A *Klebsiella pneumoniae* isolate is resistant to meropenem and imipenem but remains susceptible to aztreonam. Which mechanism of carbapenem resistance is MOST likely?

Explanation

## Carbapenem Resistance Mechanisms in Gram-Negatives **Key Point:** Aztreonam susceptibility in a carbapenem-resistant Gram-negative strongly suggests metallo-β-lactamase (MBL) production, because aztreonam (a monobactam) is NOT a substrate for MBLs. ### Differential Diagnosis: Carbapenem Resistance with Aztreonam Susceptibility ```mermaid flowchart TD A[Carbapenem-resistant Gram-negative]:::outcome --> B{Aztreonam susceptible?}:::decision B -->|Yes| C[Likely MBL producer]:::outcome B -->|No| D[Serine carbapenemase or porin loss]:::outcome C --> E[NDM-1, VIM, IMP, etc.]:::action E --> F[Zinc-dependent; inhibited by EDTA]:::action D --> G[KPC, OXA-48, or OmpK35 loss]:::action ``` ### Why Aztreonam Susceptibility Indicates MBL | Enzyme Type | Carbapenem Hydrolysis | Aztreonam Hydrolysis | Clavulanic Acid Inhibition | |-------------|----------------------|----------------------|----------------------------| | **Metallo-β-lactamase (MBL)** | **Yes** | **No** | No (Zn²⁺-dependent) | | Serine carbapenemase (KPC) | Yes | Yes | Yes (partial) | | OmpK35 loss | Yes (indirect) | Yes | N/A (porin loss) | | Efflux pump | Variable | Variable | No | **High-Yield:** Aztreonam is a **monobactam** with a different β-lactam ring structure. MBLs (which require Zn²⁺ in their active site) do not hydrolyze aztreonam efficiently, making it a useful discriminator in the laboratory. ### Mechanism of NDM-1 (New Delhi Metallo-β-lactamase) 1. Zinc-dependent serine protease mechanism (different from serine carbapenemases) 2. Hydrolyzes carbapenems, cephalosporins, penicillins 3. **NOT inhibited** by clavulanic acid or β-lactamase inhibitors 4. Inhibited by metal chelators (EDTA, 1,10-phenanthroline) 5. Plasmid-encoded; rapidly spreading in India and globally **Clinical Pearl:** The aztreonam-susceptible phenotype is a red flag for MBL and mandates infection control measures and contact tracing, as MBL-producing organisms are often multidrug-resistant and associated with nosocomial outbreaks. ### Why Other Options Are Wrong **OmpK35 Loss:** Porin loss reduces carbapenem influx but does NOT selectively spare aztreonam (both are hydrophilic and require porins). Aztreonam would also be resistant. **Serine Carbapenemase (KPC):** KPC-type enzymes hydrolyze both carbapenems AND aztreonam. Aztreonam resistance would be expected. **Efflux Pump:** Upregulation would affect multiple substrates non-selectively; aztreonam would also be resistant. [cite:Koneman's Textbook of Diagnostic Microbiology 6e Ch 6; Harrison 21e Ch 139]