A 52-year-old woman with end-stage renal disease on hemodialysis presents with fever and hypotension. Blood cultures grow a gram-negative rod identified as *Klebsiella pneumoniae*. The organism is resistant to meropenem and imipenem but susceptible to colistin and tigecycline. PCR testing detects a *bla*_NDM-1_ gene. What is the primary mechanism of carbapenem resistance in this isolate?

Explanation

## Carbapenem-Resistant *Klebsiella pneumoniae* (CRKP) via Metallo-β-Lactamase ### Molecular Identification: *bla*_NDM-1_ Gene **Key Point:** The presence of *bla*_NDM-1_ gene directly identifies a **New Delhi metallo-β-lactamase (NDM-1)**, a class B serine-dependent metallo-β-lactamase that confers broad carbapenem resistance. ### Mechanism of Metallo-β-Lactamase (MBL) Resistance ```mermaid flowchart TD A["*bla*_NDM-1_ gene"]:::outcome --> B["NDM-1 protein synthesis"]:::action B --> C["Zinc-dependent active site"]:::outcome C --> D["Hydrolyzes carbapenems<br/>meropenem, imipenem"]:::action D --> E["Resistance to all β-lactams<br/>except aztreonam"]:::outcome F["Colistin & tigecycline<br/>remain active"]:::outcome ``` ### Classification of β-Lactamases (Ambler Classification) | Class | Type | Mechanism | Inhibited by Clavulanic Acid? | Carbapenem Resistance? | |-------|------|-----------|-------------------------------|------------------------| | A | Serine β-lactamase (ESBL, AmpC) | Serine nucleophile | Yes (ESBL); No (AmpC) | No | | B | **Metallo-β-lactamase (MBL)** | **Zinc cofactor** | **No** | **Yes** | | C | AmpC | Serine nucleophile | No | No | | D | Oxacillinase | Serine nucleophile | No | No | ### NDM-1 Characteristics **High-Yield:** NDM-1 (and other MBLs like VIM, IMP) are: 1. **Zinc-dependent enzymes** — require Zn²⁺ cofactor in active site 2. **Broad-spectrum hydrolyzers** — cleave all β-lactams including carbapenems and monobactams 3. **NOT inhibited by classical β-lactamase inhibitors** (clavulanic acid, sulbactam, tazobactam) 4. **Inhibited by metal chelators** (EDTA, aspergillomarasmine A) — experimental agents 5. **Colistin-susceptible** — because MBL does not affect colistin's mechanism (membrane disruption) ### Epidemiology **Clinical Pearl:** NDM-1 was first identified in *K. pneumoniae* from India (hence "New Delhi") and has now spread globally. It is associated with: - Healthcare-associated infections - High mortality in immunocompromised hosts (like dialysis patients) - Rapid horizontal gene transfer via plasmids ### Treatment Implications - **DOC for CRKP-MBL**: Colistin (polymyxin E) or tigecycline - **Avoid**: All β-lactams (including carbapenems, cephalosporins, penicillins) - **Combination therapy**: Often used (colistin + tigecycline or colistin + meropenem in high-dose regimens) for severe infections - **Prognosis**: Poor, especially in immunocompromised patients [cite:Harrison 21e Ch 173; Koneman's Textbook of Diagnostic Microbiology 6e Ch 6]