MICROBIOLOGY

• Gram-negative, aerobic, motile bacilli of the Enterobacteriaceae family that ferment lactose and form mucoid colonies [Fig].
  • Twenty-two species belong to the Enterobacter genus.[13]
  • 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,[23] and Pantoea agglomerans.
  
  • E. sakazakii is now classified as Cronobacter.[15]
• High levels of drug resistance are often seen and are due to the mechanisms reviewed below.
  • AmpC β-lactamases - Ambler class C
    • Chromosomal AmpC β-lactamases hydrolyze β-lactams. They can be constitutive (always active) or inducible (variably active) and are resistant to β-lactam-based β-lactamase inhibitors, such as clavulanate, sulbactam, and tazobactam.[11]
    • In the absence of β-lactams, AmpR, a regulatory protein, reduces or represses AmpC β-lactamase expression to very low levels.[14] Whereas β-lactams can reduce AmpR repression of ampC, thereby increasing ampC transcription and AmpC expression.
    • Inducible strains can generate mutants that stably de-repress or upregulate AmpC expression, leading to constitutive expression.
      
      • Basal production of AmpC β-lactamases in E. cloacae confers resistance to ampicillin, amoxicillin-clavulanate, ampicillin-sulbactam, and first- and second-generation cephalosporins.
      • Emergence of resistance due to upregulation of AmpC production can occur during antibiotic treatment with ceftriaxone, cefotaxime, or ceftazidime.
        • Since β-lactams must be present to activate inducible β-lactamases, initial susceptibility reports may not detect resistance that can emerge during therapy.
        • Resistance can be detected after even a few doses.[1][5][7]
      • ’Weak inducers’ of ampC transcription and increased AmpC production include: piperacillin-tazobactam, aztreonam, ceftriaxone, cefotaxime, and ceftazidime.
        • AmpC β-lactamases hydrolyze these antibiotics.
        • Despite ’weak’ induction of ampC, these agents are less likely to be effective and are not recommended to treat infections due to Enterobacterales at moderate risk of AmpC production.[1][6]
      • IDSA 2024 guidelines suggest cefepime as a preferred treatment option for E. cloacae and other organisms at moderate risk of significant AmpC production.[1]
        • Cefepime has low potential for ampC induction and AmpC production, and it can withstand hydrolysis by AmpC β-lactamases by forming a stable acyl-enzyme complex.
        • Carbapenems are ’potent inducers’ yet remain stable against hydrolysis due to the formation of an acyl-enzyme complex.
          • Imipenem, meropenem, and ertapenem are recommended options for the treatment of E. cloacae.
          • Ertapenem is highly protein-bound and, unlike meropenem and imipenem, has less reliable pharmacokinetics/pharmacodynamics in the setting of critical illness and/or hypoalbuminemia.[1]
    • Plasmid-mediated AmpC β-lactamase production
      • 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 are limited to the detection of bla_CTX-M.
    • Most often, ESBLs demonstrate elevated MICs to cefepime.
    • ESBLs inactivate most penicillins, cephalosporins, and aztreonam.[1]
    • For infections of the urinary tract, TMP-SMX, fluoroquinolones and aminoglycosides are preferred for treatment of susceptible E. cloacae.
    • Preferred treatment for infections outside of the urinary tract includes meropenem, imipenem-cilastatin, or ertapenem.
      • In the setting of critical illness or hypoalbuminemia, avoid ertepenem as it is highly protein-bound.[1]
  • Carbapenemases[22]
    • Ambler class A - The Most common are Klebsiella pneumoniae carbapenemases (KPCs), which any of the Enterobacterales can produce.
      • Preferred treatment of infections due to KPC-producing E. cloacae outside of the urinary tract includes meropenem-vaborbactam, ceftazidime-avibactam, and imipenem-cilastatin-relebactam.
    • Ambler class B - Metallo-β-lactamases include New Delhi (NDM), Verona integron-encoded (VIM), and imipenem-hydrolyzing (IMP).
      • Preferred treatment is ceftazidime-avibactam in combination with aztreonam OR cefiderocol as monotherapy.
      • NDMs hydrolyze penicillins, cephalosporins, and carbapenems.
    • Ambler class D - Oxacillinase (OXA-48-like) carbapenemases
      • Preferred treatment is ceftazidime-avibactam.
• 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 the diffusion of β-lactams into the cell
  • The presence of efflux pumps that move β-lactams out of the cell