ABSTRACT
Introduction ........................................................................................................ 344 Resistance Mechanisms in Enterobacteria ........................................................ 345
Genetic Mechanisms .............................................................................. 345 Biochemical Mechanisms ....................................................................... 346
Resistance to Major Antibiotic Classes in Enterobacteria ................................. 346 β-Lactams ............................................................................................... 346 Quinolones .............................................................................................. 351 Aminoglycosides .................................................................................... 352 Tetracyclines ........................................................................................... 352 Antifolates: Sulfonamides and Trimethoprim ........................................ 352 Chloramphenicol .................................................................................... 353
Conclusions and Future Directions .................................................................... 353 References .......................................................................................................... 354
Enterobacteria cause a variety of nosocomial and community-acquired (including foodborne) infections and include some of the most deadly pathogens. As a result, their resistance to antibiotics has profound clinical implications. The major antibiotic classes currently in use for enterobacterial infections are the β-lactams, quinolones, aminoglycosides, tetracyclines, and sulfonamides. Resistance to β-lactams is relatively common and involves mainly serine β-lactamases: inducible, typically chromosomal (class C) as well as constitutive, typically plasmid-mediated, extended spectrum (classes A and D). There have been recent reports of class B metallo-β-lactamases in Klebsiella. Integron-borne β-lactamases (classes A, B, and D) occur in Enterobacteria species together with non-β-lactam resistance genes, giving rise to multidrug-resistant bacteria. They pose a threat, particularly in the hospital environment, as non-β-lactam agents may select potent β-lactamases through integronmediated resistance. Resistance to quinolones is associated with changes in the target DNA gyrase (chromosome encoded) or target protection by the proteins QnrA, QnrB, and QnrS (plasmid encoded) and affects quinolones in use as well as in clinical development. Reduced accumulation in the cell, due to active effl ux through
the cytoplasmic membrane and decreased infl ux through the outer membrane, may facilitate the emergence of quinolone resistance. Resistance to aminoglycosides is predominantly due to enzymatic inactivation in the periplasmic space, the exact nature of the modifi cation depending on the particular aminoglycoside. The major mechanism for tetracycline resistance involves an active effl ux system; ribosomal protection is not a clinically important mechanism in Enterobacteria. Sulfonamide resistance is due to an additional, plasmid-mediated, sulfonamide-resistant, dihydropteroate synthase target. Overall, the biggest clinical concern is multidrug resistance, particularly the ongoing erosion of the effectiveness of β-lactams and quinolones, two bactericidal and generally safe antibacterial classes.
