What is the recommended treatment approach for a bacterial strain positive for New Delhi metallo-beta-lactamase-1 (NDM-1), Cefotaximase (CTX-M), and Oxacillinase (OXA-48) genes?

Treatment of Bacterial Strains Positive for NDM-1, CTX-M, and OXA-48 Genes

For infections caused by bacteria harboring NDM-1, CTX-M, and OXA-48 genes, the preferred treatment is ceftazidime-avibactam plus aztreonam (STRONG recommendation, MODERATE certainty of evidence). 1, 2

Understanding the Resistance Profile

This triple-positive strain represents an extremely challenging clinical scenario:

• NDM-1 (metallo-β-lactamase) hydrolyzes all β-lactams except aztreonam but cannot be inhibited by avibactam or vaborbactam 1, 3
• OXA-48 (Class D carbapenemase) is inhibited by ceftazidime-avibactam 1, 4
• CTX-M (ESBL) confers resistance to third-generation cephalosporins but is also covered by ceftazidime-avibactam 1

The presence of NDM-1 is the dominant factor driving treatment selection, as it renders most β-lactam antibiotics ineffective. 1, 2

First-Line Treatment Regimen

Ceftazidime-avibactam 2.5g IV every 8 hours PLUS aztreonam 2g IV every 8 hours (adjust both for renal function) 1, 2

Rationale for This Combination:

• Aztreonam remains stable against NDM-1 because metallo-β-lactamases cannot hydrolyze monobactam antibiotics 2, 3
• However, aztreonam alone would be inactivated by the co-produced CTX-M and other β-lactamases 1, 2
• Ceftazidime-avibactam protects aztreonam by inhibiting CTX-M and OXA-48, while aztreonam covers the NDM-1 gap 1, 2
• This synergistic combination restores full antimicrobial efficacy 2

Clinical Evidence:

• Patients with NDM-producing bloodstream infections treated with ceftazidime-avibactam plus aztreonam had 30-day mortality of 19.2% versus 44% with other active antibiotics (56% relative risk reduction) 2
• The highest mortality rates occurred in patients receiving colistin-containing regimens 1, 2

Alternative Treatment Option

Cefiderocol 2g IV every 8 hours (3-hour infusion) may be considered as an alternative (CONDITIONAL recommendation, LOW certainty of evidence) 1, 2

• Achieved 75% clinical cure in MBL-producing CRE infections in the CREDIBLE-CR trial 1, 2
• However, concerns exist regarding higher MICs against NDM producers 5
• Reserve this option when ceftazidime-avibactam plus aztreonam is unavailable or contraindicated 1

Critical Pitfalls to Avoid

Never use aztreonam monotherapy for NDM infections—the co-produced CTX-M and other β-lactamases will inactivate it, leading to treatment failure 1, 2

Do not delay treatment waiting for complete carbapenemase typing—if NDM is suspected based on epidemiology or rapid molecular testing, initiate ceftazidime-avibactam plus aztreonam immediately 1, 2

Avoid colistin-based regimens as first-line therapy due to significantly higher mortality compared to the aztreonam combination 1, 2

Do not use ceftazidime-avibactam monotherapy for NDM producers—it has no activity against metallo-β-lactamases and will fail 1

Do not use meropenem-vaborbactam—it has no activity against either NDM-1 or OXA-48 1, 3

Salvage Options for Extensively Drug-Resistant Cases

If the strain demonstrates resistance to ceftazidime-avibactam plus aztreonam (rare but reported 6):

• High-dose tigecycline (200mg loading dose, then 100mg IV every 12 hours) plus ceftazidime-avibactam plus aztreonam may be considered 1, 6
• Polymyxin B combinations with minocycline or rifampicin showed synergistic activity in vitro against NDM/OXA-48 co-producers 7
• These salvage regimens should only be used when no other options exist and in consultation with infectious disease specialists 6

Source Control

Regardless of antibiotic selection, adequate source control is mandatory and complementary to antimicrobial therapy 1

• Drainage of abscesses or infected collections 1
• Removal of infected devices or foreign bodies 1
• Debridement of necrotic tissue 1

Monitoring and Duration

• Obtain repeat cultures to document microbiological clearance 6, 8
• Monitor for clinical cure (resolution of fever, leukocytosis, and infection-specific symptoms) 8
• Treatment duration depends on infection site and clinical response, typically 7-14 days for most infections 8
• Adjust antibiotic doses for renal function—both ceftazidime-avibactam and aztreonam require dose adjustment 6