1 Introduction During the past 70 years, the use of successive generations of β-lactam antibiotics has selected consecutive genera- tions of β-lactamase enzymes, each more potent than the last. he spread of β-lactamases has driven the develop- ment of β-lactam antibiotics for 70 years (Easton and Knowles 1982). he irst analogue was benzylpenicillin, which penetrated Gram-negative bacteria poorly and was destroyed by penicillinases, but spread in Staphylococcus aureus. hese problems were overcome in the 1960s with the development of semi-synthetic penicillins that are known to penetrate Gram-negative bacterial cell wall and those that were stable to staphylococcal penicillinase (Fisher et al. 1980). he anti-Gram-negative analogues were compromised, in turn, by the spread of plasmid-mediated β-lactamases, which drove the development of the second-, third- and fourth-generation oxyimino-cephalosporins; and of β-lactamase inhibitors (Lauretti et al. 1999). he current rising problems of β-lactams resis- tance in Gram-negative bacteria include CTX-M type extended-spectrum β-lactamases (ESBLs), plasmid mediated AmpC β-lactamases, and carbapenemases in Enterobacteriaceae, while OXA- and metallocarbapen- emases are of growing importance since the last decade (Gavin et al. 2006). he main mechanism of bacterial resistance to β-lactam class of antibiotics consists of the production of β-lactamases, which are hydrolytic enzymes with the ability to inactivate these antibiotics before they reach the penicillin-binding proteins located at the cytoplasmic membrane (Helfand et al. 2003). he ESBLs are classiied as Ambler class A and functional (Bush-Jacoby-Medeiros) group 2be. hey are also charac- terized by the ability to hydrolyze the oxyimino-β-lactam at a rate 10% of that for benzylpenicillin along with inhi- bition by clavulanic acid (Bush et al. 1995). ESBL encoding genes are generally acquired by horizontal gene transfer and confer resistance to oxy- imino-cephalosporins, some being mutant derivatives of established plasmid-mediated β-lactamases (TEM/ SHV) or moved from environmental bacteria (CTX-M) REVIEW ARTICLE Evolution of β-lactams resistance in Gram-negative bacteria in Tunisia Chedly Chouchani 1 , Rim Marrakchi, 1,2 and Allaaeddin El Salabi 3 1 Université de Carthage, Institut Supérieur des Sciences et Technologies de l’Environnement de Borj-Cedria, Technopôle de Borj-Cedria, BP-1003, Hammam-Lif 2050, Tunisie, 2 Faculté des Sciences de Tunis, Campus Universitaire, 2092 El-Manar II, Tunisie, and 3 Department of Infection, Immunity & Biochemistry, School of Medicine, Cardif University, Heath Park, Cardif CF14 4XN, United Kingdom Abstract Antimicrobial resistance is a major health problem worldwide, but marked variations in the resistance profiles of bacterial pathogens are found between countries and in different patient settings. In Tunisia, the strikingly high prevalence of resistance of bacteria to penicillins and cephalorosporins drugs including fourth generation in clinical isolates of Gram negative bacteria has been reported. During 30 years, the emerging problem of extended-spectrum β-lactamase-producing Escherichia coli and Klebsiella pneumoniae isolates is substantial, and some unique enzymes have been found. Recently, evidence that Gram-negative bacteria are resistant to nearly all available antimicrobial agents, including carbapenems, have emerged. Keywords: Antibiotic resistance, β-lactamases, Tunisia Address for Correspondence: Dr. Chedly Chouchani, Université de Carthage, Institut Supérieur des Sciences et Technologies de l’Environnement de Borj-Cedria, Technopôle de Borj-Cedria, BP-1003, Hammam-Lif 2050, Tunisie. Tel: 0021694114443. Fax: 0021679325333. E-mail: chdoula77@yahoo.fr (Received 25 May 2010; revised 10 December 2010; accepted 05 January 2011) Critical Reviews in Microbiology, 2011, 1–11, Early Online Copyright © 2011 Informa Healthcare USA, Inc. ISSN 1040-841X print/ISSN 1549-7828 online DOI: 10.3109/1040841X.2011.552880 Critical Reviews in Microbiology Downloaded from informahealthcare.com by 41.225.90.111 on 04/29/11 For personal use only.