Journal of Hospital Infection (2009) 73, 345e354 Available online at www.sciencedirect.com www.elsevierhealth.com/journals/jhin REVIEW Extended-spectrum b-lactamase-producing organisms M.E. Falagas a,b,c,*, D.E. Karageorgopoulos a a Alfa Institute of Biomedical Sciences, Athens, Greece b Department of Medicine, Henry Dunant Hospital, Athens, Greece c Department of Medicine, Tufts University School of Medicine, Boston, Massachusetts, USA Available online 10 July 2009 KEYWORDS Summary Extended-spectrum b-lactamases (ESBLs), which hydrolyse Bacterial drug extended-spectrum cephalosporins and are inhibited by clavulanic acid, resistance; are spreading among Enterobacteriaceae. The CTX-M enzymes are repla- b-Lactam resistance; cing SHV and TEM enzymes as the prevalent type of ESBLs, principally in Cefotaximases; community-acquired infections caused by Escherichia coli. Associated in- Genetic techniques; Microbiological fectious syndromes include mainly urinary tract infections, and secondly techniques; bloodstream and intra-abdominal infections, and may be serious enough Plasmids to warrant hospitalisation. Affected patients commonly have various un- derlying risk factors. This is also observed in hospital-acquired infections. The rates of ESBL-expression among nosocomial Enterobacteriaceae isolates, particularly Klebsiella pneumoniae, have risen substantially in several countries. The hospital epidemiology of these infections is often complex; multiple clonal strains causing focal outbreaks may co-exist with sporadic ones. Relevant infection-control measures should focus on reducing patient-to-patient transmission via the inanimate environment, hospital personnel, and medical equipment. Wise use of antibiotics is also essen- tial. The available therapeutic options for the treatment of ESBL- associated infections are limited by drug resistance conferred by the ESBLs, along with frequently observed co-resistance to various antibiotic classes, including cephamycins, fluoroquinolones, aminoglycosides, tetra- cyclines, and trimethoprim/sulfamethoxazole. Relevant clinical data regarding the effectiveness of different regimens for ESBL-associated in- fections are limited. Although certain cephalosporins may appear active in vitro, associated clinical outcomes are often suboptimal. b-Lactam/ b-lactamase inhibitor combinations may be of value, but the supporting evidence is weak. Carbapenems are regarded as the agents of choice, * Corresponding author. Address: Alfa Institute of Biomedical Sciences, 9 Neapoleos Street, 151 23 Marousi, Athens, Greece. Tel.: þ30 210 683 9604; fax: þ30 210 683 9605. E-mail address: [email protected] 0195-6701/$ - see front matter ª 2009 The Hospital Infection Society. Published by Elsevier Ltd. All rights reserved. doi:10.1016/j.jhin.2009.02.021 346 M.E. Falagas, D.E. Karageorgopoulos and may be more effective than fluoroquinolones for serious infections. Ti- gecycline and polymyxins have substantial antimicrobial activity against ESBL-producing Enterobacteriaceae, and, along with fosfomycin, merit further evaluation. ª 2009 The Hospital Infection Society. Published by Elsevier Ltd. All rights reserved. Introduction on the Tigecycline Evaluation and Surveillance Trial (TEST) global surveillance database, the The main mechanism of bacterial resistance to the rate of ESBL production was highest among the b-lactam class of antibiotics consists of the pro- K. pneumoniae isolates collected in Latin America, duction of b-lactamases, which are hydrolytic followed by Asia/Pacific Rim, Europe, and North enzymes with the ability to inactivate these America (44.0%, 22.4%, 13.3% and 7.5%, respec- 7 antibiotics before they reach the penicillin-binding tively). The same ranking order between the proteins located at the cytoplasmic membrane. different geographical regions was observed The extended-spectrum b-lactamases (ESBLs) are regarding the prevalence of ESBLs among the E. classified in the molecular (Ambler) class A and coli isolates, although the corresponding rates functional (BusheJacobyeMedeiros) group 2be; were lower (13.5%, 12.0%, 7.6%, and 2.2%, respec- 7 they are characterised by the ability to hydrolyse tively). It should be mentioned that the above an oxyimino-b-lactam at a rate 10% of that for data refer to isolates related to hospital-acquired benzylpenicillin along with inhibition by clavulanic infections obtained from various clinical acid.1,2 The presence of ESBLs in various members specimens. of the Enterobacteriaceae family, particularly Detailed data derived from the TEST database Klebsiella pneumoniae and Escherichia coli,isof regarding the prevalence of ESBL production great microbiological and clinical importance. among Enterobacteriaceae isolates in Europe 8 ESBLs are also found in non-fermentative Gram- have recently been presented. According to these negative bacteria, such as Pseudomonas aerugi- data that refer to 22 European countries for the nosa and Acinetobacter baumannii.3 period of 2004 to 2007, the rate of ESBL production The ESBL enzymes were initially recognised in among 515 K. pneumoniae isolates and 794 E. coli clinical isolates in the 1980s; they derived mainly isolates was 15.5% and 9.8%, respectively. Marked from the TEM or SHV types of b-lactamases, by point differences were observed in the country-specific mutations in the parent enzymes which did not data; the highest rate of ESBL production was possess extended-spectrum b-lactam substrate noted in Greece, while the lowest was noted in activity.3 The CTX-M type of ESBLs is becoming in- Denmark. Relevant data collected by the European creasingly more prevalent, particularly in E. coli Antimicrobial Resistance Surveillance System and K. pneumoniae.4,5 More than 50 enzymes of (EARSS Annual Report 2007. Bilthoven. The Nether- the latter type have so far been identified, which lands. ISBN:978-90-6960-214-1. available at: can be divided into five main groups on the basis http://www.rivm.nl/earss/) regarding resistance of amino acid changes (CTX-M1, CTX-M2, CTX-M8, rates to third-generation cephalosporins of CTX-M9 and CTX-M25, respectively).6 The origin of K. pneumoniae and E. coli clinical isolates col- some of these enzymes has been traced to chromo- lected in 31 European countries are consistent somally encoded enzymes of the Kluyvera spp. of with those of the TEST database. environmental bacteria. The relevant genes are Particular attention should be paid to the in- thought to have been mobilised into conjugative creasing prevalence of the CTX-M type ESBLs 6 plasmids and thus transferred to pathogenic bac- worldwide. This can be attributed to the spread teria.6 Additional clinically relevant types of ESBLs of CTX-M genes among bacterial species by plas- include mainly the VEB, PER, GES, TLA, IBC, mids or other mobile genetic elements, as well as SFO-1, BES-1 and BEL-1 types.3 to the clonal expansion of epidemic strains carry- ing these genes.5 The prevalence of specific types or groups of CTX-M ESBLs has acquired endemic Global epidemiology proportions in many countries. Among European countries, relevant examples include CTX-M-1 en- The rate of ESBL production among Enterobacter- zymes in Italy, CTX-M-9 and CTX-M-14 enzymes in iaceae varies worldwide. In a recent study based Spain, CTX-M-3 enzymes in Poland, and CTX-M-15 ESBL-producing organisms 347 enzymes in the UK.5,6,9 Notably, the CTX-M-15 type of ESBL present in a micro-organism, which ESBLs exhibit a nearly worldwide distribution.5 may be particularly useful for epidemiological Nevertheless CTX-M enzymes have rarely been purposes.9 Moreover, they can detect low-level found responsible for ESBL production among clin- resistance, and can be performed without prior ical isolates collected in the USA. However, a re- culture of the microbiological specimen. cent study highlights the increasing prevalence of CTX-M type ESBLs in a large US institution.10 Clinical relevance and impact of ESBL- associated infections Laboratory detection It is increasingly being recognised that the pro- In the microbiological laboratory, detection of duction of ESBLs is not relevant to nosocomial ESBLs can be done with phenotypic or genotypic infections only, but is becoming an important public tests. The phenotypic tests are routinely used in health issue also with regard to infections acquired clinical diagnostic laboratories, whereas the geno- in the community. Community-onset ESBL-associ- typic tests are mainly used in reference or re- ated infections are principally caused by E. coli pro- search laboratories. ducing CTX-M type ESBLs.9 Urinary tract infections The phenotypic tests for ESBL detection involve constitute the main clinical syndrome observed in screening and confirmatory steps. The screening this setting. Bloodstream infections may also be step consists of testing for resistance to cefpodox- observed, mainly of urinary or biliary tract origin. ime (which is hydrolysed by all TEM, SHV, and CTX-M Community-acquired ESBL-associated infections types of ESBLs), cefotaxime, ceftazidime, ceftriax- typically affect patients with various complicating one, or aztreonam.11 The confirmatory step is based factors. A relevant caseecontrol study identified on the demonstration of synergy between the above various risk factors for community-acquired agents and clavulanic acid.11 Several methods in- infection by ESBL-producing E. coli, including cluding the double disc synergy test, the combina- increased age, female sex, diabetes mellitus, re- tion disc method, or specific ESBL Etests can be current urinary