What is the recommended treatment for New Delhi metallo-beta-lactamase (NDM)-producing Pseudomonas aeruginosa infections?

Treatment of New Delhi Metallo-beta-lactamase (NDM)-producing Pseudomonas aeruginosa Infections

For NDM-producing Pseudomonas aeruginosa infections, novel β-lactam/β-lactamase inhibitor combinations such as ceftazidime-avibactam or ceftolozane-tazobactam are the first-line treatment options, with colistin-based therapy as an alternative when these newer agents are not available or the organism shows resistance. 1

First-line Treatment Options

• Novel β-lactam/β-lactamase inhibitor combinations should be prioritized if susceptibility is confirmed:

  • Ceftazidime-avibactam 2.5g IV every 8 hours (infused over 3 hours) 1
  • Ceftolozane-tazobactam (dosing based on infection site and renal function) 1
  • Imipenem-cilastatin-relebactam (if susceptible) 1

• Antimicrobial susceptibility testing is essential to guide therapy selection, as NDM-producing strains may have variable susceptibility patterns 1

Alternative Treatment Options

• Colistin-based therapy when newer agents are unavailable or resistance is present:

  • Loading dose of 9 MU of colistin methanesulfonate (CMS) followed by 4.5 MU CMS twice daily as maintenance 1
  • For pediatric patients: 0.15 MU/kg loading dose followed by 0.075 MU/kg every 12 hours (though this may be inadequate for MICs ≥1 mg/L) 1

• Cefiderocol may be considered as a potential alternative for NDM-producing strains 1

Combination Therapy Considerations

• For severe infections with NDM-producing P. aeruginosa, combination therapy may be considered:

  • When using polymyxins (colistin), aminoglycosides, or fosfomycin, consider using two in vitro active drugs 1
  • Colistin-carbapenem combinations showed highest success rates in network meta-analyses (SUCRA 83.6% for clinical cure) 1
  • Colistin-tigecycline combinations showed lowest mortality rates in some analyses 1

• For non-severe infections, monotherapy with an active agent may be sufficient 1

Monitoring and Considerations

• Renal function should be closely monitored during colistin therapy due to high nephrotoxicity risk 1

• Adjust dosing based on renal function, particularly for colistin and other potentially nephrotoxic agents 1

• Extended infusion of β-lactams may provide clinical benefit for difficult-to-treat P. aeruginosa infections 2

Special Considerations for NDM-producing Strains

• NDM-producing P. aeruginosa often exhibits "difficult-to-treat resistance" (DTR), defined as non-susceptibility to all first-line agents 1

• The molecular mechanism of NDM (New Delhi metallo-beta-lactamase) confers resistance to virtually all β-lactams including carbapenems, with the exception of aztreonam (which is hydrolyzed by other β-lactamases often co-produced in these strains) 1, 3

• Treatment decisions should be guided by comprehensive susceptibility testing, including testing for newer agents 1

Pitfalls and Caveats

• Empirical combination therapy is often necessary while awaiting susceptibility results for suspected NDM-producing P. aeruginosa infections 4, 3

• Development of resistance during therapy is a significant concern, with emergence rates of 27-72% reported in patients with initially susceptible P. aeruginosa isolates 3

• Colistin has a narrow therapeutic window and high nephrotoxicity risk, requiring careful monitoring and dosage adjustment 1

• The evidence base for treating NDM-producing P. aeruginosa specifically (versus other carbapenem-resistant P. aeruginosa) is limited, requiring extrapolation from studies of difficult-to-treat resistant P. aeruginosa 1