Episode #28 – AMR: Anniversary, Match, Resistance!

As many of you might already know, there was new IDSA guidance released at the end of Nov 2021 on the treatment of antimicrobial-resistant infections released – version 2.0

• Version 2 focused on ampC b-lactamase producing Enterobacterales, carbapenem resistant Acinetobacter baumannii (CRAB), and Stenotrophomonas maltophilia infections
• Previous Version 1 from 2020 focused on extended spectrum b-lactamase-producing Enterobacterales (ESBL), carbapenem-R Enterobacterales (CRE), and Pseudomonas aeruginosa 

Then the European Society of Clinical Microbiology and Infectious Diseases (ESCMID) released their guidelines for multidrug resistant gram negative bacilli Dec 2021 as well.  I decided to try to combine these and pull out some compare/contrast notes you can listen to. 

We started with a brief reminder/summary of AmpC  β-lactamases, ESBLs, and carbapenemases:

• AmpC β-lactamases: 
  • • Class C serine β-lactamase enzymes that can be produced by Enterobacterales and glucose non-fermenting GN organisms
    • We are mostly focused on those organisms that have inducible chromosomal resistance – 
      • • Inducible ampC expression leads to increased ampC enzyme production which increases MICs and results in ceftriaxone and ceftazidime resistance
        • Resistance to penicillins (except piperacillin), amp-sulbactam, amoxicillin/clavulanate, first and 2nd gen cephalosporins and cephamycins
    • But there are other mechanisms including plasmid-mediated ampC genes.  The other types are often constitutive rather than induced (so they likely already test non-susceptible to ceftriaxone and ceftazidime)
    • In IDSA guidance version 2, there is a question (Question 2) that outlines how beta lactams fall in spectrum for potential to induce ampC:
      • • Aminopenicillins (amoxicillin, ampicillin), narrow spectrum 1st gen cephalosporins, cephamycins = potent inducers
          • • However organisms at mod to high risk for ampC induction hydrolyze these abxs even at basal ampC expression levels (so prob already test as non-susceptible)
        • Imipenem = potent inducer
          • • Usu resistant to ampC hydrolysis because of formation of stable acyl enzyme complexes
        • Ertapenem, meropenem = generally able to resist ampC hydrolysis
        • Piperacillin, ceftriaxone, ceftazidime, aztreonam = relatively weak ampC inducers
          • • Despite limited ability of ceftriaxone and ceftazidime to induce ampC production, susceptibility of these agents to hydrolysis makes them unlikely to be effective for treatment of infections by organisms at mod to high risk 
        • Cefepime = weak inducer of ampC and withstanding hydrolysis because of stable acyl enzyme complex formation → generally effective
        • Fluoroquinolones, aminoglycosides, TMP-SMX, tetracycline, other non-BL abxs do not induce ampC and are also not substrates for hydrolysis
• Extended spectrum beta-lactamases (ESBLs)
  • • Acquired via mobile genetic elements and there are hundreds of variations
    • Any gram negative can harbor ESBL genes but most prevalent in E.coli, Klebsiella pneumoniae, Klebsiella oxytoca, Proteus mirabilis
    • Most ESBLs cause resistance to:
      • • Penicillins
        • First to third generation cephalosporins, sometimes fourth generation cephalosporins
        • High level expression can also cause resistance to ertapenem but most generally are susceptible to carbapenems
• Carbapenemases
  • • Acquired via mobile genetic elements – huge topic, not even scratching surface
    • Cause resistance to most, if not all, beta-lactam antimicrobials – but the spectrum depends on the type of carbapenemase
    • Most common in the US is KPC (Klebsiella pneumoniae carbapenemase)
    • Others: 
      • • Metallo-beta-lactamase: NDM (new Delhi metallo-β-lactamase), IMP (imipenem-hydrolyzing metallo-β-lactamase), VIM (Verona integron-encoded metallo-β-lactamase), etc
        • Oxacillinases: OXA (some remain susceptible to cephalosporins while resistant to carbapenems)
    • CRE = Enterobacterales resistant to at least one carbapenem or producing a carbapenemase enzyme
    • **Heterogenous group of pathogens with multiple potential mechanisms

I used the structure and layout of Table 1 from ESCMID guidelines.  We did NOT cover the Pseudomonas selection from the newest ESCMID guidelines (and corresponding IDSA guidance version 1)

Check out the infographics for a summary/compare-and-contrast charts