Treatment of Severe NDM-Producing Klebsiella Infection
For severe NDM-producing Klebsiella pneumoniae infections, use ceftazidime-avibactam 2.5g IV every 8 hours PLUS aztreonam 2g IV every 8 hours as first-line therapy, NOT cefiderocol monotherapy. 1
First-Line Recommendation: Combination Therapy
Ceftazidime-avibactam plus aztreonam is the strongly recommended first-line agent for MBL-producing (including NDM) CRE with MODERATE certainty of evidence. 2, 1
This combination achieves synergistic activity because aztreonam remains stable against NDM (metallo-β-lactamases cannot hydrolyze monobactams), while ceftazidime-avibactam neutralizes co-produced β-lactamases like CTX-M and OXA-48 that would otherwise inactivate aztreonam. 1
Mortality data strongly favors this combination: Patients with NDM-producing Klebsiella pneumoniae bloodstream infections treated with ceftazidime-avibactam plus aztreonam had 19.2% 30-day mortality versus 44% with other active antibiotics—representing a 56% relative risk reduction in mortality. 1
Cefiderocol as Alternative (Not First-Line)
Cefiderocol is only a CONDITIONAL alternative option with LOW certainty of evidence for NDM-producing CRE. 2, 1
While cefiderocol achieved 75% clinical cure in MBL-producing CRE in the CREDIBLE-CR trial, and pooled data showed 70.8% clinical cure rates with 12.5% 28-day mortality, significant concerns limit its use. 2
Critical concerns about cefiderocol in NDM infections include:
- High MIC values against some NDM producers raise resistance concerns 2
- Emergence of cefiderocol resistance during therapy has been documented in NDM-5-producing K. pneumoniae within 32 days, associated with mutations in siderophore receptor genes (cirA, fiu) 3
- Primary cefiderocol resistance in NDM-producing K. pneumoniae has been reported even without prior drug exposure 4
- Clinical failures have occurred before susceptibility results were available 4
The European guidelines conditionally recommend AGAINST cefiderocol for CRAB infections (LOW evidence), suggesting caution with this agent. 5
Critical Pitfalls to Avoid
Never use aztreonam monotherapy for NDM infections—co-produced β-lactamases (CTX-M, OXA-48) will inactivate it, leading to treatment failure. 1
Never use ceftazidime-avibactam monotherapy for NDM producers—it has no activity against metallo-β-lactamases and will fail. 1
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
Avoid colistin-based regimens as first-line therapy—they have significantly higher mortality compared to the aztreonam combination. 1
Combination Therapy Guidance
For severe infections caused by CRE carrying metallo-β-lactamases, combination therapy with aztreonam and ceftazidime-avibactam is suggested (CONDITIONAL recommendation, MODERATE evidence). 5
For patients with CRE infections susceptible to and treated with cefiderocol monotherapy, combination therapy is NOT recommended (STRONG recommendation, LOW evidence), though this applies when cefiderocol susceptibility is confirmed. 5
Dosing Adjustments
Adjust both ceftazidime-avibactam and aztreonam for renal function. 1
Cefiderocol (if used) requires dose adjustment based on creatinine clearance, with approximately 60% removed by 3-4 hour hemodialysis sessions. 6
Source Control
- Adequate source control is mandatory and complementary to antimicrobial therapy, including drainage of abscesses, removal of infected devices, and debridement of necrotic tissue. 1