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Management of infection/colonization caused by Producing Extended-Spectrum Lactamases (ESBLs) in the Community. Jean-Ralph Zahar1, Olivier Lortholary2, Patrice Nordmann3, Gilles Potel4, Patrick Plesiat5, Claude Martin6. 1 Hygiène hospitalière, CHU Necker Enfants – Malades, Université René Descartes, Paris V, Paris France 2 Service de Maladies Infectieuses et tropicales, CHU Necker Enfants – Malades, Université René Descartes, Paris V, Paris France 3 Laboratoire de microbiologie, CHU Kremlin Bicêtre, Université Kremlin Bicêtre, France 4 EA 3826 « Thérapeutiques Cliniques et Expérimentales des infections » Faculté de Médecine, Nantes 5 Laboratoire de Bactériologie, CHU Jean Minjoz, Besançon, France 6 Département d’Anesthésie – Réanimation Corresponding author: Pr Claude Martin Département d’Anesthésie – Réanimation Assistance Publique Hôpitaux de Marseille Hôpital Nord email: [email protected] Phone : 33 (0) 491 968 650 Fax : 33(0) 491 962 818 Keywords : Extended-Spectrum -lactamases, CTXM, Resistant. Infection control, Multidrug- 1 Abstract (words ): Since 2000’s, community extended-spectrum-lactamases (ESBLs) have spread worldwide. Mostly Escherichia coli that produce ESBLs such as CTX-M enzymes. Organisms that produce CTX-M enzymes have now become the most prevalent type of ESBLs, reaching up to 89% of ESBL-producing E coli isolates in some countries. These organisms are most often isolated from the urinary tract , but also cause bacteraemia. Cephalosporins and fluoroquinolones usage are the two most frequent risk factors identified in patients that harbor ESBL-producing bacteria. In addition surveys have shown an alarming trend of associated resistance to others classes of antimicrobial agents among isolates. The emergence of ESBLproducing isolates limits the therapeutic option considerably. For systemic infections, carbapenems should be regarded as drugs of choice for serious infections due to ESBLproducing bacteria. Clinicians and infection control practitioners should be aware of these data to prevent the spread and control infections caused by these pathogens. 2 Introduction: Over the past decade, multidrug resistant Gram-negative bacteria (mdr GNB) have become a matter of concern for infection control practitioners, hospital epidemiologists, microbiologists and clinicians in many countries [1] [2]. Mdr GNB potentially increase the risk of morbidity and mortality associated with inadequate initial antibiotic therapy as well as the risk of diffusion of resistance genes in populations submitted to high antibiotic pressure. Extendedspectrum lactamases (ESBLs) strongly contribute to the emergence of mdr GNB [3]. For instance, an increasing prevalence of Enterobacteriaceae (mostly Escherichia coli and Klebsiella pneumoniae) producing ESBLs (mostly CTX-M enzymes) has been reported in the community over the last 5 years [4]. In Canada, 6.3% of E. coli and 13.7% of K. pneumoniae were found to harbour ESBLs, versus 89.7% and 58.5% in Taiwan, respectively [5] . Microbiology : The first report of a plasmid–encoded lactamase capable of hydrolyzing extended-spectrum cephalosporins was published in 1983 [6]. The gene encoding this ESBL appeared to derive by a point mutation from the K. pneumoniae gene encoding penicillinase SHV1. Other lactamases were discovered shortly thereafter, which also had the ability to confer a resistance to extended-spectrum cephalosporins [7]. These variants of TEM and SHV enzymes were almost exclusively found in nosocomial bacteria such as Klebsiella spp. In the 1990’s, large outbreaks caused by a few epidemic clones affected multiple hospitals with a predilection for intensive care units (ICUs) [8-9]. A survey from 23 ICUs of Western and Southern Europe found ESBLs in 25% of all Klebsiella spp in 1997 and 1998 [10]. Since then, the epidemiology of ESBL producing Enterobacteriaceae has dramatically changed with the rise of CTX-M enzymes. The name CTX-M itself reflects the potent hydrolytic activity of these -lactamases against cefotaxime. Organisms producing CTX-M-type ESBLs typically have cefotaxime 3 and cefepime MICs in the resistance range (> 64 g/ml), whereas ceftazidime MICs are usually in the susceptibility range (2 to 8 g/ml) [11]. It should be noted that some CTX-Mtype ESBLs such as CTX-M-15 may actually hydrolyze ceftazidime and confer high resistance (up to 256 g/ml) to this antibiotic as well [11-13]. Interestingly, CTX-M enzymes are not active against cephamycins, temocillin [14] and carbapenems. They are inhibited by tazobactam, sulbactam and to a lesser extend by clavulanate [15], but CTX-M producers are often resistant to lactam/inhibitor combinations because of concurrent production of inhibitor-resistant penicillinase (OXA-1) [16]. Moreover, the same organism may harbor two different ESBLs such as CTX-M and SHV-type enzymes. Plasmids carrying the blaCTX-M genes also usually contain a plethora of resistance genes to other antbiotic classes such as aminoglycosides, tetracyclines, trimethoprim, chloramphenicol, and sulfonamides. Analysis of 285 ESBLs-producing isolates recovered from June 1989 through January 2004 in Spain showed the following overall co-resistance rates: gentamicin 27,4%, tobramycin 27,4%, amikacin 6,7%, chloramphenicol 29,1%, sulfonamides 61,7%, trimethoprim 52,3%, and ciprofloxacin 37,2% (17). In a long term survey initiated in 1993 by the microbiology laboratories of the Assistance Publique des Hôpitaux de Paris, co-resistance of isolates recovered between 2003 and 2005 from patients hospitalized in short-term care facilities were as follows: gentamicin 58%, tobramycin 76%, amikacin 43,5%, and ciprofloxacin 67,5% [18]. Most of CTX-M producing bacteria are now resistant to fluoroquinolones [19] because of drug target alterations (i.e., mutations in the QRDRs of topoisomerase genes), the presence of different qnr genes, and/or production of the new variant -cr of aminoglycoside-modifying enzyme AAC(6’)-Ib that inactivates quinolones with a piperazinyl substituent such as ciprofloxacin [19, 20]. In a study conducted in Barcelona between 2003 and 2004, the prevalence of qnr genes among clinical ESBL-positive enterobacteria was 4.9%, with a majority of qnrA [21]. This gene is located on the same mobile genetic elements as the 4 blaCTX-M-9 and blaCTX-M-14 genes [22]. Obviously, the mdr phenotype of most ESBL-GNB complicates the choice of initial antibiotics used empirically, particulary in patients with serious infections. 5 Epidemiology: Until recently, ESBL-producing Enterobacteriaceae were considered to be exclusively nosocomial pathogens [23], while SHV and TEM were the two most frequent -lactamase enzymes identified. Number of recent publications reported on the spread of ESBL-positive GNB in the community (urine, blood, fecal samples) in Saudi Arabia, Israel, Spain, UK, Canada and many other countries. The most frequent CTX-M-type β-lactamase is currently CTX-M-15 which was isolated first in Bicêtre from an Indian isolate [24]. However, there is a considerable geographical heterogeneity in the occurrence of ESBLs throughout the world. Indeed, a recent study [25] assessed the fecal carriage of ESBL-producing organisms in 272 inpatients and 162 outpatients in Saudi Arabia. Among the 860 stool samples examined, 151 (17.7%) yielded ESBL-producing organisms (26.1% from inpatients, 15.4% from outpatients, 13.1% from healthy individuals). In Tel-Aviv, Israel [26], among 80 bacteremic Enterobacteriaceae isolated from June to December 2003 at admission to the hospital, 13.7% produced ESBLs. Moreover, 10.8% of 241 patients screened at admission had fecal carriage of ESBL-producing Enterobacteriaceae. In Madrid, Spain [27], the rate of fecal carriage of ESBL-producing isolates in outpatients increased from 0.7% in 1991 to 5.5% in 2003. The situation in France and the United States seems to be less critical so far. Indeed, in a recent French survey, [28] aimed at determining the antibiotic susceptibility patterns of bacterial strains isolated from adults with community-acquired urinary tract infections, only 1.1% of 6,771 isolates were ESBLs producers (56% CTX-M, 68% E. coli). In the United States, Harris et al [29] conducted a prospective study to analyze the risk factors for colonization with ESBL-producing bacteria upon ICU admission. One hundred and seventeen (2.2%) patients were found to be colonized with ESBL–producing Enterobacteriaceae. In Europe, several authors noted a dramatic change in ESBL types over the past 10 years. Indeed, in the mid-1990s CTX-M ESBLs were rarely recorded despite large outbreaks 6 of Salmonella typhimurium harboring CTX-M-4 and CTX-M-5 enzymes in Eastern Europe [30]. At that time, CTX-M ESBLs were predominantly found in South America, the far East and Eastern Europe. Since then, the number of CTX-M type ESBLs has rapidly been expanding in every continent. A recent review provides the epidemiological data of CTX-Mtype -lactamases in Europe [31]. CTX-M 15 is now widespread in Southern and Eastern France [32,33]. Within the CTX-M family, the CTX-M-9 cluster has been shown to be highly represented in Spain. For instance, CTX-M-14 is frequently detected in E. coli isolates recovered from non-hospitalised patients [34]. These enzymes have also been reported in Portugal, France and the UK [34]. Within the CTX-M-1 cluster, CTX-M-1 and CTX-M-32 were originally found to be prevalent in the Mediterranean area. CTX-M-3 has mainly been described in Eastern European countries and CTX-M-15 has risen to prominence all over Europe. The successful dissemination of CTX-M-15 is associated with specific bacterial clones, particulary in the UK. While no isolate with CTX-M enzymes had been detected in the UK before year 2000, a prospective survey undertaken late 2004 and covering 16 laboratories in London and south-east England found that 58% of E. coli and 39.4% K. pneumoniae of 1,127 cephalosporin resistant Enterobacteriaceae produced these ESBLs [35]. Thus, epidemiology of ESBLs and ESBL-producing isolates is changing as a result of unprecedended diffusion of CTX-M genes in E. coli. The majority of these isolates are now recovered from community patients and in non-ICU wards. Rates of isolates harboring CTXM enzymes, among ESBL-producing E.coli and K. pneumoniae, are respectively, 54,8% and 12,3% in Italy, 80% and 50% in Argentina and 89,7% and 58,5% in Taiwan [5] . Risk factors for colonization and infection 7 Before spread of ESBL-producer organisms into the community, numerous studies tried to assess risk factors for colonization and infection with ESBL-producer organisms. Despite conflicting data due to differences in study populations, some general comments can be raised. Patients at high risk for developing colonization or infection with ESBL–producing organisms are often seriously ill, with prolonged hospital stays and in whom invasive medical devices are present for prolonged duration. Duration of hospitalization is one of the risk factors identified [36,37]. Invasive medical devices consist of nasogastric tubes [38], gastrostomy or jejunostomy tubes [38,] and arterial lines. In addition, recent surgery [39], hemodialysis [40], decubitus ulcers [38] and poor nutritional status [41] are listed from some studies. More important, antibiotic use appears as a major risk factor for acquisition of an ESBL-producing organism [42,43]. Various antibiotic classes have been found to be associated with subsequent infections due to ESBL producers. This includes third-generation cephalosporins, quinolones [44], trimethoprim-sulfamethoxazole [38,44,45], aminoglycosides [37,45] and metronidazole [45]. Thus most studies concern patients colonized or infected with ESBLs in hospitals and long-term care facilities ; these factors identified patients with nosocomially-acquired, and/or healthcare-associated ESBL producers. Due to the fact that some studies published after 2000s underline the fact that some patients without any of these factors [46] could be colonized or infected with ESBL-producing organisms, the challenge for the clinician and the infection control practitioner is to identify these patients not only to initiate adequate antibiotic therapy but also to prevent secondary transmission. In one study [47], among 311 non-hospitalized patients (128 with ESBL-positive strains and 183 with ESBL-negative strains) with community-acquired urinary tract infections, several risk factors were found to be associated to the presence of ESBL-positive strains. Previous hospitalization, antibiotic treatment during the past 3 months, age above 60 years, diabetes 8 mellitus, male gender, K. pneumoniae infection, previous use of cephalosporins, quinolones, and penicillins, were significantly associated with isolation of ESBL-positive strains. A case-control study [48], conducted between 2000 and 2004 in an acute care teaching hospital serving a population of 300,000 habitants in Spain, evaluated the risk factors for community-onset urinary tract infections due to ESBL E. coli. The prevalence of the ESBL infections increased from 0.47% in 2000 to 1.7% in 2003, and appeared to be associated only with previous exposure to oral second generation cephalosporins. Recently, Ben Ami et al [26] reported high rates of bacteremia or colonization with ESBL-producing Enterobacteriaceae within the 48 hours following hospital admission. In a case-control study including 72 ESBL-negative isolates and 38 ESBL-positive isolates, two factors were significantly associated with isolation of ESBL-producing isolates: male gender and nursing home residence. In the same study, the authors screened 241 persons at admission and found 10.8% of fecal carriage with ESBL-positive Enterobacteriaceae. Predictors of fecal carriage were: poor functional status, current antibiotic use, chronic renal insufficiency, liver disease, and use of anti-histamine 2 blockers [26]. Rodriguez-Bano et al [49], in a case-control study over a 4-year period in Seville, Spain, found that diabetes mellitus, prior hospital admissions, prior quinolone use, recurrent urinary tract infection and older age were independent risk factors for ESBL-producing E. coli infections in non-hospitalized patients. The same authors [50], in a case-control study in which 43 cases (70% producing CTX-M enzymes) were compared to (i) 86 patients with bacteremia caused by non-ESBLproducing E. coli and (ii) 86 hospitalised patients, identified urinary catheterisation and use of cephalosporins or fluoroquinolones as independent risk-factors for ESBL-producing E. coli in bacteremia. Previous use of oxyimino-beta-lactams (i.e cephalosporins) or fluoroquinolones were independent risk-factors among hospitalized patients. 9 Harris et al [29] conducted a prospective cohort study on patients admitted to either surgical or medical ICU at the University of Maryland Medical Center from September 2001 to June 2005. Multivariate analysis showed that piperacillin-tazobactam administration (OR 2.05), vancomycin treatment (OR 2.11), age > 60 years (OR 1.79), and chronic disease score (OR 1.15) were independently associated with a higher risk of harboring ESBLs. Finally, in a recent study, Lavigne et al [51] identified urinary tract infections or the presence of a urinary catheter in diabetic or renal failure patients as the main risk factors for acquiring CTX-M E. coli isolates. Overall characteristics of infections caused by ESBL-producing isolates in the community onset could be summarized by several risk factors such as, repeated urinary tract infections, previous antibiotic administration including cephalosporins and fluoroquinolones, previous hospitalisation, diabetes mellitus and underlying liver pathology Infection control implications of ESBL producing organisms Until recently, efforts were concentrated to control meticillin-resistant Staphylococcus aureus (MRSA) within the hospital setting. Effective MRSA control has been achieved by implementing stringent infection control policies [52]. Recommendations for controlling spread of MRSA include two key-components: (i) identification of MRSA by clinical and screening cultures and (ii) contact precautions for MRSA-positive patients [53]. However, Gram-negative bacteria differ from Gram-positive species by their ability to share, via genetic transfers, and to accumulate multiple antibiotic resistance mechanisms. In 2004. Thouverez et al [54], concluded that due to the low prevalence of ESBL-producing Enterobacteriaceae carriers on admission (0.45% of 7,777 specimens analyzed), screening cultures was not costeffective for the control of ESBLs and that the use of clinical cultures would be sufficient in non-epidemic situations. Because of the increasing prevalence of ESBL-producers 10 throughout the community, recommendations to prevent future outbreaks need to be reevaluated. For example, should we identify the BLSE carriers. Indeed, these patients may represent a reservoir for subsequent dissemination in medical, surgical wards, and long-term care facilities unless the organism is identified through routine screening at admission and early isolation precautions are taken. One major problem is the fact that only a systematic and repeated screening would be able to detect and follow up colonized patients. In one study [55] conducted in a 825-bed academic medical center in Chicago, from 2000 through 2003, the authors screened 17,872 patients hospitalized in designated high-risk units for the presence in rectal samples of ESBLproducing Enterobacteriaceae. One of the main results was that, among 413 patients colonized with ESBL-producing organisms, only 35 (8.5%) developed a subsequent ESBLbacteremia. In the Harris’s study [29], including patients admitted to either surgical or medical ICU at the University of Maryland Medical Center from September 2001 to June 2005, 25% of carriers with ESBL-producing Enterobacteriaceae had a subsequent ESBLorganism positive culture. What does it mean ? From an infection control practitioner’s point of view, it means that 75% of carriers are clinically silent and may form a reservoir for subsequent dissemination. On the other hand, only 25% of carriers would require a carbapenem treatment in case of subsequent infection. As Enterobacteriaceae are a frequent cause of bacteremia, the spread of ESBLs could result in a significance increase in the use of carbapenems what might in turn contribute to promote the resistance to this important class of antibiotics. There are theoretical arguments for a systematic screening of ESBLs at admission in high risk units (e.g., the high transmissibility of the genes coding for these enzymes). Should we move BLSE-positive patients into single rooms or cohort nursing to reduce the risk of cross 11 infection? National guidelines for preventing the spread of MRSA recommend contact precautions and isolation of infected or colonized patients in a single room or grouping them geographically with designated staff. Regarding ESBL-producing organisms, this attitude warrants to be discussed for many reasons. Firstly, ESBL-producing organisms are mostly found in urinary and fecal samples compared to the cutaneous carriage of MRSA. In this situation, one could expect standard precautions be sufficient to limit the spread of ESBLpositive organisms. Secondly, as far as we know, very few publications have highlighted the spread of CTX-M beta-lactamases into the hospitals [56, 57]. Until now, ESBL-harboring E. coli have not been not associated with large outbreaks. Thirdly, patients’ isolation could lead to adverse events and less documented care [58]. Finally, most of the data used as a rationale for defining prevention strategies were gleaned from K. pneumoniae or Enterobacter sp. outbreaks. It is not sure that these strategies would be useful for controlling ESBLpositive E. coli. In addition, the current surge of isolation of these latter in hospitals (from community patients) makes implementation of strict isolation measures of carriers of ESBLs just impossible. In our opinion, admission from other hospitals or from residential care should generate automatic alerts to detect readmitted patients known for carrying ESBL producers. In acute care hospitals, implementing contact precautions routinely for each patient infected or previously identified as being colonized with ESBL-positive organisms would help to improve care and limit the spread of CTX-M enzymes. However, despite the recent English experience [59] arguing for cohorting, we think that in an endemic setting this attitude could not be justified. 12 Treatment and outcome: Occurrence of ESBLs in community pathogens complicates the empirical choice of antibiotics, notably in the case of urinary tract infections. For example, most international guidelines suggest the use of fluoroquinolones or thrimethoprim-sulfamethoxazole for treatment of cystitis, and third-generation cephalosporins in case of pyelonephritis. ESBLproducing bacteria are not only resistant to third-generation cephalosporins but also crossresistant to most of the antibiotics used in urinary tract infections (e.g., fluoroquinolones, trimethoprim, aminoglycosides). Since ESBLs are able to hydrolyze lactam antibiotics with an oxyimino group (e.g., ceftazidime, ceftriaxone, cefotaxime or aztreonam), rates of clinical failure become high when the MICs of cephalosporins raise (4 or 8 g/ml) [60, 61]. However, combination of cefotaxime and sulbactam remains synergistic [57]. In a randomized trial [62] of cefepime versus imipenem for treatment of nosocomial pneumonia, a positive clinical response (mortality, length of hospital stay ?) in infections with ESBLproducing organisms was seen in 100% patients treated with imipenem but only in 69% patients of the cefepime arm. Oxyiminocephalosporins in combination with clavulanate are active in vitro against most ESBL-producing E. coli and Klebsiella spp isolates at < 1-2 µg/ml but are ineffective against Enterobacter spp, because of ESBL-independent hydrolysis by clavulanate-induced AmpC enzymes. A recent trial from Turkey [63], reported results on 1,196 Gram-negative clinical isolates mostly cultured from blood, urine and respiratory secretions. The resistance rates of E. coli and Klebsiella spp to sulbactam-cefoperazone was determined by the E-test method and found to be 6% and 17.7%, respectively. Cefoperazone in combination with sulbactam was the most active drug against these bacterial species after imipenem. However, the in-vitro efficacies of -lactamase inhibitors are compromised by the emergence of isolates overexpressing class C -lactamases, producing class A penicillinases such as TEM1 and TEM2, or producing low-affinity enzymes such as inhibitor-resistant TEM 13 variants. Clinical experience with the third-generation cephalosporins combined with ßlactamase inhibitors is lacking. Sulbactam-cefoperazone was found to be as successful as imipenem and ceftazidime in a prospective controlled trial for the management of bacteremia due to CTX-M-producing E. coli [64] . On the other hand, despite in vitro bacterial susceptibility to β-lactam/β-lactamase inhibitor combinations, high failure rates in patients infected with ESBL-positive bacteria have been reported [65]. The therapeutic efficacy of these combinations for treating urinary tract infections due to ESBL producers remains to be determined by randomized controlled trials. In vitro, carbapenems and cephamycins exhibit the most consistent activity against ESBLproducing organisms, given their stability to hydrolysis by ESBLs. Based on these studies, cephamycins appear as an attractive therapeutic option. However, published clinical experience with these drugs is almost completely lacking. Some reports describe in vivo selection of porin-deficient mutants during therapy with cephamycins [66-68]. Recently, authors evaluated the in vitro activity of temocillin on ESBL-positive organisms [14,69,70]. This semi-synthetic penicillin derivative of ticarcillin has an excellent activity against wild-type Enterobacteriaceae. A survey conducted in Belgium [14] showed susceptibility rates of 92% among 162 ESBL-producing E. coli isolates. MIC50 and MIC90 values where 8 and 32 µg/ml, respectively. In this study, cross-resistance to ciprofloxacin and co-trimoxazole was as high as 39%. Another study [69] performed on 846 AmpC- and ESBL-producing Enterobacteriaceae from England found susceptibility rates to temocillin of 88% and 99% with breakpoints at 16 µg/ml and 32 µg/ml, respectively. Data on 652 clinical isolates from ICU patients were screened and temocillin was active against more than 90% of the isolates including most AmpC- and ESBL-producing isolates [71]. Pivmecillinam, the pro-drug of mecillinam (amdinocillin), has been widely used as a first-line agent in the treatment of acute lower urinary tract infections, especially in the Nordic 14 countries [72]. In addition to its high intrinsic activity against most Gram-negative enteric bacteria, this oral ß-lactam often appears active in vitro against ESBL producers. However, despite its elevated concentrations in urine [73], the raise of mecillinam MICs at high bacterial inoculums suggests that its use should be restricted to uncomplicated urinary tract infections involving ESBL-positive organisms [74], although successful treatment of one case of pyelonephritis was reported [75] (E. Lindsay Scand. J. Infect. Dis. 2007;39(8):748-9). On the other hand, the lability of the molecule to some OXA-type penicillinases [76] leads for an administration in bacteriologically-documented infections. In vitro and observational studies strongly suggest that carbapenems should be regarded as the drugs of choice for the management of serious infections due to ESBL-positive bacteria. Carbapenems have a time-dependent killing activity and are particularly stable to a wide variety of -lactamases including the ESBLs and AmpC-type enzymes. Imipenem, meropenem and ertapenem are generally considered to be equally active against most Gramnegative and Gram-positive pathogens. However, in 2001, Livermore et al [77] reported differences in activity between ertapenem and imipenem against Klebsiella isolates in relation to lactamase profiles. The MIC50 and the MIC90 of ertapenem for ESBL producers were 0.03 and 0.06 µg/ml, respectively whereas those of imipenem were 0.12 and 0.5 µg/ml. By comparing the pharmacodynamic potencies of imipenem, meropenem and ertapenem, Kiffer et al [78] predicted that ertapenem was slightly less effective than imipenem or meropenem. Colodner et al [79] reported that in vitro imipenem was the most active carbapenem against ESBL-producing isolates. Pharmacokinetic parameters of the three compounds after intravenous infusion indeed show some differences. The urinary excretion rates vary from 38% (ertapenem) to 70% (imipenem and meropenem), whereas the proteinbinding rates are 95% for ertapenem, 13-20% for imipenem and 10% for meropenem. The 15 longer elimination half-life of ertapenem (4 h versus 1 h for imipenem and meropenem) allows its once daily dosing. Other therapeutic choices are limited by the fact that the plasmids harboring ESBL genes also frequently carry resistance determinants to aminoglycosides, trimethroprim-sulfamethoxazole and fluoroquinolones. Fosfomycin is still active against most of common uropathogens. For example, 417 (97.4%) out of 428 ESBL-producing isolates were found to be susceptible to fosfomycin in a recent study in Spain [80]. The resistance rates of E. coli and K. pneumoniae to fosfomycin were 0.3% and 7.2%, respectively. Tigecycline circumvents efflux and ribosomal protection, the two most frequent mechanisms of tetracycline resistance and has MICs < 2µg/ml for Enterobacteriaceae except Proteacea. In a recent report from Madrid, Spain, susceptibility rates of 285 ESBL-producer isolates to tigecycline were 97.5% [81]. There is no evidence, despite in vitro synergy, that combination therapy with a carbapenem and antibiotics of other classes is superior to the use of carbapenem alone [64,66]. Conclusions: The rapid emergence of CTX-M-producing organisms, especially E. coli, is becoming a major public health problem worldwide, as its impairs the management of nosocomial and community-acquired infections. The challenge is now to identify the potential reservoirs of these multidrug-resistant organisms in order to limit their spread into the hospitals and to target infected patients who need adapted antibiotic therapy. A urinary tract infection and a recent antibiotic therapy are two major risk factors for acquisition of ESBL-producing bacteria. Carbapenems have now been advocated as first line therapy for sever urosepsis occurring in patients coming from ESBL-endemic areas. 16 Références BLSEMSD4 : 1-National Nosocomial Infections Surveillance System. National Nosocomial Infections Surveillance (NNIS) System Report, data summary from January 1992 through June 2004, issued October 2004. Am J Infect Control. 2004;32(8):470-85. 2-DiPersio JR, Deshpande LM, Biedenbach DJ, Toleman MA, Walsh TR, Jones RN. 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Antimicrob Agents Chemother. 2006 Aug;50(8):2695-9. 23 24 Table 1: Controlling spread of Enterobacteriaceae-producing BLSEs into the hospital 1-Screen patients admitted from other ward (ICU, surgery), hospitals, long term facilities 2-Screen patients previously identified as being colonized with ESBL producer organisms within one year after discharge 3-Take standard precautions when ESBL-positive E. coli and K. pneumoniae are detected (?) 4-In case of epidemic situation think about cohorting Table 2: Proposal for treatment of urinary tract infections in the era of ESBL-producing Enterobacteriaceae (ESBLE) Cystitis First episodes, no history of antibiotic therapy: trimethoprim-sulfamethoxazole or fluoroquinolones History of antibiotic therapy or multiples episodes: fosfomycin trometanol Pyelonephritis or prostatitis A-Patient living in Europe with no risk factors for ESBLE, no history of antibiotic therapy, no sepsis or septic shock: Third-generation cephalosporin B-Patient living in Europe with no risk factors for ESBLE, no history of antibiotic therapy, with severe sepsis or septic shock: Third-generation cephalosporin plus aminoglycoside C- Patient coming from a country with high prevalence of ESBLE: C1-without risk factors for ESBLE and no sepsis or septic shock: Third-generation cephalosporin plus aminoglycoside C2-sepsis or septic schock or risk factors for ESBLE Carbapenem plus aminoglycoside Table 3 : risk factors for ESBLE carriers in the community Repeat UTIs Previous antibiotic therapy including fluoroquinolones and cephalosporins (oral or IV) Previous hospitalisation, living in nursing home or long term facilities Coming from countries with high prevalence of ESBLE 25