Review
Emerging broad-spectrum resistance in Pseudomonas aeruginosa and Acinetobacter baumannii: Mechanisms and epidemiology

https://doi.org/10.1016/j.ijantimicag.2015.03.001Get rights and content

Highlights

Abstract

Multidrug resistance is quite common among non-fermenting Gram-negative rods, in particular among clinically relevant species including Pseudomonas aeruginosa and Acinetobacter baumannii. These bacterial species, which are mainly nosocomial pathogens, possess a diversity of resistance mechanisms that may lead to multidrug or even pandrug resistance. Extended-spectrum β-lactamases (ESBLs) conferring resistance to broad-spectrum cephalosporins, carbapenemases conferring resistance to carbapenems, and 16S rRNA methylases conferring resistance to all clinically relevant aminoglycosides are the most important causes of concern. Concomitant resistance to fluoroquinolones, polymyxins (colistin) and tigecycline may lead to pandrug resistance. The most important mechanisms of resistance in P. aeruginosa and A. baumannii and their most recent dissemination worldwide are detailed here.

Introduction

The emergence and spread of bacteria resistant to multiple antibiotics and at the origin of severe infections is currently of great concern. This is particularly true for nosocomial pathogens isolated in hospitals, where these superbugs may compromise advanced medicine, including surgery, transplantation, efficient treatment of immunocompromised and haematological patients, etc. Among the increasingly reported and commonly identified multidrug-resistant or even pandrug-resistant bacteria, the lactose-non-fermenting Gram-negative pathogens Acinetobacter baumannii and Pseudomonas aeruginosa occupy an important place. These bacterial species are quick to become multidrug-resistant owing to their additional intrinsic resistance mechanisms. They are responsible for hospital-acquired infections (bloodstream, urinary tract, pulmonary and device-related infections) and are frequently isolated from immunocompromised patients hospitalised in the intensive care unit. Resistance to multiple antibiotic classes, and notably to the β-lactam cephalosporins and carbapenems, is on the rise worldwide. In this review, the emerging antibiotic resistance mechanisms in A. baumannii and P. aeruginosa are highlighted, with a special focus on the most prescribed antimicrobial agents, i.e. β-lactams, aminoglycosides and fluoroquinolones.

Section snippets

Extended-spectrum β-lactamases (ESBLs)

The class A ESBLs confer resistance to expanded-spectrum cephalosporins and are inhibited in vitro by clavulanic acid and tazobactam [1]. They have been extensively identified in members of the Enterobacteriaceae family but are also reported from non-fermenters.

Broad resistance to aminoglycosides

Aminoglycosides are used in the treatment of a broad range of life-threatening infections. The activity of aminoglycosides depends on binding to a highly conserved motif of 16S rRNA. Mechanisms of aminoglycosides resistance include decreased outer membrane permeability, active efflux and amino acid substitutions in ribosomal proteins, whereas the most common resistance mechanism is enzymatic leading to modification of the drug. Methylation of 16S ribosomal RNA has recently been demonstrated to

Broad resistance to fluoroquinolones

In Gram-negative organisms, acquisition of resistance to quinolones may be related to chromosomal mutations in genes encoding the topoisomerases or to mutations in the efflux pump regulation systems. In addition, plasmid-mediated quinolone resistance genes (coding for the Qnr proteins) have been identified in Enterobacteriaceae. These acquired Qnr proteins have not been identified in non-fermenters. In P. aeruginosa and A. baumannii, a single mutation in the gyrA gene encoding DNA gyrase is

Resistance to tigecycline

Tigecycline, a semisynthetic derivative of minocycline, has a peculiar mechanism of action and overcomes the widely distributed tet gene-encoded resistance mechanism known to confer resistance to tetracycline. Tigecycline shows good activity towards Gram-negative pathogens that may produce a large array of resistance mechanisms, including ESBLs and carbapenemases [296]. The activity of tigecycline against A. baumannii is overall good, and successful results have been reported clinically [296].

Resistance to colistin

During the past decade, we have witnessed a renewal of clinical interest in polymyxins (colistin) owing to two concomitant facts: (i) the emergence of carbapenem-, cephalosporin- and aminoglycoside-resistant Gram-negative isolates; and (ii) the paucity of novel marketed antibiotic molecules. Actually, polymyxins remain most often active against these multidrug-resistant isolates [303]. Emergence of colistin resistance in relation to increased usage is worrisome since polymyxins are the last

Concluding remarks

Increasing rates of bacterial resistance among non-fermenters are threatening the effectiveness of antibiotics used as last-resort therapeutic options. In A. baumannii and P. aeruginosa, acquisition of resistance traits to these molecules is becoming more and more frequent, leading to multidrug and pandrug resistance. The last years have shown that: (i) most of the broad-spectrum resistance patterns identified in Enterobacteriaceae may be also identified in P. aeruginosa and A. baumannii; (ii)

References (319)

  • L. Poirel et al.

    Extended-spectrum β-lactamase TEM-4 in Pseudomonas aeruginosa

    Clin Microbiol Infect

    (1999)
  • I.K. Bae et al.

    Genetic and biochemical characterization of GES-5, an extended-spectrum class A β-lactamase from Klebsiella pneumoniae

    Diagn Microbiol Infect Dis

    (2007)
  • P. Nordmann et al.

    The real threat of Klebsiella pneumoniae carbapenemase-producing bacteria

    Lancet Infect Dis

    (2009)
  • M. Iraz et al.

    Characterization of novel VIM carbapenemase, VIM-38, and first detection of GES-5 carbapenem-hydrolyzing β-lactamases in Pseudomonas aeruginosa in Turkey

    Diagn Microbiol Infect Dis

    (2014)
  • G.F. Weldhagen et al.

    Ambler class A extended-spectrum β-lactamases in Pseudomonas aeruginosa: novel developments and clinical impact

    Antimicrob Agents Chemother

    (2003)
  • D. Yong et al.

    High prevalence of PER-1 extended-spectrum β-lactamase-producing Acinetobacter spp. in Korea

    Antimicrob Agents Chemother

    (2003)
  • D. Szabó et al.

    Imported PER-1 producing Pseudomonas aeruginosa, PER-1 producing Acinetobacter baumanii and VIM-2-producing Pseudomonas aeruginosa strains in Hungary

    Ann Clin Microbiol Antimicrob

    (2008)
  • T. Naas et al.

    Multidrug-resistant Acinetobacter baumannii, Russia

    Emerg Infect Dis

    (2007)
  • T. Naas et al.

    Emergence of PER and VEB extended-spectrum β-lactamases in Acinetobacter baumannii in Belgium

    J Antimicrob Chemother

    (2006)
  • K.M. Hujer et al.

    Analysis of antibiotic resistance genes in multidrug-resistant Acinetobacter sp. isolates from military and civilian patients treated at the Walter Reed Army Medical Center

    Antimicrob Agents Chemother

    (2006)
  • T. Strateva et al.

    Emergence of a PER-1 extended-spectrum β-lactamase-producing Acinetobacter baumannii clinical isolate in Bulgaria

    J Chemother

    (2008)
  • J.P. Zhang et al.

    Molecular characteristics and resistant mechanisms of imipenem-resistant Acinetobacter baumannii isolates in Shenyang, China

    J Microbiol

    (2010)
  • S. Farajnia et al.

    Prevalence of PER and VEB type extended spectrum β-lactamases among multidrug resistant Acinetobacter baumannii isolates in North-West of Iran

    Iran J Basic Med Sci

    (2013)
  • L. Poirel et al.

    Genetic environment and expression of the extended-spectrum β-lactamase blaPER-1 gene in Gram-negative bacteria

    Antimicrob Agents Chemother

    (2005)
  • F. Pasterán et al.

    Emergence of PER-2 and VEB-1a in Acinetobacter baumannii strains in the Americas

    Antimicrob Agents Chemother

    (2006)
  • R.A. Bonnin et al.

    an extended-spectrum β-lactamase with increased activity toward broad-spectrum cephalosporins in Acinetobacter baumannii

    Antimicrob Agents Chemother

    (2011)
  • A. Opazo et al.

    Plasmid-encoded PER-7 β-lactamase responsible for ceftazidime resistance in Acinetobacter baumannii isolated in the United Arab Emirates

    J Antimicrob Chemother

    (2012)
  • L. Poirel et al.

    Molecular and biochemical characterization of VEB-1, a novel class A extended-spectrum β-lactamase encoded by an Escherichia coli integron gene

    Antimicrob Agents Chemother

    (1999)
  • L. Poirel et al.

    Outbreak of extended-spectrum β-lactamase VEB-1-producing isolates of Acinetobacter baumannii in a French hospital

    J Clin Microbiol

    (2003)
  • T. Naas et al.

    VEB-1 extended-spectrum β-lactamase-producing Acinetobacter baumannii, France

    Emerg Infect Dis

    (2006)
  • L. Poirel et al.

    ISCR2, another vehicle for blaVEB gene acquisition

    Antimicrob Agents Chemother

    (2009)
  • L. Poirel et al.

    Biochemical sequence analyses of GES-1, a novel class A extended-spectrum β-lactamase, and the class 1 integron ln52 from Klebsiella pneumoniae

    Antimicrob Agents Chemother

    (2000)
  • C. Moubareck et al.

    GES-11, a novel integron-associated GES variant in Acinetobacter baumannii

    Antimicrob Agents Chemother

    (2009)
  • P. Bogaerts et al.

    GES extended-spectrum β-lactamases in Acinetobacter baumannii isolates in Belgium

    Antimicrob Agents Chemother

    (2010)
  • N. Karah et al.

    A diversity of OXA-carbapenemases and class 1 integrons among carbapenem-resistant Acinetobacter baumannii clinical isolates from Sweden belonging to different international clonal lineages

    Microb Drug Resist

    (2011)
  • R.A. Bonnin et al.

    Wide dissemination of GES-type carbapenemases in Acinetobacter baumannii isolates in Kuwait

    Antimicrob Agents Chemother

    (2013)
  • H. Delbrück et al.

    Kinetic and crystallographic studies of extended-spectrum GES-11, GES-12, and GES-14 β-lactamases

    Antimicrob Agents Chemother

    (2012)
  • M. Castanheira et al.

    Evaluation of clonality and carbapenem resistance mechanisms among Acinetobacter baumanniiAcinetobacter calcoaceticus complex and Enterobacteriaceae isolates collected in European and Mediterranean countries and detection of two novel β-lactamases, GES-22 and VIM-35

    Antimicrob Agents Chemother

    (2014)
  • T. Naas et al.

    Panresistant extended-spectrum β-lactamase SHV-5-producing Acinetobacter baumannii from New York City

    J Antimicrob Chemother

    (2007)
  • A. Endimiani et al.

    Spread in an Italian hospital of a clonal Acinetobacter baumannii strain producing the TEM-92 extended-spectrum β-lactamase

    Antimicrob Agents Chemother

    (2007)
  • N.A. Naiemi et al.

    Widespread transfer of resistance genes between bacterial species in an intensive care unit: implications for hospital epidemiology

    J Clin Microbiol

    (2005)
  • N. Nagano et al.

    Nosocomial transmission of CTX-M-2 β-lactamase-producing Acinetobacter baumannii in a neurosurgery ward

    J Clin Microbiol

    (2004)
  • J.M. Adams-Haduch et al.

    Genetic basis of multidrug resistance in Acinetobacter baumannii clinical isolates at a tertiary medical center in Pennsylvania

    Antimicrob Agents Chemother

    (2008)
  • G. Celenza et al.

    Spread of blaCTX-M-type and blaPER-2 β-lactamase genes in clinical isolates from Bolivian hospitals

    J Antimicrob Chemother

    (2006)
  • S. Shakil et al.

    Detection of CTX-M-15-producing and carbapenem-resistant Acinetobacter baumannii strains from urine from an Indian hospital

    J Chemother

    (2010)
  • A. Potron et al.

    Genetic features of CTX-M-15-producing Acinetobacter baumannii from Haiti

    Antimicrob Agents Chemother

    (2011)
  • A. Potron et al.

    Genetic and biochemical characterization of the first extended-spectrum CARB-type β-lactamase, RTG-4, from Acinetobacter baumannii

    Antimicrob Agents Chemother

    (2009)
  • P. Nordmann et al.

    Characterization of a novel extended-spectrum β-lactamase from Pseudomonas aeruginosa

    Antimicrob Agents Chemother

    (1993)
  • G. Claeys et al.

    PER-1 β-lactamase-producing Pseudomonas aeruginosa in an intensive care unit

    J Antimicrob Chemother

    (2000)
  • F. Luzzaro et al.

    Dynamics of a nosocomial outbreak of multidrug-resistant Pseudomonas aeruginosa producing the PER-1 extended-spectrum β-lactamase

    J Clin Microbiol

    (2001)
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