Impact of Multidrug-resistant Pseudomonas aeruginosa Infection on Patient Outcomes

Elizabeth B Hirsch; Vincent H Tam

Disclosures

Expert Rev Pharmacoeconomics Outcomes Res. 2010;10(4):441-451. 

In This Article

Resistance Mechanisms & Their Effect on Bacterial Fitness

Multidrug resistance in P. aeruginosa results from the bacterium's notable inherent antibiotic resistance, in addition to its ability to acquire and harbor diverse resistance determinants (Table 1).[8,16,17] Low outer membrane permeability in combination with multidrug efflux systems account for its intrinsic mechanisms of resistance. The resistance-nodulation-cell division (RND) family of transporters is responsible for a significant portion of clinically relevant drug resistance among Gram-negative bacteria and facilitates active efflux of multiple antimicrobial substrates.[18] The broad specificity of the RND-type family allows many structurally unrelated molecules, such as biocides, detergents, dyes and organic solvents to act as substrates.[19] The majority of RND efflux systems are chromosomally encoded and are overexpressed following mutations in their respective negative regulator genes. At least seven RND efflux systems (e.g., MexAB-OprM, MexCD-OprJ, MexEF-OprN and MexXY-OprM) have been described in P. aeruginosa.[20,21] Broad antimicrobial resistance can result from overexpression of these pumps. For example, the MexAB-OprM system has the broadest substrate specificity and contributes to resistance to macrolides, aminoglycosides, sulfonamides, fluoroquinolones, tetracyclines and many bgr;-lactams.[20] The loss of the outer membrane protein (porin) OprD, is associated with imipenem resistance and reduced susceptibility to meropenem.

Additional resistance mechanisms in P. aeruginosa include enzyme production and target mutations. Expression of aminoglycoside-modifying enzymes (acetyltransferases, nucleotidyltransferases and phosphotransferases), mediating aminoglycoside resistance are common.[22] Most recently, methylation of 16S rRNA has emerged as a mechanism conferring high-level resistance against all commercially available aminoglycosides in P. aeruginosa.[23] Methylation of specific nucleotides within the A-site of 16S rRNA prevents binding of aminoglycosides to their target site. At least six distinct genes (rmtA, rmtB, rmtC, rmtD, armA and npmA) encoding their respective methylase enzymes have been reported to date.[24] The carriage of these genes on plasmids is probably responsible for their worldwide dissemination and transfer amongst various genera and species.[25,26] Furthermore, a wide variety of β-lactamases are produced by P. aeruginosa. PSE-1 and PSE-4 are those most frequently acquired but confer resistance only to the penicillins; activity of the antipseudomonal cephalosporins, carbapenems and monobactam is retained. The overexpression of chromosomally encoded cephalosporinase, AmpC, is prevalent in P. aeruginosa.[27] Antibiotic therapy may induce expression or select for stably derepressed mutants, resulting in resistance to ticarcillin, piperacillin and third-generation cephalosporins. Broad spectrum β-lactam resistance attributed to β-lactamases is generally due to the metallo-β-lactamases (MBLs): IMP, VIM, SPM and GIM.[17] These MBLs hydrolyze antipseudomonal cephalosporins and carbapenems effectively and their activity is not suppressed by the β-lactamase inhibitors that are currently commercially available. Lastly, mutations in DNA gyrase and topoisomerase IV (encoded by the gyrA and parC genes), mediate resistance to the fluoroquinolones.[28]

Confounded by the inconsistent definition of multidrug resistance in P. aeruginosa, data regarding its impact on bacterial fitness are somewhat controversial. One generally accepted school of thought regarding antibiotic resistance and virulence is that overexpression/acquisition of resistance determinants comes at a physiological cost to the bacteria, resulting in a reduction in their fitness. This decrease in fitness, however, may be restored by compensatory mutations without the loss of resistance.[29] Conversely, 'no-cost' mutations in several bacterial strains have been reported.[30,31] Several in vitro studies in P. aeruginosa suggest virulence impairment in MDR strains. In one study comparing virulence factors of clinical strains, MDR strains had reduced expression of exoenzymes and pyocyanin, and slower growth rates were observed when compared with multidrug-susceptible (MDS) strains.[32] In a second study comparing MDR mutants overexpressing MexAB-OprM and MexCD-OprJ efflux systems to their isogenic parent strain, the mutants displayed impaired survival in water and on dry surfaces, and reduced virulence in a Caenorhabditis elegans nematode model.[33] It is poorly understood how these in vitro data relate to humans, as in vitro results seem to be highly dependent on growth conditions that can be standardized in the laboratory. Ongoing in vitro and in vivo investigations in our laboratory are also generating rather conflicting results [ABDELRAOUF K ET AL., Unpublished Data]. Consequently, inferring the in vivo fitness of bacteria based on in vitro studies may not always be accurate.

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