Nosocomial Infections Due to Multidrug-Resistant Pseudomonas Aeruginosa: Epidemiology and Treatment Options

Marilee D. Obritsch, PharmD; Douglas N. Fish, PharmD, FCCM; Robert MacLaren, PharmD; Rose Jung, PharmD

Disclosures

Pharmacotherapy. 2005;25(10):1353-1364. 

In This Article

Mechanisms of Multidrug Resistance

The selection of target-mediated resistance is thought to be responsible for compromising a single antipseudomonal agent and perhaps one class of drugs. In the United States, derepression of the chromosomal AmpC β-lactamases is mainly responsible for reduction in susceptibility to β-lactam antibiotics.[26] The loss of OprD, an outer membrane porin that forms narrow transmembrane channels accessible to carbapenems, is associated with resistance to imipenem and reduced susceptibility to meropenem.[27] Mutations to topoisomerase II and IV enzymes confer resistance to fluoroquinolones.[28] Permeability mutations, amino-glycoside-modifying enzymes, and decreased membrane penetration are blamed for aminoglycoside resistance.[29] Finally, resistance to the polymyxins is postulated to be induced by a gene (PmrA) that, in the presence of low magnesium concentrations, modifies the lipopolysaccharide, resulting in reduced binding affinity of colistin and perhaps related antimicrobial peptides to the outer membrane.[30,31]

Contributions of individual resistance mechanisms to produce clinically significant levels of multidrug resistance among P. aeruginosa isolates remain largely unknown. However, sequential accumulation of resistance mechanisms after exposure to many classes of antibiotics is thought to be facilitated by multidrug-resistant efflux pumps. Because a single type of efflux pump may extrude multiple antibiotics and a single bacterial cell may contain multiple efflux pumps, efflux may contribute significantly to decreased intracellular concentrations of multiple antibiotics and allow subsequent accumulation of target-mediated resistance to several antipseudomonal agents. An upregulated efflux system, MexAB-OprM, has been reported to simultaneously decrease susceptibility to penicillins, cephalosporins, fluoroquinolones, and to some extent meropenem, while maintaining susceptibility to imipenem.[32] Other efflux systems, such as MexCD-OprJ and MexEF-OprN, have been associated with resist-ance to fluoroquinolones and some β-lactams. The MexXY-OprM system has been shown to confer resistance to aminoglycosides.[33,34]

The evidence supporting upregulated antibiotic efflux working additively with target-mediated resistance to select for multidrug resistance is limited. A recent study evaluated mechanisms of resistance with seven clinical P. aeruginosa isolates from a Texas hospital, which involved two clonal MDRPA strains.[35] Fluoroquinolone resistance was linked to single amino acid substitution within gyrA as well as mexXY efflux pump upregulation in the MDR isolates. It was hypothesized that the mexXY upregulation may have also contributed to the decreased susceptibility to aminoglycosides. Resistance to β-lactams in the multidrug-resistant isolates was associated with high-level constitutive production of AmpC β-lactamases. Reduction of OprD in the outer membrane correlated with carbapenem resistance in these strains. This study suggests the ability of P. aeruginosa to develop multiple mechanisms of resistance that may be selected by various antimicrobial classes. More molecular epidemiology studies are required to identify further the impact of efflux systems in MDRPA, investigate the ability of efflux systems to facilitate the selection of target-mediated resistance, and determine the role and expression of efflux systems once high-level resistance is achieved with reduced permeability, β-lactamase expression, or topoisomerase mutations.

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