What are the major carbapenemase genes (KPC, OXA‑48‑like, NDM) in Gram‑negative bacteria, how are they detected, and what are the recommended treatment options?

Carbapenemase Genes: KPC, OXA-48, and NDM

Rapid identification of specific carbapenemase genes (KPC, NDM, OXA-48-like) is essential because each enzyme class requires completely different treatment strategies that directly impact patient survival. 1

Classification by Ambler System

The three major carbapenemase genes belong to distinct molecular classes with fundamentally different mechanisms:

• KPC (Class A): Serine-based carbapenemase representing 47.4% of meropenem-resistant Enterobacterales globally, making it the most common type 1, 2
• NDM (Class B): Metallo-β-lactamase (MBL) requiring zinc ions for activity, accounting for 20.6% of carbapenem-resistant isolates 1, 2
• OXA-48-like (Class D): Oxacillinase-type carbapenemase representing approximately 19% of carbapenem resistance 1, 2

Critical Mechanistic Differences

The most clinically important distinction is that NDM and other MBLs hydrolyze all β-lactam antibiotics except aztreonam, while KPC and OXA-48 have different hydrolytic profiles. 1, 2

• MBLs (NDM, VIM, IMP) cannot be inhibited by classic serine β-lactamase inhibitors like avibactam or vaborbactam due to their zinc-dependent mechanism 1, 2
• KPC and OXA-48 are serine-based enzymes that can be inhibited by newer β-lactamase inhibitor combinations 1, 2

Detection Methods

Genotypic Testing (Preferred)

Genotypic testing should be used where available due to superior speed and accuracy. 1

• Real-time PCR: Achieves 98.0% sensitivity and 100% specificity with <3 hour turnaround time 1
• Loop-mediated isothermal amplification (LAMP): Provides 2-3 hour turnaround with sensitivity/specificity consistent with PCR 1, 3
• Multiplex PCR assays: Can simultaneously detect KPC, NDM, VIM, IMP, and OXA-48-like genes with 100% sensitivity and specificity 4, 5

Phenotypic Testing (Resource-Limited Settings)

When genotypic testing is unavailable, use these phenotypic methods:

• Combined Disc Test (CDT): Meropenem disc plus 3-aminophenylboronic acid (for KPC) or meropenem disc plus EDTA (for MBLs) achieves 100% sensitivity for detecting KPC or MBL producers alone, 96.8% for co-producers, and 98.8% specificity 1
• Modified carbapenem inactivation method (mCIM)/EDTA-modified CIM (eCIM): Shows 95% compliance with genetic detection 1
• Immunochromatographic assays (OKN K-SeT): Rapid lateral flow test detecting OXA-48-like, KPC, and NDM with 100% sensitivity and specificity in 15 minutes 6

Important Limitations

• CDT has low specificity (79%) and sensitivity (88%) for metallo-β-lactamases and cannot accurately detect IMP variants 1
• Modified Hodge test identified only 47 of 48 carbapenemase producers in validation studies 1

Treatment Strategies by Carbapenemase Type

KPC Producers

First-line treatment: Ceftazidime/avibactam OR meropenem/vaborbactam (STRONG recommendation, MODERATE evidence) 1, 2

• Alternative options: Imipenem/relebactam or cefiderocol (CONDITIONAL recommendation, LOW evidence) 1
• These novel β-lactam/β-lactamase inhibitor combinations effectively inhibit Class A serine enzymes 1, 2

NDM and Other MBL Producers

First-line treatment: Ceftazidime/avibactam PLUS aztreonam (STRONG recommendation) 2

• Alternative: Cefiderocol monotherapy 2
• Critical rationale: Aztreonam remains stable against MBLs because they cannot hydrolyze monobactams, while ceftazidime/avibactam protects aztreonam from co-produced ESBLs 1, 2
• Do NOT use ceftazidime/avibactam or meropenem/vaborbactam alone—MBLs are not inhibited by these agents 2

OXA-48-like Producers

First-line treatment: Ceftazidime/avibactam (CONDITIONAL recommendation, VERY LOW evidence) 2

Clinical Implementation Algorithm

1. Obtain rapid carbapenemase testing immediately when carbapenem resistance is suspected or confirmed 1
2. Identify specific carbapenemase family (KPC vs. NDM/MBL vs. OXA-48) before finalizing treatment 1
3. Select treatment based on enzyme class using the strategies above 1, 2
4. Time from blood culture to active therapy directly influences mortality in critically ill patients with carbapenemase-producing infections 1

Critical Pitfalls to Avoid

• Never assume all carbapenem-resistant bacteria have the same carbapenemase—treatment efficacy depends entirely on the specific enzyme class 2
• Do not delay rapid carbapenemase testing—phenotypic susceptibility testing alone is insufficient for optimal treatment selection 1
• Never use ceftazidime/avibactam or meropenem/vaborbactam monotherapy for MBL producers—these agents do not inhibit metallo-β-lactamases 2
• Do not rely solely on CDT for detecting IMP-type MBLs—this method has poor accuracy for IMP variants 1

Epidemiological Context

Carbapenem resistance has increased more than seven-fold since 2006 in Europe, with some countries (Italy, Greece) reporting >50% carbapenem resistance in K. pneumoniae 1, 2