Abstract
Acinetobacter spp. have emerged as significant pathogens causing nosocomial infections. Treatment of these pathogens has become a major challenge to clinicians worldwide, due to their increasing tendency to antibiotic resistance. To address this, much revenue and technology are currently being dedicated toward developing novel drugs and antibiotic combinations to combat antimicrobial resistance. To address this issue, we have constructed a panel of Acinetobacter spp. strains expressing different antimicrobial resistance determinants such as narrow spectrum β-lactamases, extended-spectrum β-lactamases, OXA-type-carbapenemase, metallo-beta-lactamase, and over-expressed AmpC β-lactamase. Bacterial strains exhibiting different resistance phenotypes were collected between 2008 and 2013 from Severance Hospital, Seoul. Antimicrobial susceptibility was determined according to the CLSI guidelines using agar dilution method. Selected strains were sequenced using Ion Torrent PGM system, annotated using RAST server and analyzed using Geneious pro 8.0. Genotypic determinants, such as acquired resistance genes, changes in the expression of efflux pumps, mutations, and porin alternations, contributing to the relevant expressed phenotype were characterized. Isolates expressing ESBL phenotype consisted of blaPER−1 gene, the overproduction of intrinsic AmpC beta-lactamase associated with ISAba1 insertion, and carbapenem resistance associated with production of carbapenem-hydrolyzing Ambler class D β-lactamases, such as OXA-23, OXA-66, OXA-120, OXA-500, and metallo-β-lactamase, SIM-1. We have analyzed the relative expression of Ade efflux systems, and determined the sequences of their regulators to correlate with phenotypic resistance. Quinolone resistance-determining regions were analyzed to understand fluoroquinolone-resistance. Virulence factors responsible for pathogenesis were also identified. Due to several mutations, acquisition of multiple resistance genes and transposon insertion, phenotypic resistance decision scheme for for evaluating the resistance proved inaccurate, which highlights the urgent need for modification to this scheme. This complete illustration of mechanism contributing to specific resistance phenotypes can be used as a target for novel drug development. It can also be used as a reference strain in the clinical laboratory and for the evaluation of antibiotic efficacy for specific resistance mechanisms.
Highlights
Acinetobacter spp. are non-motile, non-fermenting Gramnegative bacteria
Extended-Spectrum Beta-Lactamases In Korea a high prevalence of blaPER−1 ESBL-producing Acinetobacter spp. was reported between 2001 and 2005 (Yong et al, 2003), and the level has been reducing over the years
The blaPER−1 belongs to class A extended-spectrum beta-lactamase, which has been detected in P. aeruginosa (Ranellou et al, 2012), P. mirabilis (Pagani et al, 2004), S. enterica (Poirel et al, 2005), and Acinetobacter spp. (Naas et al, 2006), and disseminated worldwide since its first detection in France on 1993 (Nordmann et al, 1993)
Summary
Acinetobacter spp. are non-motile, non-fermenting Gramnegative bacteria. Over the years, several species have been identified, and the most common and clinically significant are Acinetobacter baumannii, Acinetobacter pittii, and Acinetobacter nosocomialis (Chen et al, 2014). Among the 4,000 Acinetobacter spp. screened initially, we selected 26 isolates showing different phenotypic resistances, i.e., two ESBL-, six high-level AmpC β-lactamase-, ten OXA-typecarbapenemase-, five MBL-, two narrow-spectrum β-lactamase-, one narrow-spectrum oxacillinase-producing strains, in addition to a wild type strain, susceptible to all tested antibiotics (Table S1). A) Acinetobacter baumannii YMC2009/2/B6756 was only susceptible to imipenem and meropenem, but resistant to all other antibiotics and beta-lactamase inhibitor combinations used in the study (Table 1).
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