What is the most appropriate empiric antibiotic for a urinary tract infection caused by carbapenem‑resistant Enterobacter with PCR‑detected NDM metallo‑β‑lactamase?

Treatment of Carbapenem-Resistant Enterobacter UTI with NDM Gene

For a urinary tract infection caused by carbapenem-resistant Enterobacter with PCR-detected NDM metallo-β-lactamase, the first-line treatment is ceftazidime-avibactam 2.5 g IV every 8 hours PLUS aztreonam 2 g IV every 8 hours for 10-14 days, with dose adjustments for renal function. 1, 2

Rationale for Combination Therapy

• NDM metallo-β-lactamases hydrolyze all β-lactams except aztreonam, but aztreonam cannot be used as monotherapy because NDM-producing organisms co-produce ESBLs and AmpC enzymes that inactivate aztreonam. 1, 2

• Ceftazidime-avibactam neutralizes the co-produced ESBL and AmpC enzymes (such as CTX-M), while aztreonam remains stable against the NDM enzyme, creating synergistic activity that restores full antimicrobial efficacy. 1, 2

• Ceftazidime-avibactam monotherapy will fail against NDM producers because avibactam has no activity against metallo-β-lactamases—this is a critical pitfall to avoid. 1, 3

Clinical Evidence Supporting This Regimen

• In patients with bloodstream infections caused by NDM-producing organisms, the combination of ceftazidime-avibactam plus aztreonam reduced 30-day mortality from 44% to 19.2%, representing a 56% relative risk reduction compared to other active antibiotics including colistin-based regimens. 1, 2

• This recommendation carries a STRONG recommendation with MODERATE certainty of evidence from the Italian Society of Infection and Tropical Diseases and multiple international infectious disease societies. 1, 2

• Colistin-based regimens showed the highest mortality rates and should be avoided as first-line therapy for NDM infections. 1, 2

Dosing and Administration

• Ceftazidime-avibactam should be infused over 2 hours (2.5 g IV every 8 hours) to maximize time-above-MIC, the critical pharmacodynamic parameter. 2

• Aztreonam 2 g IV every 8 hours should be administered concurrently. 1, 2

• Both agents require renal dose adjustment—adjust based on creatinine clearance in patients with moderate to severe renal impairment. 2, 4

Alternative Treatment Option

• Cefiderocol may be considered as an alternative with a CONDITIONAL recommendation and LOW certainty of evidence, achieving approximately 75% clinical cure in MBL-producing CRE infections. 1, 2, 5

• Cefiderocol is FDA-approved for complicated UTIs and has demonstrated in vitro activity against NDM-producing Enterobacterales, with activity maintained against isolates containing metallo-carbapenemases. 6, 4

• Concerns with cefiderocol include higher MIC values against some NDM producers, risk of treatment-emergent resistance, and unclear role of combination therapy—making it a second-line option. 5

Critical Implementation Points

• Do not delay treatment waiting for complete carbapenemase typing—if NDM is suspected based on epidemiology (e.g., recent travel to Indian subcontinent, known local outbreaks) or rapid PCR detection, initiate ceftazidime-avibactam plus aztreonam immediately. 1, 2, 3

• Never use aztreonam monotherapy for NDM infections—it will fail due to co-produced β-lactamases. 1, 2

• Meropenem-vaborbactam has no activity against NDM and should not be used. 1, 3

• Fourth-generation cephalosporins and carbapenems are ineffective against carbapenem-resistant Enterobacter with NDM. 1

Source Control Considerations

• Adequate source control is mandatory and complementary to antimicrobial therapy for complicated UTIs, including drainage of obstructions, removal of infected catheters, and management of any urinary tract abnormalities. 1

• In critically ill patients with sepsis or septic shock, urgent source control procedures should be performed alongside timely antibiotic administration to improve outcomes. 1