Extended spectrum beta-lactamases

Dr Lee Tau HongConsultantDepartment of Infectious DiseasesNational Centre for Infectious Diseases

Beta-lactam antibiotics

• Large class of antibiotics• Betalactam ring structure

àPenicillins : amoxicillin, cloxacillin, ampicillinàCephalosporins: cefazolin, cephalexin, cefoxitin, cefuroxime,

cefexime, ceftriaxone, ceftazidime, cefotaxime, cefepime, ceftaroline, cefiderocol

àCarbapenems: ertapenem, imipenem, meropenem, doripenem

àBL-betalactamase inhibitors (BLBLI): amoxicillin-clavulanate, ampicillin-sulbactam, piperacillin-tazobactam, ceftalozone-tazobactam, ceftazidime-avibactam, imipenem-relebactam, meropenem-vaborbactam

Beta-lactamases

• Enzymes that open up the beta-lactam ring, therby inactivating the antibiotic

• Extended spectrum beta-lactamases (ESBL) inactivate expended spectrum cephalosporins with oxyimino side chain (ceftriaxone, ceftazidime, cefotaxime) and aztreonam

• Many types of ESBLs, not all are equal: TEM, SHV, CTX-M, OXA, others

• Typically inhibit penicillins, 1-3rd

generation cephalosporin (but not cephamycin such as cefoxitin/ cefotetan) and are susceptible to BLBLI

NEJM 2005

Agents to treat infections caused by organismswith ESBL+/ 3rd generation cephosporin resistance

What NOT to use

• Not cephalosporins (including cephamycins such as cefoxitin or cefotetan) even if tested susceptible (?Loss of porin channels)

• Not aztreonam

• Not amoxicillin-clavulanate or ampicillin-sulbactam or piperacillin-tazobactam (?inoculum effect, ?other reasons)

• Multi-centre RCT in 9 countries• E coli or K. pneumoniae bacteraemia• Resistant to 3rd GC but susceptible to pip/tazo and mero• Randomised 1: 1 (N= 391) to either agents for 4 days• Trial terminated early• 23 of 187 patients (12.3%) randomized to pip/tazo met the primary

outcome of mortality at 30 days compared with 7 of 191 (3.7%) randomized to meropenem (P = .90 for noninferiority)

• No difference in clinical/microbiological success at day 4

JAMA. 2018 Sep 11;320(10):984-994

What you may use

• Carbapenems (first choice esp in severe infections/ ill patients)

• Fluoroquinolones

• Aminoglycosides

• Fosfomycin/ nitrofurantoin (cystitis only)

• Specific indications, less well studied: Tigecycline (only if alternatives not suitable) , eravacycline, plazomycin, ceftolozane-tazobactam, ceftazidime-avibactam, cefiderocol

AmpC beta-lactamase

• Genes found on chromosome in ESCAPPM* bacteria

àInducible to different extend esp after antibiotic exposure

àAvoid 3rd GC and BLBLI esp in severe infections

• Some found on plasmids (e.g. E coli)

*Enterobacter spp, Serratia spp, Citrobacter fruendii, Aeromonas, Proteus vulgaris, Providencia spp, Morganella morganii

Thank you

tau_hong_lee@ncid.sg