What is the recommended treatment for multidrug-resistant (MDR) Klebsiella pneumoniae infection?

Treatment of Multidrug-Resistant Klebsiella pneumoniae Infections

For multidrug-resistant (MDR) Klebsiella pneumoniae infections, ceftazidime-avibactam is recommended as first-line therapy for susceptible isolates, with treatment selection guided by antimicrobial susceptibility testing. 1, 2

Initial Management Approach

• Infectious disease consultation is highly recommended for all MDR Klebsiella pneumoniae infections (Strong recommendation, low quality of evidence) 2
• Antimicrobial susceptibility testing is essential to guide appropriate antibiotic selection 2, 1
• Molecular characterization of resistance mechanisms (e.g., KPC, NDM, OXA-48) should be performed when available to optimize therapy 2

First-Line Treatment Options Based on Resistance Mechanism

For KPC-producing K. pneumoniae:

• Ceftazidime-avibactam 2.5g (ceftazidime 2g/avibactam 0.5g) IV q8h infused over 2 hours 3, 2
• Meropenem-vaborbactam 4g IV q8h (for susceptible isolates) 2, 1

For OXA-48-producing K. pneumoniae:

• Ceftazidime-avibactam 2.5g IV q8h 2, 1

For MBL-producing K. pneumoniae (NDM, VIM, IMP):

• Ceftazidime-avibactam plus aztreonam combination therapy 1, 4
• Polymyxin-based combination therapy with one or more active agents 2

Treatment by Infection Site

Bloodstream Infections:

• Ceftazidime-avibactam 2.5g IV q8h 2, 5
• Alternative: Polymyxin-based combination therapy with carbapenem for CRE-BSI 2

Complicated Urinary Tract Infections:

• Ceftazidime-avibactam 2.5g IV q8h 3, 2
• Alternatives:
  • Meropenem-vaborbactam 4g IV q8h 2
  • Imipenem-cilastatin-relebactam 1.25g IV q6h 2
  • Plazomicin 15 mg/kg IV q12h for susceptible isolates 2

Complicated Intra-abdominal Infections:

• Ceftazidime-avibactam 2.5g IV q8h plus metronidazole 3, 2
• Alternative: Tigecycline 100mg IV loading dose then 50mg IV q12h 2

Hospital-acquired/Ventilator-associated Pneumonia:

• Ceftazidime-avibactam 2.5g IV q8h 3
• Alternative: Meropenem-vaborbactam (better lung penetration) 1

Duration of Therapy

• Bloodstream infections: 10-14 days 1
• Complicated UTI: 7-14 days 3
• Complicated intra-abdominal infections: 5-14 days 3
• Hospital-acquired/ventilator-associated pneumonia: 7-14 days 3

Clinical Evidence Supporting Recommendations

Ceftazidime-avibactam has demonstrated excellent activity against KPC-producing K. pneumoniae with clinical cure rates of 70.1% in patients with MDR infections 5. In vitro studies show MIC50/90 values of 0.5/2 μg/ml with 96.6% of MDR isolates inhibited at the FDA breakpoint 6.

Case reports have documented successful treatment of recurring KPC-producing K. pneumoniae infections using ceftazidime-avibactam, even in patients who failed previous combination therapies 7, 8.

Important Considerations and Pitfalls

• Resistance development: Resistance to ceftazidime-avibactam can emerge during treatment, particularly with KPC-3 variants. Monitor clinical response and consider repeat cultures if improvement is not observed 2

• Metallo-β-lactamases (MBL): Ceftazidime-avibactam alone is NOT active against MBL-producing strains (NDM, VIM, IMP). For these isolates, combination with aztreonam is necessary 4

• Dosage adjustment: Modify dosing based on renal function to prevent treatment failure and resistance development 3

• Combination therapy: For severe infections or high-resistance settings, combination therapy with more than one active agent may be beneficial 2

• Prolonged infusion: Consider extended infusion of β-lactams for pathogens with high MICs 2

By following these evidence-based recommendations and considering the specific resistance mechanisms and infection sites, clinicians can optimize treatment outcomes for patients with MDR K. pneumoniae infections.