tion of additional mechanisms or is a consequence of mutational events under selective pressure. 2. Intrinsic resistance of Pseudomonas aeruginosa P. aeruginosa shows inherent resistance to antimicrobial agents through a variety of mechanisms: (1) decreased permeability of the outer membrane, (2) efflux systems which actively pump antibiotics out of the cell, and (3) production of antibiotic-inactivating enzymes [6]. 2.1. Outer membrane permeability The outer membrane of Gram-negative bacteria is a barrier which prevents large hydrophilic molecules to pass through it. Aminoglycosides and colistin interact with lipopolysaccharides changing the permeability of the membrane in order to pass whereas beta-lactams and quinolones need to diffuse through certain porin channels. Bacteria produce two major classes of porins: general; which allow almost any hydrophilic molecule to pass [7] and specific; which have binding sites for certain molecules, allowing them to be oriented and pass in the most energy-efficient way [8]. Most bacteria posses lots of general porins and relatively few specific ones. However, the exact opposite occurs for P. aeruginosa that expresses mainly specific porins [7]. 2.2. Efflux systems P. aeruginosa expresses several efflux pumps that expel drugs together with other substances out of the bacterial cell. These pumps consist of three proteins: (1) a protein transporter of the cytoplasmatic membrane that uses energy in the form of proton motive force, (2) a periplasmic connective protein, and (3) an outer membrane porin [5]. Most antibiotics-except polymyxins-are pumped out [9,10] by these efflux systems (Table 1) therefore their first two components are named multidrug efflux (Mex) along with a letter (e.g. MexA and MexB). The outer membrane porin is called Opr along with a letter (e.g. OprM) [11]. 2.3. Antibiotic-inactivating enzymes P. aeruginosa belongs to the SPICE group of bacteria (Serratia spp., P. aeruginosa, Indole positive Proteus, Citrobacter spp., Enterobacter spp.). These microorganisms share a common characteristic: the ability to produce chromosomal-encoded and inducible AmpC beta-lactamases. These are cephalosporinases that hydrolyze most beta-lactams and are not inhibited by the beta lactamase inhibitors. Another endogenous beta-lactamase produced by P. aeruginosa is the class D oxacillinase PoxB [12,13]. This enzyme however has only been found in laboratory mutants and is not clinically significant.

No abstract