Clinical significance of extended - spectrum β - lactamases

www.expert-reviews.com ISSN 1478-7210 © 2008 Expert Reviews Ltd 10.1586/14787210.6.5.671 The potential options available for treating serious infections caused by enterobacteria include penicillins (with or without β-lactamase inhibitors), cephalosporins, aztreonam, carbapenems, fluoroquinolones and, in certain situations only, aminoglycosides and colistin. Recently, tigecycline has been added to the therapeutic arsenal for intra-abdominal and complicated soft-tissue infections. Most protocols have traditionally recommended keeping agents with the broadest spectrum in reserve, as a second or third option, as a way of limiting their use and preserving them. However, two facts seriously challenge this approach: first, the evidence that, in cases of severe infection, inadequate empirical therapy is associated with a worse outcome [1] and, second, the increasingly frequent resistance of Gram-negative bacilli to first-line agents [2]. As a consequence, a new paradigm has been put in place, which includes initiating broad-spectrum empirical therapy early on for patients with severe infections or those at risk of acquiring resistant organisms, but de-escalating to reduced-spectrum antimicrobials wherever possible, subject to the results of susceptibility tests [3]. In this context, there is an increased interest in assessing the clinical significance of different resistance mechanisms, particularly when they are associated with low-level or heterogeneous resistance. Microbiology & epidemiology overview Production of β-lactamase is the most frequent β-lactam resistance mechanism in Gram-negative organisms. In the varied and complex world of β-lactamases, extended-spectrum β-lactamases (ESBLs) have played a leading role in the clinical field in recent decades. Their importance resides in the fact that they significantly expand the spectrum of previous β-lactamases to include hydrolysis of all penicillins and cephalosporins (with the exception of cephamycins) and aztreonam. Moreover, non-β-lactam agents are frequently useless against ESBL-producing organisms, since the latter may also show resistance to aminoglycosides, trimethoprim–sulfamethoxazole and fluoroquinolones; as a result, many of these organisms become truly multidrug resistant [4]. Since some ESBLs show limited in vitro activity against certain cephalosporins (e.g., ESBLs from the TEM and SHV families are usually less active against cefotaxime, while many ESBLs from the CTX-M family are less active against ceftazidime) and are inhibited by β-lactamase inhibitors, such as clavulanic acid, tazobactam or sulbactam, it is useful from a clinical perspective to review the clinical efficacy of the less-affected cephalosporins and of β-lactam/β-lactamase inhibitor associations for infections caused by ESBL-producing organisms. Jesús Rodríguez-Baño† and Alvaro Pascual Author for correspondence Sección de Enfermedades Infecciosas, Hospital Universitario Virgen Macarena, Avda. Dr. Fedriani 3, 41009 Seville, Spain Tel.: +34 955 009 024 [email protected] The spread of extended-spectrum β-lactamases (ESBLs) in nosocomial and community-acquired enterobacteria is an important challenge for clinicians as the therapeutic options for these organisms are limited. The emergence of ESBL-producing Escherichia coli in the community, associated with the spread of CTX-M ESBL, is one of the most significant epidemiologic changes in infectious diseases during recent years. The epidemiology of these infections is complex and combines the expansion of mobile genetic elements with clonal spread. Infections caused by ESBL producers are associated with increased mortality, length of stay and increased cost. An inadequate empirical therapy for serious infections caused by these organisms is independently associated with increased mortality. Carbapenems are the drugs of choice for serious infections caused by ESBL-producing organisms but their overuse is a cause of concern.