ESBL- and carbapenemase-producing microorganisms; state of the art Laurent POIREL Medical and Molecular Microbiology Unit Dept of Medicine University of Fribourg Switzerland INSERM U914 «Emerging Resistance to Antibiotics» Associate National Reference Center on Antibiotic Resistance South-Paris Medical School Hospital Bicêtre France
Broad-spectrum ß-lactams
Escherichia coli: wild-type susceptibility profile AMX : amoxicillin CAZ : ceftazidime AMC : amoxicilline + clav FEP : cefepime TCC : ticarcillie + clav TZP : piperacillin + tazobactam CTX : cefotaxime CS : colistine CF : cefalotine TIC : ticarcillin TM : tobramycin AN : amikacine GM : gentamicin OFX : ofloxacin CIP : ciprofloxacin IPM : imipenem
Resistance to ß-lactams in Gram negatives Modification of penicillin-binding proteins Decrease of permeability Overexpression of efflux ß-lactam Pump ß-lactam β-lactamases
Hydrolysis activity of broad-spectrum ß-lactamases Enzyme Ambler class Penicillins Cephalosporins 1st et 2 nd generation * Cephalosporins 3 rd generation cefepime**, cefpirome** ß-lactams/ Inhibitors of ß-lactamases Carbapenems A ESBLs B C D Metallo-enzymes) Cephalosporinases Overexpressed cephalosporinases/plasmid-mediated Oxacillinases * Cephamycins excluded for ESBLs ** Cefepime, cefpirome excluded for overexpressed cephalosporinase
EXTENDED-SPECTRUM ß-LACTAMASES What was the emergence scenario in the 80 s? First description in Germany, 1983 Second description in France, 1984 Recognized in the USA in 1987 3 rd generation cephalosporin use Aminoglycoside use in hospitals Difficulties in recognition of ESBL producing isolates - Lack of adequate breakpoints - No accurate phenotypic methods for detection Numerous nosocomial outbreaks
EXTENDED-SPECTRUM ß-LACTAMASES New epidemiological scenario Increased prevalence of ESBL-producing isolates Increased isolates from the community, mainly E. coli Higher prevalence in E. coli than in K. pneumoniae Increased prevalence in other Enterobacteriaceae Accelerated evolution of ESBL in single institutions Complex population structure - High clonal variability but coexisting with clonal spread - Spread of gene capture units (plasmids, In,Tn)
Inferring ESBLs; synergy with clav is diagnostic General rule (there are exceptions) -CAZ > CTX = «classic» ESBL - CTX > CAZ = CTX-M type -Be wary of - hyper-k1 in K. oxytoca -AmpC in Serratia
E. coli isolate producing CTX-M-1
ESBL Detection on a disc diffusion antibiogram
Clavulanic-acid inhibited ESBLs are rising.
Clavulanic-acid inhibited ESBL producers are different 6 5 4 %ESBL 3 Escherichia coli Klebsiella spp 2 1 0 1997 1998 1999 2000 2001 2002 2003 2004 2005 Ann 仔 s Hospital Bicetre
Clavulanic-acid inhibited ESBL producers are different 6 5 4 %ESBL 3 Escherichia coli Klebsiella spp 2 1 0 1997 1998 1999 2000 2001 2002 2003 2004 2005 Ann 仔 s Hospital Bicetre
Resistance trends for resistance to 3GC in Europe E. coli K. pneumoniae 2002 I: 1.12 % R: 0.76 % Explanation: ESBLs! 2005 I: 0.97 % R: 4.13 % 2010 I: 1.53 % R: 7.25 % 2010 I: 1.43 % R: 17.83%
Geographical dissemination of bla CTX-M genes TOHO-like CTX-M-1, 3, 15 CTX-M-2, -5 CTX-M-9, -14, 18, 19, 20, 21 CTX-M-9, -13, -14 CTX-M-, 3, 15 CTX-M-2, -5 CTX-M-4, -6 CTX-M-3, 15 CTX-M-16, -17 CTX-M-9, (-14) CTX-M-10 CTX-M-9, -16 CTX-M-8 CTX-M-2 CTX-M-1 CTX-M-2 CTX-M-8 CTX-M-9 Endemicity Sporadic reports prepared by Teresa Coque, 2001-02
Geographical dissemination of bla CTX-M genes TOHO-like CTX-M-2 CTX-M-3, 15 CTX-M-14 CTX-M-1, 3, 15 CTX-M-2, -5 CTX-M-9, -14, 18, 19, 20, 21 CTX-M-, 3, 15 CTX-M-2, -5 CTX-M-9, -13, -14 CTX-M-3 CTX-M-9,-14 CTX-M-1,10,15 CTX-M-15 CTX-M-4, -6 CTX-M-3, 15 CTX-M-16, -17 CTX-M-9,-14 CTX-M-3 CTX-M-1,10,15,32 CTX-M-3 CTX-M-9, -16 CTX-M-8 CTX-M-2 CTX-M-1 CTX-M-2 CTX-M-8 CTX-M-9 Endemicity Sporadic reports
Worldwide prevalence of ESBL producers K. pneumoniae E. coli USA 5.3% 2.8% Latin America 27.6% 12.0% Northern Europe 5.2% 1.4% Southern/East. Europe 25.7% 6.6% China 37.3% 31.3% Australasia 4.6% 1.6%
ESBL-producing Enterobacteriaceae Prevalence of ESBL-producing isolates among 18,845 E. coli, K. pneumoniae and K. oxytoca isolates (SMART study, 2003-2007) Prevalence, % 0 45 40 35 30 25 20 15 10 5 Asia/Pacific Latin America Middle East/Africa Europe North America 2003 2004 2005 2006 2007 Adapted from Badal R et al. Poster presented at 48th Annual ICAAC; Oct 2008
ESBL evolution; from TEM/SHV penicillinases
TEM/SHV The novel ESBLs
CTX-Ms: cefotaxime and ceftazidime hydrolysis CTX-M-3 E. coli CTX-M-15
Where are those CTX-M producers? Community-aquired infections Urinary tract infections E. coli (+ + + ), K. pneumoniae, Salmonella sp Shigella sp, Citrobacter sp, Enterobacter sp, Serratia sp.. Consequences for hospitals; ESBL producers now in the emergency unit, maternity, urology nephrology, gastro-enterology, internal medicine, pediatrics.
Where do they originate from?