Treatment of OXA-48, NDM, and CTX-M Positive Infections
Treat immediately with ceftazidime-avibactam 2.5g IV every 8 hours PLUS aztreonam 2g IV every 8 hours (adjusted for renal function), as this triple-carbapenemase/ESBL combination requires dual-agent therapy to cover both the metallo-β-lactamase (NDM) and the serine carbapenemase (OXA-48). 1, 2
Why Combination Therapy is Mandatory
This organism presents a uniquely challenging resistance profile that requires understanding each mechanism:
- NDM (metallo-β-lactamase) hydrolyzes all β-lactams except aztreonam, but aztreonam alone will fail because the co-produced CTX-M and other β-lactamases inactivate it 1, 2
- OXA-48 (Class D carbapenemase) is a serine-based enzyme that IS inhibited by avibactam, making ceftazidime-avibactam active against it 3, 2
- CTX-M (ESBL) confers resistance to third-generation cephalosporins but is also covered by ceftazidime-avibactam 2
The synergistic mechanism works as follows: Ceftazidime-avibactam neutralizes the OXA-48 and CTX-M enzymes through avibactam's inhibitory activity, while aztreonam remains stable against the NDM enzyme because metallo-β-lactamases cannot hydrolyze monobactam antibiotics 1, 2
Evidence Supporting This Regimen
- In patients with bloodstream infections caused by NDM-producing Klebsiella pneumoniae, those who received ceftazidime-avibactam plus aztreonam had 30-day mortality of 19.2% versus 44% with other active antibiotics—a 56% relative risk reduction in mortality 1, 2
- For NDM + OXA-48 co-producers specifically, the curative rate was 77.5% with ceftazidime-avibactam plus aztreonam combination therapy 3
- This recommendation carries a STRONG recommendation with MODERATE certainty of evidence from the Italian Society of Infection and Tropical Diseases and multiple international guidelines 1, 2
Critical Treatment Pitfalls to Avoid
Do NOT use ceftazidime-avibactam monotherapy even though it covers OXA-48 and CTX-M—it has zero activity against metallo-β-lactamases and will fail catastrophically 3, 2
Do NOT use aztreonam monotherapy—the co-produced CTX-M and other β-lactamases will inactivate it immediately, leading to treatment failure 1, 2
Do NOT use meropenem-vaborbactam—vaborbactam has no activity against either NDM or OXA-48 carbapenemases 3, 2
Do NOT use colistin-based regimens as first-line therapy—the highest mortality rates were observed in patients receiving colistin-containing regimens compared to the ceftazidime-avibactam/aztreonam combination 1, 2
Do NOT delay treatment waiting for complete carbapenemase typing—if NDM is suspected based on epidemiology (travel to Indian subcontinent, known local outbreaks) or rapid molecular testing, initiate the combination immediately 3, 2
Alternative Treatment Option
- Cefiderocol may be considered as an alternative with a CONDITIONAL recommendation and LOW certainty of evidence, achieving 75% clinical cure in MBL-producing CRE infections 1, 2
- However, concerns exist regarding higher MIC values against NDM producers, risk of treatment-emergent resistance, and unclear role of combination therapy 1
Source Control Requirements
- Adequate source control is mandatory and complementary to antimicrobial therapy 2
- This includes drainage of abscesses or infected collections, removal of infected devices or foreign bodies, and debridement of necrotic tissue 2
Monitoring Considerations
- Early microbiological eradication and clinical response within 7 days are major determinants of survival 4
- Time to active treatment significantly affects outcomes—earlier recognition through rectal screening offers the advantage of prompt empirical treatment 4
- Monitor for emergence of ceftazidime-avibactam resistance, which can occur through OXA-48 mutations 3