AAC Accepted Manuscript Posted Online 17 August 2020 Antimicrob. Agents Chemother. doi:10.1128/AAC.01025-20 Copyright © 2020 American Society for Microbiology. All Rights Reserved. 1 Achromobacter Infections and Treatment Options 2 Burcu Isler 1 2,3 3 Timothy J. Kidd Downloaded from 4 Adam G. Stewart 1,4 5 Patrick Harris 1,2 6 1,4 David L. Paterson http://aac.asm.org/ 7 1. University of Queensland, Faculty of Medicine, UQ Center for Clinical Research, 8 Brisbane, Australia 9 2. Central Microbiology, Pathology Queensland, Royal Brisbane and Women’s Hospital, 10 Brisbane, Australia on August 18, 2020 at University of Queensland 11 3. University of Queensland, Faculty of Science, School of Chemistry and Molecular 12 Biosciences, Brisbane, Australia 13 4. Infectious Diseases Unit, Royal Brisbane and Women’s Hospital, Brisbane, Australia 14 15 Editorial correspondence can be sent to: 16 Professor David Paterson 17 Director 18 UQ Center for Clinical Research 19 Faculty of Medicine 20 The University of Queensland 1 21 Level 8, Building 71/918, UQCCR, RBWH Campus 22 Herston QLD 4029 AUSTRALIA 23 T: +61 7 3346 5500 Downloaded from 24 F: +61 7 3346 5509 25 E: [email protected] 26 http://aac.asm.org/ 27 28 29 on August 18, 2020 at University of Queensland 30 31 32 33 34 35 36 37 38 39 2 40 Abstract 41 Achromobacter is a genus of non-fermenting Gram negative bacteria under order 42 Burkholderiales. Although primarily isolated from respiratory tract of people with cystic Downloaded from 43 fibrosis, Achromobacter spp. can cause a broad range of infections in hosts with other 44 underlying conditions. Their rare occurrence and ever-changing taxonomy hinder defining 45 their clinical features, risk factors for acquisition and adverse outcomes, and optimal 46 treatment. Achromobacter spp. are intrinsically resistant to several antibiotics (e.g. most http://aac.asm.org/ 47 cephalosporins, aztreonam and aminoglycosides), and are increasingly acquiring resistance to 48 carbapenems. Carbapenem resistance is mainly caused by multidrug efflux pumps and 49 metallo-β-lactamases, which are not expected to be overcome by new β-lactamase 50 inhibitors. Among the other new antibiotics, cefiderocol and eravacycline were used as on August 18, 2020 at University of Queensland 51 salvage therapy for a limited number of patients with Achromobacter infections. In this 52 article, we aim to give an overview of the antimicrobial resistance in Achromobacter species, 53 highlighting the possible place of new antibiotics in their treatment. 54 Introduction 55 Taxonomy. Genus Achromobacter was first established in 1923 by the Committee of the 56 Society of American Bacteriologists (today the American Society for Microbiology) as “non- 57 pigment forming, motile or non-motile Gram negative bacteria occurring in water and soil” 58 (1). Close resemblance of genus Achromobacter to genus Alcaligenes, both of which are 59 members of the Alcaligenaceae family of the order Burkholderiales, prompted reassignment 60 of several Achromobacter species to genus Alcaligenes and vice versa. Genus Achromobacter 61 currently comprises 19 officially designated species, most of which were characterized within 62 the last decade (2). Fifteen species to date have been isolated from clinical specimens, 63 including Achromobacter xylosoxidans, Achromobacter denitrificans, Achromobacter 3 64 ruhlandii, Achromobacter piechaudii (3), Achromobacter animicus, Achromobacter 65 mucicolens, Achromobacter pulmonis (4), Achromobacter insolitus, Achromobacter spanius 66 (5), Achromobacter deleyi (6), Achromobacter aegreficans, Achromobacter insuavis, Downloaded from 67 Achromobacter anxifer, Achromobacter dolens (7) and Achromobacter marplatensis (8). 68 Worldwide, A. xylosoxidans is the most common species recovered from clinical samples, 69 including those derived from persons with cystic fibrosis (CF). Distribution of other species 70 show geographical diversity. A. ruhlandii is the second most common species in the Americas http://aac.asm.org/ 71 (9-11), whereas A. dolens and A. insuavis are more prevalent in Europe (12-14). Clinical 72 significance of species variation is not well characterized. 73 Identification. Genus Achromobacter is an obligately aerobic, non-fermentative; oxidase and 74 catalase positive; indole, urease and DNase negative bacteria (15). Achromobacter spp. are on August 18, 2020 at University of Queensland 75 frequently misidentified as other common (i.e., Pseudomonas aeruginosa, Stenotrophomonas 76 maltophilia, Burkholderia cepacia complex, Acinetobacter spp.), and rare (i.e., Pandoraea spp. 77 and Ralstonia spp.) non-fermenting Gram negative bacilli with conventional methods due to 78 biochemical similarities (16-18). Furthermore, most Achromobacter species were referred as 79 A. xylosoxidans with conventional methods. More accurate speciation became possible with 80 the utilization of the genotypic methods such as nrdA gene sequencing and the multilocus 81 sequence typing (MLST) (8, 9). However, for many routine clinical microbiology laboratories 82 sequence-based identification using these techniques is not feasible. Matrix-assisted laser 83 desorption/ionization time-of-flight mass spectrometry (MALDI-TOF MS) was successful at 84 distinguishing Achromobacter from other non-fermenters at the genus level (17, 19, 20). 85 Identification to the species level has been hampered by the limited number of species 86 included in the MALDI-TOF databases (e.g., two and six species for VITEK MS V3.0 and MALDI 87 Biotyper IVD-CE, respectively) (21). MALDI-TOF was successful at identifying most species (i.e. 4 88 ≥ 90%) accurately when its database was expanded using 18 and 9 different Achromobacter 89 species in two different studies (21). Correct identification rates with the default MALDI 90 Biotyper database in these studies were 51% and 66%, respectively, misidentification mainly Downloaded from 91 stemming from referring the species not involved in the database as A. xylosoxidans (22). 92 These results are promising, and their incorporation into the commercial databases will 93 facilitate a more accurate identification at the species level. Until then, confirmation of the 94 MALDI-TOF results with genotypic methods is warranted for correct species identification. http://aac.asm.org/ 95 Host predisposition and clinical spectrum. Achromobacter spp. are predominantly recovered 96 from persons with CF as chronic respiratory pathogens, and are common causes of CF post- 97 lung transplant infections with poor outcomes (23-25). 98 Outside the context of CF, data on the clinical spectrum of Achromobacter infections come on August 18, 2020 at University of Queensland 99 from case reports and case series. Pneumonia and bacteremia are the two most common 100 clinical presentations of Achromobacter infections in non-CF hosts (26). Infections of the skin 101 and soft tissue, urinary tract, intraabdominal organs, central nervous system (CNS), eye and 102 ear are less frequently reported, endocarditis and bone infections being very rare (27-34). 103 Most Achromobacter infections are either hospital acquired or health care associated, and 104 often develop in relation to foreign devices (35). Achromobacter infections do not solely 105 occur in immunocompromised hosts as previously thought. Patients with devices, (e.g., 106 catheters and endotracheal tubes), underlying conditions (e.g., diabetes mellitus, chronic 107 renal failure, chronic heart diseases) and with current or previous hospitalization or health- 108 care exposure are at risk (26, 36). 109 Antibiotic resistance mechanisms 5 110 The two main intrinsic resistance mechanisms of Achromobacter species comprise multidrug 111 efflux pumps and chromosomal OXA-114-like β-lactamases (Table 1). Extended spectrum β- 112 lactamases (ESBLs), AmpC type β-lactamases and metallo-β-lactamases (MBLs) have been Downloaded from 113 detected in Achromobacter isolates and appear to contribute to resistance to β-lactams, 114 including carbapenems. 115 Multidrug efflux pumps. Achromobacter species harbor two well characterized multidrug 116 efflux pumps and several putative efflux pump genes (37). AxyABM efflux pump is found in http://aac.asm.org/ 117 all publicly available Achromobacter genomes and share common properties with the 118 MexAB-OprM efflux pump of P. aeruginosa (38). AxyABM plays a major role in the extrusion 119 of cephalosporins other than cefepime and cefuroxime, and of aztreonam, but does not 120 appear to be the sole mechanism of resistance for these agents as aztreonam and on August 18, 2020 at University of Queensland 121 cephalosporin susceptibilities were not restored after AxyABM inhibition in vitro (39). 122 AxyABM inhibition resulted in decreases in cefotetan, cefoxitin, cefotaxime, ceftriaxone and 123 aztreonam Minimum Inhibitory Concentrations (MICs) from >256 µg/ml to 32, 128, 12, 12 124 and 16 µg/ml, respectively (39). Ceftazidime MIC dropped from 4 to 1.5 µg/ml, whereas 125 cefuroxime, cefepime, amikacin, colistin, tigecycline and carbapenem (i.e., meropenem and 126 imipenem) MICs remained unchanged. Changes in fluoroquinolone MICs were not significant 127 (drop from 0.75 µg/ml to 0.5 and 0.38 µg/ml for ciprofloxacin and levofloxacin, respectively). 128 The second efflux pump AxyXY-OprZ has a broader spectrum, and is involved in the extrusion 129 of aminoglycosides, cefepime, carbapenems, fluoroquinolones, tetracyclines, and 130 erythromycin to varying degrees (40). AxyXY-OprZ is the main resistance determinant that