Download Emerging of Extended-Spectrum β

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.
Evolution and dissemination of extended-spectrum beta-lactamase-producing Klebsiella
pneumoniae: epidemiology and molecular report from the SENTRY Antimicrobial
Surveillance Program (1997-2003). Diagn Microbiol Infect Dis. 2005;51(1):1-7.
3-Paterson DL. Resistance in gram-negative bacteria: enterobacteriaceae. Am J Med. 2006
;119(6 Suppl 1):S20-8; discussion S62-70
4-Cantón R, Coque TM. The CTX-M beta-lactamase pandemic. Curr Opin Microbiol. 2006
;9(5):466-75.
5-Rossolini GM, D'Andrea MM, Mugnaioli C. The spread of CTX-M-type extendedspectrum beta-lactamases. Clin Microbiol Infect. 2008 Jan;14 Suppl 1:33-41.
6-Knothe H, Shah P, Krcmery V, Antal M, Mitsuhashi S. Transferable resistance to
cefotaxime, cefoxitin, cefamandole and cefuroxime in clinical isolates of Klebsiella
pneumoniae and Serratia marcescens. Infection. 1983;11(6):315-7.
7-Sirot D, Sirot J, Labia R, Morand A, Courvalin P, Darfeuille-Michaud A, Perroux R, Cluzel
R. Transferable resistance to third-generation cephalosporins in clinical isolates of Klebsiella
pneumoniae: identification of CTX-1, a novel beta-lactamase. J Antimicrob Chemother.
1987;20(3):323-34.
8-Yuan M, Aucken H, Hall LM, Pitt TL, Livermore DM. Epidemiological typing of
klebsiellae with extended-spectrum beta-lactamases from European intensive care units. J
Antimicrob Chemother. 1998 ;41(5):527-39
9-Lucet JC, Decré D, Fichelle A, Joly-Guillou ML, Pernet M, Deblangy C, Kosmann MJ,
Régnier B. Control of a prolonged outbreak of extended-spectrum beta-lactamase-producing
enterobacteriaceae in a university hospital. Clin Infect Dis. 1999 ;29(6):1411-8
10-Babini GS, Livermore DM. Antimicrobial resistance amongst Klebsiella spp. collected
from intensive care units in Southern and Western Europe in 1997-1998. J Antimicrob
Chemother. 2000 ;45(2):183-9
11-Tzouvelekis LS, Tzelepi E, Tassios PT, Legakis NJ. CTX-M-type beta-lactamases: an
emerging group of extended-spectrum enzymes. Int J Antimicrob Agents. 2000 ;14(2):137-42
12-Baraniak A, Fiett J, Hryniewicz W, Nordmann P, Gniadkowski M. Ceftazidimehydrolysing CTX-M-15 extended-spectrum beta-lactamase (ESBL) in Poland. J Antimicrob
Chemother. 2002;50(3):393-6.
17
13- Stürenburg E, Kühn A, Mack D, Laufs R. A novel extended-spectrum beta-lactamase
CTX-M-23 with a P167T substitution in the active-site omega loop associated with
ceftazidime resistance. J Antimicrob Chemother. 2004;54(2):406-9.
14-Glupczynski Y, Huang TD, Berhin C, Claeys G, Delmée M, Ide L, Ieven G, Pierard D,
Rodriguez-Villalobos H, Struelens M, Vaneldere J. In vitro activity of temocillin against
prevalent extended-spectrum beta-lactamases producing Enterobacteriaceae from Belgian
intensive care units. Eur J Clin Microbiol Infect Dis. 2007;26(11):777-83.
15-Bush K, Macalintal C, Rasmussen BA, Lee VJ, Yang Y. Kinetic interactions of
tazobactam with beta-lactamases from all major structural classes. Antimicrob Agents
Chemother. 1993;37(4):851-8.
16-Mendonça N, Louro D, Castro AP, Diogo J, Caniça M. CTX-M-15, OXA-30 and TEM-1producing Escherichia coli in two Portuguese regions. J Antimicrob Chemother. 2006
;57(5):1014-6.
17-Morosini MI, García-Castillo M, Coque TM, Valverde A, Novais A, Loza E, Baquero F,
Cantón R. Antibiotic coresistance in extended-spectrum-beta-lactamase-producing
Enterobacteriaceae and in vitro activity of tigecycline. Antimicrob Agents Chemother. 2006
;50(8):2695-9.
18- Nicolas-Chanoine MH, Jarlier V; 'La Collégialé de Bactériologie-Virologie-Hygiène
Hospitalière de l'Assistance Publique, Hôpitaux de Paris, France. Extended-spectrum betalactamases in long-term-care facilities. Clin Microbiol Infect. 2008;14 Suppl 1:111-6.
19-Nordmann P, Poirel L. Emergence of plasmid-mediated resistance to quinolones in
Enterobacteriaceae. J Antimicrob Chemother. 2005;56(3):463-9.
20-Fihman V, Lartigue MF, Jacquier H, Meunier F, Schnepf N, Raskine L, Riahi J, Sanson-le
Pors MJ, Berçot B. Appearance of aac(6')-Ib-cr gene among extended-spectrum betalactamase-producing Enterobacteriaceae in a French hospital. J Infect. 2008 Apr 25.
21-Lavilla S, González-López JJ, Sabaté M, García-Fernández A, Larrosa MN, Bartolomé
RM, Carattoli A, Prats G. Prevalence of qnr genes among extended-spectrum{beta}lactamase-producing enterobacterial isolatesin Barcelona, Spain. J Antimicrob Chemother.
2007
22- Klugman KP, Levin BR. One enzyme inactivates two antibiotics. Nat Med. 2006
Jan;12(1):19-20.
23-Paterson DL, Bonomo RA. Extended-spectrum beta-lactamases: a clinical update. Clin
Microbiol Rev. 2005;18(4):657-86.
24- Karim A, Poirel L, Nagarajan S, Nordmann P. Plasmid-mediated extended-spectrum βlactamase (CTX-M-3) from India and gene association with insertion sequence ISEcp1.
FEMS Microbiol Lett; 2001; 201: 237-241
18
25-Kader AA, Kumar A, Kamath KA. Fecal carriage of extended-spectrum beta-lactamaseproducing Escherichia coli and Klebsiella pneumoniae in patients and asymptomatic healthy
individuals. Infect Control Hosp Epidemiol. 2007 ;28(9):1114-6.
26-Ben-Ami R, Schwaber MJ, Navon-Venezia S, Schwartz D, Giladi M, Chmelnitsky I,
Leavitt A, Carmeli Y. Influx of extended-spectrum beta-lactamase-producing
enterobacteriaceae into the hospital. Clin Infect Dis. 2006;42(7):925-34.
27-Valverde A, Coque TM, Sánchez-Moreno MP, Rollán A, Baquero F, Cantón R. Dramatic
increase in prevalence of fecal carriage of extended-spectrum beta-lactamase-producing
Enterobacteriaceae during nonoutbreak situations in Spain. J Clin Microbiol. 2004
;42(10):4769-75.
28-onerba
29-Harris AD, McGregor JC, Johnson JA, Strauss SM, Moore AC, Standiford HC, Hebden
JN, Morris JG Jr. Risk factors for colonization with extended-spectrum beta-lactamaseproducing bacteria and intensive care unit admission. Emerg Infect Dis. 2007 ;13(8):1144-9.
30-Bradford PA, Yang Y, Sahm D, Grope I, Gardovska D, Storch G. CTX-M-5, a novel
cefotaxime-hydrolyzing beta-lactamase from an outbreak of Salmonella typhimurium in
Latvia. Antimicrob Agents Chemother. 1998 ;42(8):1980-4.
31-Livermore DM, Canton R, Gniadkowski M, Nordmann P, Rossolini GM, Arlet G, Ayala J,
Coque TM, Kern-Zdanowicz I, Luzzaro F, Poirel L, Woodford N. CTX-M: changing the face
of ESBLs in Europe. J Antimicrob Chemother. 2007 ;59(2):165-74.
32-Bernard H, Tancrede C, Livrelli V, Morand A, Barthelemy M, Labia R. A novel plasmidmediated extended-spectrum beta-lactamase not derived from TEM- or SHV-type enzymes. J
Antimicrob Chemother. 1992 ;29(5):590-2.
33-Brasme L, Nordmann P, Fidel F, Lartigue MF, Bajolet O, Poirel L, Forte D, VernetGarnier V, Madoux J, Reveil JC, Alba-Sauviat C, Baudinat I, Bineau P, Bouquigny-Saison C,
Eloy C, Lafaurie C, Siméon D, Verquin JP, Noël F, Strady C, De Champs C. Incidence of
class A extended-spectrum beta-lactamases in Champagne-Ardenne (France): a 1 year
prospective study. J Antimicrob Chemother. 2007 ;60(5):956-64.
34- Cantón R, Novais A, Valverde A, Machado E, Peixe L, Baquero F, Coque TM.
Prevalence and spread of extended-spectrum beta-lactamase-producing Enterobacteriaceae in
Europe. Clin Microbiol Infect. 2008 Jan;14 Suppl 1:144-53
35-Potz NA, Hope R, Warner M, Johnson AP, Livermore DM; London & South East ESBL
Project Group. Prevalence and mechanisms of cephalosporin resistance in Enterobacteriaceae
in London and South-East England. J Antimicrob Chemother. 2006;58(2):320-6
36- Bisson G, Fishman NO, Patel JB, Edelstein PH, Lautenbach E. Extended-spectrum betalactamase-producing Escherichia coli and Klebsiella species: risk factors for colonization and
19
impact of antimicrobial formulary interventions on colonization prevalence. Infect Control
Hosp Epidemiol. 2002 ;23(5):254-60.
37- Asensio A, Oliver A, González-Diego P, Baquero F, Pérez-Díaz JC, Ros P, Cobo J,
Palacios M, Lasheras D, Cantón R. Outbreak of a multiresistant Klebsiella pneumoniae strain
in an intensive care unit: antibiotic use as risk factor for colonization and infection. Clin Infect
Dis. 2000 ;30(1):55-60.
38-Wiener J, Quinn JP, Bradford PA, Goering RV, Nathan C, Bush K, Weinstein RA.
Multiple antibiotic-resistant Klebsiella and Escherichia coli in nursing homes. JAMA. 1999
10;281(6):517-23.
39-de Champs C, Sirot D, Chanal C, Poupart MC, Dumas MP, Sirot J. Concomitant
dissemination
of
three
extended-spectrum
beta-lactamases
among
different
Enterobacteriaceae isolated in a French hospital. J Antimicrob Chemother. 1991;27(4):44157.
40- D'Agata E, Venkataraman L, DeGirolami P, Weigel L, Samore M, Tenover F. The
molecular and clinical epidemiology of enterobacteriaceae-producing extended-spectrum
beta-lactamase in a tertiary care hospital. J Infect. 1998;36(3):279-85.
41-Mangeney N, Niel P, Paul G, Faubert E, Hue S, Dupeyron C, Louarn F, Leluan G. A 5year epidemiological study of extended-spectrum beta-lactamase-producing Klebsiella
pneumoniae isolates in a medium- and long-stay neurological unit. J Appl Microbiol. 2000
;88(3):504-11.
42-Peña C, Gudiol C, Tubau F, Saballs M, Pujol M, Dominguez MA, Calatayud L, Ariza J,
Gudiol F. Risk-factors for acquisition of extended-spectrum beta-lactamase-producing
Escherichia coli among hospitalised patients. Clin Microbiol Infect. 2006 ;12(3):279-84.
43-Ariffin H, Navaratnam P, Mohamed M, Arasu A, Abdullah WA, Lee CL, Peng LH.
Ceftazidime-resistant Klebsiella pneumoniae bloodstream infection in children with febrile
neutropenia. Int J Infect Dis. 2000;4(1):21-5.
44-Lautenbach E, Patel JB, Bilker WB, Edelstein PH, Fishman NO. Extended-spectrum betalactamase-producing Escherichia coli and Klebsiella pneumoniae: risk factors for infection
and impact of resistance on outcomes. Clin Infect Dis. 2001;32(8):1162-71
45-De Champs C, Rouby D, Guelon D, Sirot J, Sirot D, Beytout D, Gourgand JM. A casecontrol study of an outbreak of infections caused by Klebsiella pneumoniae strains producing
CTX-1 (TEM-3) beta-lactamase. J Hosp Infect. 1991;18(1):5-13.
46-Zahar JR, Lecuit M, Carbonnelle E, Ribadeau-Dumas F, Nassif X, Lortholary O. Is it time
to reconsider initial antibiotic treatment strategies for severe urinary tract infections in
Europe? Clin Microbiol Infect. 2007 ;13(3):219-21.
47-Colodner R, Rock W, Chazan B, Keller N, Guy N, Sakran W, Raz R. Risk factors for the
development of extended-spectrum beta-lactamase-producing bacteria in nonhospitalized
patients. Eur J Clin Microbiol Infect Dis. 2004 ;23(3):163-7.
20
48-Calbo E, Romaní V, Xercavins M, Gómez L, Vidal CG, Quintana S, Vila J, Garau J. Risk
factors for community-onset urinary tract infections due to Escherichia coli harbouring
extended-spectrum beta-lactamases. J Antimicrob Chemother. 2006;57(4):780-3.
49-Rodríguez-Baño J, Navarro MD, Romero L, Muniain MA, Perea EJ, Pérez-Cano R,
Hernández JR, Pascual A. Clinical and molecular epidemiology of extended-spectrum betalactamase-producing Escherichia coli as a cause of nosocomial infection or colonization:
implications for control. Clin Infect Dis. 2006 ;42(1):37-45.
50- Rodríguez-Baño J, Navarro MD, Romero L, Muniain MA, de Cueto M, Gálvez J, Perea
EJ, Pascual A. Risk-factors for emerging bloodstream infections caused by extendedspectrum beta-lactamase-producing Escherichia coli. Clin Microbiol Infect. 2007;
51-Lavigne JP, Marchandin H, Delmas J, Moreau J, Bouziges N, Lecaillon E, Cavalie L,
Jean-Pierre H, Bonnet R, Sotto A. CTX-M beta-lactamase-producing Escherichia coli in
French hospitals: prevalence, molecular epidemiology, and risk factors. J Clin Microbiol.
2007 ;45(2):620-6.
52-Lucet JC, Paoletti X, Lolom I, Paugam-Burtz C, Trouillet JL, Timsit JF, Deblangy C,
Andremont A, Regnier B. Successful long-term program for controlling methicillin-resistant
Staphylococcus aureus in intensive care units. Intensive Care Med. 2005;31(8):1051-7.
53-Muto CA, Jernigan JA, Ostrowsky BE, Richet HM, Jarvis WR, Boyce JM, Farr BM;
SHEA. SHEA guideline for preventing nosocomial transmission of multidrug-resistant strains
of Staphylococcus aureus and enterococcus. Infect Control Hosp Epidemiol. 2003;24(5):36286
54-Thouverez M, Talon D, Bertrand X. Control of Enterobacteriaceae producing extendedspectrum beta-lactamase in intensive care units: rectal screening may not be needed in nonepidemic situations. Infect Control Hosp Epidemiol. 2004;25(10):838-41.
55-Reddy P, Malczynski M, Obias A, Reiner S, Jin N, Huang J, Noskin GA, Zembower T.
Screening for extended-spectrum beta-lactamase-producing Enterobacteriaceae among highrisk patients and rates of subsequent bacteremia. Clin Infect Dis. 2007;45(7):846-52.
56-Kassis-Chikhani N, Vimont S, Asselat K, Trivalle C, Minassian B, Sengelin C, Gautier V,
Mathieu D, Dussaix E, Arlet G. CTX-M beta-lactamase-producing Escherichia coli in longterm care facilities, France. Emerg Infect Dis. 2004 Sep;10(9):1697-8.
57-Kiratisin P, Apisarnthanarak A, Saifon P, Laesripa C, Kitphati R, Mundy LM. The
emergence of a novel ceftazidime-resistant CTX-M extended-spectrum
beta-lactamase, CTX-M-55, in both community-onset and hospital-acquired
infections in Thailand. Diagn Microbiol Infect Dis. 2007 Jul;58(3):349-55. Epub 2007 Apr
20.
58-Stelfox HT, Bates DW, Redelmeier DA. Safety of patients isolated for infection control.
JAMA. 2003 Oct 8;290(14):1899-905.
21
59-Warren RE, Harvey G, Carr R, Ward D, Doroshenko A. Control of infections due to
extended-spectrum beta-lactamase-producing organisms in hospitals and the community. Clin
Microbiol Infect. 2008 Jan;14 Suppl 1:124-33.
60-Kim YK, Pai H, Lee HJ, Park SE, Choi EH, Kim J, Kim JH, Kim EC. Bloodstream
infections by extended-spectrum beta-lactamase-producing Escherichia coli and Klebsiella
pneumoniae in children: epidemiology and clinical outcome. Antimicrob Agents Chemother.
2002 ;46(5):1481-91.
61-Paterson DL, Ko WC, Von Gottberg A, Casellas JM, Mulazimoglu L, Klugman KP,
Bonomo RA, Rice LB, McCormack JG, Yu VL. Outcome of cephalosporin treatment for
serious infections due to apparently susceptible organisms producing extended-spectrum betalactamases: implications for the clinical microbiology laboratory. J Clin Microbiol. 2001
;39(6):2206-12.
62-Zanetti G, Bally F, Greub G, Garbino J, Kinge T, Lew D, Romand JA, Bille J, Aymon D,
Stratchounski L, Krawczyk L, Rubinstein E, Schaller MD, Chiolero R, Glauser MP, Cometta
A; Cefepime Study Group,. Cefepime versus imipenem-cilastatin for treatment of nosocomial
pneumonia in intensive care unit patients: a multicenter, evaluator-blind, prospective,
randomized study. Antimicrob Agents Chemother. 2003 Nov;47(11):3442-7.
63-Akova M. Sulbactam-containing beta-lactamase inhibitor combinations. Clin Microbiol
Infect. 2008 Jan;14 Suppl 1:185-8.
64- Bin C, Hui W, Renyuan Z, Yongzhong N, Xiuli X, Yingchun X, Yuanjue Z, Minjun C.
Outcome of cephalosporin treatment of bacteremia due to CTX-M-type extended-spectrum
beta-lactamase-producing Escherichia coli. Diagn Microbiol Infect Dis. 2006 Dec;56(4):3517. Epub 2006 Aug 23
65-Karadenizli A, Mutlu B, Okay E, Kolayli F, Vahaboglu H. Piperacillin with and without
tazobactam against extended-spectrum beta-lactamase-producing Pseudomonas aeruginosa in
a rat thigh abscess model. Chemotherapy. 2001 Jul-Aug;47(4):292-6.
66-Pangon B, Bizzet C, Bure A et al. In vivo selection of a cephamycin resistant, porin
deficient mutant of Klebsiella pneumoniae producing a TEM-3 beta-lactamase . J Infect Dis
1989; 159: 1005 6.
67-Martinez-MartinezL, Hernandez-AllesS, AlbertiS et al. In vivo selection of porin-deficient
mutants of Klebsiella pneumoniae with increased resistance to cefoxitin and expandedspectrum cephalosporins . Antimicrob Agents Chemother 1996; 40: 342 8.
68-Gazouli M, KaufmannME, TzelepiE et al. Study of an outbreak of cefoxitin-resistant
Klebsiella pneumoniae in a general hospital . J Clin Microbiol 1997; 35: 508 10.
69-Livermore DM, Hope R, Fagan EJ, Warner M, Woodford N, Potz N. Activity of
temocillin against prevalent ESBL- and AmpC-producing Enterobacteriaceae from south-east
England. J Antimicrob Chemother. 2006 ;57(5):1012-4.
22
70-Rodriguez-Villalobos H, Malaviolle V, Frankard J, de Mendonça R, Nonhoff C, Struelens
MJ. In vitro activity of temocillin against extended spectrum beta-lactamase-producing
Escherichia coli. J Antimicrob Chemother. 2006 ;57(4):771-4.
71-Du B, Long Y, Liu H, Chen D, Liu D, Xu Y, Xie X. Extended-spectrum beta-lactamaseproducing Escherichia coli and Klebsiella pneumoniae bloodstream infection: risk factors and
clinical outcome. Intensive Care Med. 2002 ;28(12):1718-23.
72-Graninger W. Pivmecillinam--therapy of choice for lower urinary tract infection. Int J
Antimicrob Agents. 2003 Oct;22 Suppl 2:73-8. Review.
73-Kerrn MB, Frimodt-Møller N, Espersen F. Urinary concentrations and urine ex-vivo effect
of mecillinam and sulphamethizole. Clin Microbiol Infect. 2004 Jan;10(1):54-61.
74-Thomas K, Weinbren MJ, Warner M, Woodford N, Livermore D. Activity of mecillinam
against ESBL producers in vitro. J Antimicrob Chemother. 2006 Feb;57(2):367-8.
7576-Sougakoff W, Jarlier V. Comparative potency of mecillinam and other beta-lactam
antibiotics against Escherichia coli strains producing different beta-lactamases. J Antimicrob
Chemother. 2000 Sep;46 Suppl 1:9-14; discussion 63-5.
77-Livermore DM, Oakton KJ, Carter MW, Warner M. Activity of ertapenem (MK-0826)
versus Enterobacteriaceae with potent beta-lactamases. Antimicrob Agents Chemother. 2001
Oct;45(10):2831-7.
78-Kiffer CR, Kuti JL, Eagye KJ, Mendes C, Nicolau DP. Pharmacodynamic profiling of
imipenem, meropenem and ertapenem against clinical isolates of extended-spectrum betalactamase-producing Escherichia coli and Klebsiella spp. from Brazil. Int J Antimicrob
Agents. 2006 Oct;28(4):340-4. Epub 2006 Aug 22
79-Colodner R, Samra Z, Keller N, Sprecher H, Block C, Peled N, Lazarovitch T,
Bardenstein R, Schwartz-Harari O, Carmeli Y; Israel ESBL Group. First national surveillance
of susceptibility of extended-spectrum beta-lactamase-producing Escherichia coli and
Klebsiella spp. to antimicrobials in Israel. Diagn Microbiol Infect Dis. 2007 Feb;57(2):201-5.
80-de Cueto M, López L, Hernández JR, Morillo C, Pascual A. In vitro activity of fosfomycin
against extended-spectrum-beta-lactamase-producing Escherichia coli and Klebsiella
pneumoniae: comparison of susceptibility testing procedures. Antimicrob Agents Chemother.
2006 Jan;50(1):368-70.
81-Morosini MI, García-Castillo M, Coque TM, Valverde A, Novais A, Loza E, Baquero F,
Cantón R. Antibiotic coresistance in extended-spectrum-beta-lactamase-producing
Enterobacteriaceae and in vitro activity of tigecycline. 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