What is the preferred empiric regimen for a patient with a confirmed Verona integron‑encoded metallo‑β‑lactamase (VIM)‑producing Pseudomonas aeruginosa infection?

Treatment of VIM-Positive Pseudomonas aeruginosa

For confirmed VIM-producing Pseudomonas aeruginosa infections, cefiderocol monotherapy is the preferred first-line agent, with aztreonam combined with ceftazidime-avibactam as the primary alternative when cefiderocol is unavailable or contraindicated. 1, 2, 3

Rationale for Cefiderocol as First-Line

• Cefiderocol demonstrates potent in vitro activity against VIM-producing Pseudomonas aeruginosa, including difficult-to-treat resistant strains, through its unique siderophore-mediated active transport mechanism that bypasses traditional porin-dependent entry. 1

• Cefiderocol maintains activity against P. aeruginosa harboring VIM metallo-β-lactamases and has shown efficacy in clinical case series treating serious VIM-CRPA infections, with favorable outcomes in respiratory and bloodstream infections. 1, 3

• The drug is stable against metallo-carbapenemases including VIM and IMP, making it particularly suited for MBL-producing organisms where carbapenems and most β-lactams are ineffective. 1, 2

Alternative: Aztreonam-Avibactam Combination

• Aztreonam combined with ceftazidime-avibactam represents the primary alternative regimen, with clinical experience demonstrating efficacy in treating VIM-CRPA infections without detected resistance development during therapy. 2, 3

• This combination exploits aztreonam's stability against metallo-β-lactamases (MBLs do not hydrolyze aztreonam) while avibactam protects against other β-lactamases commonly co-produced by these strains. 2, 3

• In a recent US outbreak of VIM-2-producing P. aeruginosa (ST111), 62.2% of infections were successfully treated with aztreonam-avibactam regimens, with no resistance emergence documented. 3

Critical Implementation Considerations

Dosing Specifications

• Cefiderocol: 2 grams IV every 8 hours as a 3-hour infusion for patients with normal renal function, with dose adjustment required for renal impairment. 1

• Aztreonam-ceftazidime/avibactam: Aztreonam 2 grams IV every 8 hours PLUS ceftazidime-avibactam 2.5 grams IV every 8 hours, both as extended infusions when feasible. 3

Combination Therapy Considerations

• For critically ill patients with septic shock or high mortality risk (>15%), consider adding a second antipseudomonal agent such as an aminoglycoside (amikacin preferred) or colistin to either cefiderocol or aztreonam-avibactam during the first 3-5 days. 4, 2

• Dual coverage is particularly important when treating ventilator-associated pneumonia or in patients with prior antibiotic exposure within 90 days, as these factors increase risk of treatment failure. 4, 5

• De-escalate to monotherapy after 3-5 days if clinical response is favorable, as prolonged combination therapy increases nephrotoxicity risk without preventing resistance emergence. 4

Major Pitfalls and Resistance Concerns

Cefiderocol Resistance Development

• Rapid cefiderocol resistance can emerge during therapy through mutations in siderophore receptor genes (cirA, fiu), with documented cases showing resistance development within 3 weeks of treatment initiation. 6

• Monitor clinical response closely and obtain repeat cultures at 3-7 days to detect resistance emergence early, particularly in patients with prolonged courses or high bacterial burden. 6

• If clinical deterioration occurs on cefiderocol monotherapy, immediately switch to aztreonam-avibactam combination rather than adding agents to failing cefiderocol. 6

Colistin as Last Resort Only

• Reserve colistin-based regimens as last-resort options when both cefiderocol and aztreonam-avibactam are unavailable, contraindicated, or have failed, due to significant nephrotoxicity and limited efficacy data. 2

• Colistin should never be used as monotherapy for serious VIM-producing P. aeruginosa infections; always combine with another active agent if colistin must be used. 2, 7

Treatment Duration and Monitoring

• Standard treatment duration is 7-14 days depending on infection source and severity, with 7-8 days appropriate for uncomplicated infections with good clinical response. 5

• For ventilator-associated pneumonia or bacteremia, target 10-14 days of therapy, adjusting based on source control and clinical improvement. 5

• Obtain surveillance cultures from the original infection site at end of therapy to document microbiological clearance, particularly important given resistance emergence potential. 6

Source Control Imperatives

• Aggressive source control is mandatory for VIM-producing P. aeruginosa infections, including removal of infected catheters, drainage of abscesses, and debridement of necrotic tissue. 3

• Antibiotic therapy alone is insufficient without adequate source control, as biofilm-associated organisms and high bacterial burden facilitate resistance development. 3, 6

Infection Prevention Measures

• Implement strict contact precautions and enhanced environmental cleaning for all patients with VIM-producing organisms, as horizontal transmission is well-documented in outbreak settings. 3

• Screen high-risk contacts (roommates, patients sharing equipment) with rectal or respiratory surveillance cultures to identify asymptomatic carriers and prevent further spread. 3