 60 Bador J, Amoureux L, Duez JM, Drabowicz A, Siebor E, Llanes C, Neuwirth C. First description of an RND-type multidrug efﬂux pump in Achromobacter xylosoxidans, AxyABM. Antimicrob Agents Chemother 2011;55:4912–4914. 61 Schnappinger D, Hillen W. Tetracyclines: antibiotic action, uptake, and resistance mechanisms. Arch Microbiol 1996;165:359–369. 62 Arroyo-Cozar ´ M, Ruiz-Garc´ıa M, Merlos EM, Vielba D, Mac´ıas E. Case report: respiratory infection due to Alcaligenes xylosoxidans in a patient with Mounier-Kuhn syndrome [in Spanish]. Rev Chilena Infectol 2012;29:570–571.
AnnalsATS Volume 12 Number 2 | February 2015