MICROBIOLOGY

• Gram-negative, aerobic, motile bacilli of the Enterobacteriaceae family that ferments lactose and forms mucoid colonies. Twenty-two species belong to the Enterobacter genus.[11]Enterobacter spp. are commensals of the human gut and are commonly found in water, sewage, and soil.
• Opportunistic human pathogens include E. cloacae (most common), E. aerogenes (renamed Klebsiella aerogenes), E. gergoviae[20] , and Pantoea agglomerans.
  
  • E. sakazakii is now classified as Cronobacter.[13]
• High levels of drug resistance are often seen and are due to:
  • AmpC β-lactamases - Ambler class C
    • Chromosomal AmpC β-lactamases can be constitutive (always active) or inducible (variably active) and are not inhibited by β-lactam β-lactamase inhibitors.
      • Enterobacter spp. have intrinsic resistance to ampicillin, amoxicillin, first-generation cephalosporins, and cefoxitin due to expression of constituitive AmpC β-lactamase.[11]
      • β-lactams must be present to activate inducible β-lactamases, so initial susceptibility reports may not detect resistance that can emerge during therapy. In the absence of β-lactams, AmpR, a regulatory protein, reduces or represses AmpC β-lactamase expression to very low levels.[12]
      • Certain β-lactams induce the production of cell wall degradation products and decrease AmpR repression of AmpC, which results in increased ampC transcription and AmpC expression.
        • ’Potent inducers’ of AmpC production include aminopenicillins, amoxicillin-clavulanate, narrow-spectrum cephalosporins, and cephamycins. AmpC producers, such as E. cloacae, can hydrolyze these agents and are intrinsically resistant.[12]
          
          • Imipenem is a potent inducer but remains stable against hydrolysis due to forming an acyl-enzyme complex.
        • ’Weak inducers’ of AmpC production include piperacillin-tazobactam, aztreonam, and extended-spectrum cephalosporins, and these antibiotics can be hydrolyzed to a variable extent depending on the amount of β-lactamase production. This results in increased drug-specific MICs.[12]
          • Cefepime is a weak inducer and can withstand hydrolysis by AmpC β-lactamases due to forming a stable acyl-enzyme complex.
    • Plasmid-mediated
      • Phenotypic assays cannot distinguish between AmpC β-lactamase production due to derepression of chromosomal versus plasmid-associated ampC gene.
  • Plasmid-encoded extended-spectrum β-lactamases (ESBLs)
    • ESBL genes include bla_CTX-M, bla_SHV, and bla_TEM. Commercially available molecular platforms limited to detection bla_CTX-M.
    • Most often, such organisms demonstrate elevated MICs to cefepime.
    • ESBLs inactivate most penicillins, cephalosporins, and aztreonam.[1]
  • Carbapenemases[16]
    • Ambler class A - Most common are Klebsiella pneumoniae carbapenemases (KPC) that any Enterobacterales can produce.
    • Ambler class B - Metallo-β-lactamases include New Delhi (NDMs), Verona integron-encoded (VIM), and imipenem-hydrolyzing (IMPs)
    • Ambler class D - Oxacillinase (OXA-48-like) carbapenemases
• Ceftriaxone MIC ≥ 2 is used as a proxy for ESBL production.
• Other resistance mechanisms
  • Alterations in the active site of penicillin-binding protein
  • Defects in outer membrane permeability that reduce diffusion of β-lactams into the cell
  • The presence of efflux pumps that move β-lactams out of the cell