Treatment of NDM-Producing Klebsiella and Enterobacter cloacae: Limited Role for Ceftriaxone-Sulbactam-EDTA
Ceftriaxone-sulbactam-EDTA should NOT be used as first-line therapy for confirmed NDM-producing Klebsiella or Enterobacter cloacae infections; instead, use ceftazidime-avibactam plus aztreonam, which reduces 30-day mortality from 44% to 19.2% compared to alternative regimens. 1, 2
Guideline-Recommended First-Line Treatment
For confirmed NDM-producing Enterobacterales (including Klebsiella and Enterobacter cloacae), ceftazidime-avibactam 2.5g IV every 8 hours PLUS aztreonam 2g IV every 8 hours is the preferred regimen (STRONG recommendation, MODERATE certainty of evidence). 1, 2
This combination achieved a 56% relative risk reduction in mortality (hazard ratio 0.37,95% CI 0.13-0.74) in patients with NDM-producing bloodstream infections compared to other active antibiotics including colistin-based regimens. 2, 3
The mechanistic rationale is critical: NDM metallo-β-lactamases hydrolyze all β-lactams except aztreonam, but aztreonam cannot be used alone because co-produced enzymes (ESBLs, other cephalosporinases) inactivate it; ceftazidime-avibactam neutralizes these co-produced enzymes, allowing aztreonam to work against the NDM enzyme. 1, 2
Alternative Option
- Cefiderocol may be considered as an alternative with 75% clinical cure rates in MBL-producing CRE infections (CONDITIONAL recommendation, LOW certainty of evidence). 1, 2
The Limited Role of Ceftriaxone-Sulbactam-EDTA
Ceftriaxone-sulbactam-EDTA demonstrated 95% in vitro sensitivity against ESBL- and MBL-producing Enterobacteriaceae in one Indian ICU study, with clinical cure in 83% of nosocomial infections when used empirically. 4, 5
However, this evidence comes from retrospective observational studies without comparison to guideline-recommended regimens, and the studies did not specifically analyze outcomes for confirmed NDM producers versus other resistance mechanisms. 4, 5
Ceftriaxone-sulbactam-EDTA may have a role only as empiric therapy in settings with high MBL prevalence when newer agents are unavailable, but must be switched to ceftazidime-avibactam plus aztreonam once NDM is confirmed. 4, 5
Critical Pitfalls to Avoid
Never use aztreonam monotherapy for NDM infections—the co-produced β-lactamases (CTX-M, other ESBLs) will inactivate it, leading to treatment failure. 1, 2
Avoid colistin-based regimens as first-line therapy—they demonstrated the highest mortality rates in comparative studies and significantly worse outcomes than ceftazidime-avibactam plus aztreonam. 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. 2
Do not use ceftazidime-avibactam monotherapy for NDM producers—it has no activity against metallo-β-lactamases and will fail. 2, 3
When Ceftriaxone-Sulbactam-EDTA Might Be Considered
In resource-limited settings where ceftazidime-avibactam and aztreonam are unavailable, ceftriaxone-sulbactam-EDTA may serve as a carbapenem-sparing option for empiric therapy of suspected MDR gram-negative infections. 4, 5
The combination showed 86% sensitivity to isolates in ICU settings compared to 78% for meropenem in one study, suggesting potential utility when newer agents cannot be accessed. 4
However, this should be viewed as a suboptimal alternative driven by resource constraints, not an evidence-based preference, and therapy should be escalated to guideline-recommended regimens when possible. 4, 5
Resistance Profile Context
All NDM-producing Enterobacterales are multidrug-resistant by definition, with 42.2% being extensively drug-resistant and 75.3% displaying difficult-to-treat resistance in U.S. surveillance data. 6
Only 18.2% of NDM-producing isolates were susceptible to aztreonam alone, reinforcing why combination therapy with ceftazidime-avibactam is essential. 6