What is the recommended treatment for Carbapenem-Resistant Klebsiella pneumoniae (CRKP) complicated pyelonephritis?

Treatment of Carbapenem-Resistant Klebsiella pneumoniae (CRKP) Complicated Pyelonephritis

Polymyxin-based combination therapy is recommended as the preferred treatment for CRKP complicated pyelonephritis, with the combination agent selected based on susceptibility testing results. 1

First-Line Treatment Options

• Polymyxin (colistin or polymyxin B) combination therapy is recommended over monotherapy for CRKP infections, with 119 fewer treatment failures per 1000 patients compared to monotherapy 1
• The selection of the combination agent should be guided by antimicrobial susceptibility testing results 1
• Common effective combination options include:
  • Polymyxin + aminoglycoside (particularly effective for urinary tract infections) 1
  • Polymyxin + carbapenem (if meropenem MIC ≤8 mg/L for CRE) with extended-infusion of meropenem for 3 hours 1
  • Polymyxin + tigecycline (though tigecycline has limited urinary concentration) 1

Newer Agents (When Available and Susceptible)

• Ceftazidime-avibactam (2.5 g IV q8h) is recommended for CRE infections when the isolate is susceptible 1
• Meropenem-vaborbactam (4 g IV q8h infused over 3 hours) is particularly effective for complicated UTIs including pyelonephritis caused by KPC-producing Enterobacteriaceae 1, 2
• Imipenem-cilastatin-relebactam (1.25 g IV q6h) is recommended for CRE bloodstream infections and may be effective for complicated pyelonephritis 1

Aminoglycoside Considerations

• Aminoglycoside-containing regimens (particularly gentamicin or amikacin) have shown 417 fewer clinical treatment failures per 1000 patients in CRE infections 1
• Aminoglycosides are especially useful for urinary tract infections due to their high urinary concentrations 1, 3
• Therapeutic drug monitoring (TDM) should be performed during aminoglycoside treatment, especially with high doses 1
• Monitor renal function closely and avoid other nephrotoxic drugs when using aminoglycosides 1

Fosfomycin Considerations

• Intravenous fosfomycin-containing combination therapy may be considered when the CRKP isolate is susceptible to fosfomycin or when synergistic effect is demonstrated 1, 4
• Fosfomycin susceptibility rates in CRKP are variable (39-99%) 1, 4
• Patients with hypernatremia, cardiac or renal insufficiency should avoid fosfomycin 1
• For complicated UTIs or pyelonephritis, fosfomycin monotherapy is likely insufficient, and combination therapy should be considered 4

Important Clinical Considerations

• Perform therapeutic drug monitoring (TDM) for polymyxins, aminoglycosides, or carbapenems when treating CRKP infections, especially in critically ill patients 1
• Monitor renal function closely during polymyxin treatment, as nephrotoxicity is a common adverse effect 1
• Avoid combining polymyxins with other nephrotoxic or ototoxic drugs 1
• For polymyxin dosing: 1 million U colistin = 80 mg mass CMS = 33 mg colistin base activity (CBA) 1
• The INCREMENT cohort demonstrated that combination therapy significantly lowered mortality by 44% in patients with CRE bloodstream infections with high-mortality scores 1

Pitfalls to Avoid

• Avoid tigecycline monotherapy for urinary tract infections due to its low urinary concentration 1
• Avoid using beta-lactamase-inducing antibiotics (e.g., cefoxitin, imipenem) concurrently with aztreonam due to potential antagonism 5
• Be aware that baseline renal insufficiency is associated with a 6-fold increase in clinical failure of polymyxin B monotherapy after adjusting for septic shock 6
• Monitor for breakthrough infections with organisms intrinsically resistant to polymyxins during treatment 6
• Consider the risk of developing resistance to polymyxins in subsequent CRKP isolates with prolonged therapy 6, 7