Acquisition and horizontal diffusion of beta-lactam resistance among clinically relevant microorganisms.

Abstract

Since their introduction into clinical medicine more than 60 years ago, antibiotics have become the main means of controlling bacterial infection. However, the emergence of microorganisms that are resistant to antimicrobial agents has increased and continues to increase at an alarming rate, making the effective control of infectious diseases a major challenge to public health. The emergence of resistance to antibiotics is no more than an unavoidable and perhaps irreversible consequence of bacterial adaptation to the selective pressure of antibiotics. The unlimited and indiscriminate use of antibiotics over long periods of time in biological systems, such as humans, other animals, and/or plants, has allowed and even promoted the emergence and spread of resistance to antibiotics. Antimicrobial agents have been found in sewage, and they later contaminate rivers, lakes, and oceans. This interconnection between ecosystems promotes a strong selective pressure, altering the environment and advancing the emergence and spread of resistant microorganisms. β-Lactams are the most varied and widely used of all the groups of antimicrobial agents in human and veterinary medicine. They act by inhibiting the final phase of bacterial cellwall synthesis. These drugs have little toxicity and a broad therapeutic margin. Penicillins and cephalosporins, which are based on 6-aminopenicillanic acid and 7-aminocephalosporanic acid, respectively, are the two classical β-lactam families. Moreover, β-lactams such as monobactams and carbapenems have also been developed. Although β-lactams are the treatment of choice for a large number of infections, the progressive emergence of acquired resistance has limited their use and their efficacy in certain situations. Bacteria may become resistant through several mechanisms: production of enzymes that inactivate an antibiotic, alteration of the target (the bacterial molecule with which the antimicrobial agent interacts), alteration of permeability, and activation of trans-membrane efflux (active pumping out). Mutations of cellular genes, acquisition of exogenous resistance genes, or a combination of these two events are responsible for these mechanisms. A good example of acquired resistance due to point mutations is provided by the acquired resistance to nearly all cephalosporins and monobactams in some gram-negative bacteria due to the derepression of a chromosomal cephalosporinase encoded by the β-lactaminducible ampC gene. Organisms such as Enterobacter spp., Citrobacter freundii, Serratia marcescens, Morganella morganii, and Pseudomonas aeruginosa express low levels of an AmpC β-lactamase; however, the enzyme is induced in response to β-lactams (e.g., cefoxitin or imipenem). AmpC β-lactamases are active-site serine enzymes that are primarily INTERNATIONAL MICROBIOLOGY (2006) 9:79-81 www.im.microbios.org