What antibiotics are required for treating carbapenem-resistant Klebsiella (CR-Klebsiella) urinary tract infections (UTIs)?

Treatment of Carbapenem-Resistant Klebsiella UTIs

For carbapenem-resistant Klebsiella urinary tract infections, ceftazidime-avibactam 2.5g IV q8h is the recommended first-line treatment, followed by meropenem-vaborbactam 4g IV q8h or imipenem-cilastatin-relebactam 1.25g IV q6h as alternatives. 1

First-Line Treatment Options

1. Ceftazidime-avibactam

   • Dosage: 2.5g IV q8h infused over 3 hours
   • Mechanism: Novel β-lactam/β-lactamase inhibitor that restores antibacterial activity against Ambler class A (e.g., KPC), class C, and some class D enzymes (e.g., OXA-48)
   • Evidence: Recommended for complicated UTIs caused by carbapenem-resistant Enterobacteriaceae (CRE) 1

2. Meropenem-vaborbactam

   • Dosage: 4g IV q8h infused over 3 hours
   • Mechanism: Carbapenem combined with boron-based β-lactamase inhibitor that inhibits Ambler class A (KPC) and class C β-lactamases
   • Evidence: TANGO-II trial showed increased clinical cure and decreased mortality compared to best available therapy 1

3. Imipenem-cilastatin-relebactam

   • Dosage: 1.25g IV q6h
   • Mechanism: Active against class A carbapenemase and class C cephalosporinase
   • Evidence: Recommended for CRE-UTI based on susceptibility data 1

Alternative Options for Specific Situations

For Lower UTI (Cystitis)

1. Fosfomycin

   • Dosage: 3g oral single dose
   • Evidence: High susceptibility rates (94-98.9%) against CR E. coli and Klebsiella spp. 2
   • Advantages: High urinary concentrations, favorable efficacy ratios 2

2. Aminoglycosides

   • Consider single-dose aminoglycoside for CRE-associated cystitis 1
   • Evidence: Patients treated with aminoglycosides were less likely to fail therapy (adjusted OR for failure 0.34,95% CI 0.15-0.73) 3
   • Note: Gentamicin is indicated for serious UTIs caused by susceptible strains of Klebsiella species 4

3. Nitrofurantoin

   • Consider for CR E. coli (56% susceptibility) but not for Klebsiella spp. 2
   • Limited to lower UTI only due to inadequate tissue penetration

For Severe or Complicated UTIs

1. Polymyxin-based combination therapy

   • Consider for severe infections when newer agents are unavailable
   • Warning: High risk of nephrotoxicity, including acute renal failure and acute tubular necrosis 5
   • Evidence: Colistin-based combination therapy showed lower 30-day mortality compared to monotherapy (35.7% vs 55.5%) 1

2. Plazomicin

   • Novel aminoglycoside stable against aminoglycoside-modifying enzymes
   • Active against KPC and OXA-48 producing CRE
   • Evidence: CARE trial showed numerically fewer deaths and lower acute renal injury compared to colistin-based regimens 1

Treatment Algorithm

1. Assess infection severity:

   • Lower UTI/cystitis vs. complicated UTI/pyelonephritis
   • Presence of sepsis or septic shock
   • Immunocompromised status

2. For severe/complicated UTI:

   • First choice: Ceftazidime-avibactam 2.5g IV q8h
   • Alternatives: Meropenem-vaborbactam 4g IV q8h or imipenem-cilastatin-relebactam 1.25g IV q6h

3. For lower UTI/cystitis:

   • Consider oral options if susceptible: Fosfomycin 3g single dose
   • Alternative: Single-dose aminoglycoside if susceptible
   • For E. coli only: Nitrofurantoin if susceptible

4. For patients with renal impairment:

   • Avoid polymyxins if possible due to nephrotoxicity
   • Adjust dosing of all agents according to creatinine clearance
   • Avoid nitrofurantoin if creatinine clearance <30 mL/min

Important Considerations

• Susceptibility testing is crucial for guiding therapy, as resistance patterns vary
• Combination therapy may be beneficial for severe infections, particularly with polymyxin-based regimens 1
• Monitor renal function closely, especially with polymyxins and aminoglycosides
• Duration of therapy:
  • Lower UTI: 5-7 days
  • Complicated UTI: 7-14 days

Pitfalls and Caveats

1. Resistance development: Emergence of ceftazidime-avibactam resistance has been reported in KPC-producing K. pneumoniae, particularly after prior administration 1

2. Tigecycline limitations: Despite in vitro activity against some CRE, tigecycline has limited efficacy for UTIs due to low urinary concentrations and is associated with higher failure rates (aOR for failure 2.29,95% CI 1.03-5.13) 1, 3

3. Strain-specific outcomes: ST258A strain type is associated with higher clinical failure rates (aOR 5.82,95% CI 1.47-28.50), highlighting the importance of molecular characterization when available 3

4. Asymptomatic bacteriuria: Most patients with CR-Klebsiella in urine (80%) have asymptomatic bacteriuria that doesn't require treatment 6

5. Polymyxin nephrotoxicity: Despite efficacy, polymyxins can cause acute renal failure and should be used cautiously 5