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

Treatment for NDM-producing Klebsiella Infections

For NDM-producing Klebsiella infections, ceftazidime-avibactam plus aztreonam is the first-line treatment option with the strongest evidence for reducing mortality and improving clinical outcomes. 1

First-Line Treatment Options

Primary Recommendation

• Ceftazidime-avibactam plus aztreonam
  • Strong recommendation with moderate certainty of evidence 1
  • Associated with significantly lower 30-day mortality (19.2% vs 44%) compared to other active antimicrobials 1
  • Mechanistically sound: aztreonam is not hydrolyzed by metallo-β-lactamases, while avibactam protects aztreonam from other β-lactamases often co-produced by these strains 1

Alternative Option

• Cefiderocol
  • Conditional recommendation with low certainty of evidence 1
  • Shows activity against MBL-producing organisms including NDM 1
  • Clinical cure achieved in 75% of patients with MBL-producing CRE infections in the CREDIBLE-CR study 1
  • Caution: higher MICs against NDM producers have been reported 2

Combination Therapy Considerations

For severe infections or when first-line options are unavailable:

• Triple combination therapy with rifampin-meropenem-colistin

  • Demonstrated synergistic and bactericidal effects against NDM-producing K. pneumoniae in vitro 3
  • Consider when other options are unavailable

• High-dose tigecycline-based combinations

  • May be effective in certain cases where other options have failed 4
  • High-dose regimen (loading dose 200 mg, maintenance 100 mg every 12h) shows lower mortality compared to standard dose 1
  • Not recommended as monotherapy for bloodstream infections due to poor outcomes 5

• Polymyxin (colistin) combinations

  • Addition of polymyxin B to aztreonam plus ceftazidime-avibactam can improve bacterial killing and reduce inflammation 6
  • Consider in severe infections with limited options
  • Monitor renal function closely 1

Implementation Considerations

1. Rapid testing for carbapenemase type

   • Essential to guide appropriate therapy 5
   • Confirm NDM production before initiating targeted therapy

2. Therapeutic drug monitoring (TDM)

   • Recommended when using polymyxins or aminoglycosides 1
   • Helps optimize dosing and minimize toxicity

3. Catheter management

   • Remove infected catheters when possible, especially with MDR gram-negative infections 1

4. Duration of therapy

   • 7-14 days for most infections 1
   • May need extended treatment for complicated infections or persistent bacteremia

Special Considerations

• Renal function

  • Adjust dosing of ceftazidime-avibactam, aztreonam, and polymyxins based on renal function 1
  • Polymyxins should be used cautiously in patients with renal insufficiency

• Treatment failures

  • In cases of treatment failure with ceftazidime-avibactam plus aztreonam, consider adding high-dose tigecycline or polymyxin B 4
  • Some NDM-producing strains may develop resistance to the ceftazidime-avibactam plus aztreonam combination 4

Common Pitfalls to Avoid

1. Monotherapy with agents that lack activity against NDM

   • Carbapenems, ceftazidime-avibactam alone, or meropenem-vaborbactam alone are ineffective against NDM-producing strains

2. Delayed appropriate therapy

   • Inappropriate initial therapy is associated with increased mortality 5
   • Start effective combination therapy promptly while awaiting susceptibility results

3. Inadequate dosing

   • Standard doses may be insufficient for severe infections
   • Consider high-dose regimens when appropriate

4. Overlooking synergistic combinations

   • The efficacy of ceftazidime-avibactam plus aztreonam relies on synergistic activity
   • In vitro susceptibility testing alone may not predict clinical success 7

By following these evidence-based recommendations, clinicians can optimize outcomes when treating these challenging multidrug-resistant infections.