Pseudomonas Aeruginosa: Resistance to the Max

Abstract

Pseudomonas aeruginosa is intrinsically resistant to a variety of antimicrobials and can develop resistance during anti-pseudomonal chemotherapy both of which compromise treatment of infections caused by this organism. Resistance to multiple classes of antimicrobials (multidrug resistance) in particular is increasingly common in P. aeruginosa, with a number of reports of pan-resistant isolates treatable with a single agent, colistin. Acquired resistance in this organism is multifactorial and attributable to chromosomal mutations and the acquisition of resistance genes via horizontal gene transfer. Mutational changes impacting resistance include upregulation of multidrug efflux systems to promote antimicrobial expulsion, derepression of ampC, AmpC alterations that expand the enzyme's substrate specificity (i.e., extended-spectrum AmpC), alterations to outer membrane permeability to limit antimicrobial entry and alterations to antimicrobial targets. Acquired mechanisms contributing to resistance in P. aeruginosa include β-lactamases, notably the extended-spectrum β-lactamases and the carbapenemases that hydrolyze most β-lactams, aminoglycoside-modifying enzymes, and 16S rRNA methylases that provide high-level pan-aminoglycoside resistance. The organism's propensity to grow in vivo as antimicrobial-tolerant biofilms and the occurrence of hypermutator strains that yield antimicrobial resistant mutants at higher frequency also compromise anti-pseudomonal chemotherapy. With limited therapeutic options and increasing resistance will the untreatable P. aeruginosa infection soon be upon us?

Primary mechanisms mediating aminoglycoside resistance in the multidrug-resistant Pseudomonas aeruginosa clinical isolate PA7

“…Aminoglycosides such as amikacin, gentamicin and tobramycin are a vital component of antipseudomonal chemotherapy for a variety of infections, particularly pulmonary infections in cystic fibrosis (CF) patients (Poole, 2005(Poole, , 2011. Aminoglycoside resistance in P. aeruginosa has often arisen via acquired aminoglycoside-modifying enzymes (AMEs) and 16S rRNA methylases (RMTs), typically involving the MexXY endogenous efflux system (Poole, 2011).…”

“…Henrichfreise Sekiguchi et al, 2007;Samuelsen et al, 2010;Poole, 2011). Each AME has limited substrate specificity, but individual aminoglycoside-resistant P. aeruginosa isolates can carry multiple (2-5) AMEs and thus exhibit broad-spectrum aminoglycoside resistance (Poole, 2005).…”

“…overexpression of the efflux pump) and lateral gene transfer (e.g. acquisition of metallob-lactamase) (Lister et al, 2009;Poole, 2011). The emergence and spread of multidrug-, extensive drug-and pan-drug-resistant P. aeruginosa infections are very serious and of great concern, as few agents are effective against these organisms.…”

“…The emergence and spread of multidrug-, extensive drug-and pan-drug-resistant P. aeruginosa infections are very serious and of great concern, as few agents are effective against these organisms. In addition, antibiotic-resistant Gram-negative bacteria, including P. aeruginosa, increase the hospital costs and length of stay associated with healthcare-associated infections (Mauldin et al, 2010).Aminoglycosides such as amikacin, gentamicin and tobramycin are a vital component of antipseudomonal chemotherapy for a variety of infections, particularly pulmonary infections in cystic fibrosis (CF) patients (Poole, 2005(Poole, , 2011. Aminoglycoside resistance in P. aeruginosa has often arisen via acquired aminoglycoside-modifying enzymes (AMEs) and 16S rRNA methylases (RMTs), typically involving the MexXY endogenous efflux system (Poole, 2011).…”

“…Among the AMEs, AAC(69)-II and ANT(299)-I are the most prevalent mechanisms for aminoglycoside resistance in P. aeruginosa (Armstrong & Miller, 2010;Poole, 2005). RMTs were recently discovered in P. aeruginosa (Yokoyama et al, 2003) and these promote high-level resistance to clinically used aminoglycosides, such as gentamicin, tobramycin and amikacin (Doi & Arakawa, 2007;Doi & Arakawa, 2007;Poole, 2011).The complete genome sequence of P. aeruginosa PA7, which exhibits resistance to multiple antibiotics, including amikacin, was recently reported (Roy et al, 2010). The identification of mexXY-oprA (PSPA7_3269-3270-3271), encoding a multidrug efflux pump, and aacC4 (PSPA7_3724.1), encoding an AAC(69)-II, as aminoglycoside resistance determinants from the PA7 genome was very interesting, although there are several other AMEs in the PA7 genome that are not considered to be clinically relevant judging from their putative substrate specificities.…”