What is the drug of choice for treating pan-resistant Klebsiella (carbapenem-resistant Klebsiella pneumoniae)?

Drug of Choice for Pan-resistant Klebsiella pneumoniae

For pan-resistant Klebsiella pneumoniae (carbapenem-resistant Klebsiella pneumoniae), ceftazidime-avibactam is the first-line treatment option, particularly for KPC-producing strains, while ceftazidime-avibactam plus aztreonam is recommended for MBL-producing strains. 1

Treatment Selection Based on Carbapenemase Type

KPC-producing Carbapenem-resistant K. pneumoniae

• Ceftazidime-avibactam or meropenem-vaborbactam should be the first-line treatment options 1
• These newer β-lactam/β-lactamase inhibitor combinations have demonstrated superior clinical outcomes compared to traditional antibiotic regimens 1
• Ceftazidime-avibactam has shown favorable results in several observational studies with higher clinical success rates compared to other regimens 1
• Meropenem-vaborbactam demonstrated higher clinical cure rates and decreased mortality compared to best available therapy in the TANGO II study 1

OXA-48-like Producing Carbapenem-resistant K. pneumoniae

• Ceftazidime-avibactam should be the first-line treatment option 1
• Limited clinical data are available, but promising results have been observed in comparative studies where OXA-48 was the predominant carbapenemase 1

MBL-producing Carbapenem-resistant K. pneumoniae (NDM, VIM)

• Ceftazidime-avibactam plus aztreonam is the recommended combination 1
• This combination has demonstrated efficacy against MBL-producing strains in observational studies 1
• MBLs can hydrolyze all β-lactams except monobactams (aztreonam), making this combination particularly effective 1

Alternative Treatment Options

For KPC-producing strains when first-line options are unavailable:

• Imipenem-relebactam or cefiderocol may be considered as alternatives 1
• Tigecycline is a viable option due to its favorable in vitro activity against carbapenemase-producing Enterobacteriaceae 1
• Polymyxins (colistin) and fosfomycin, often in combination therapy, may be used as last-resort options 1

For extremely resistant cases:

• Combination therapy may be necessary, particularly for severe infections 1
• High-dose extended-infusion meropenem-polymyxin combination therapy may be effective when MICs are ≤16 mg/L 1
• Fosfomycin-containing combination therapies have shown promising results in observational studies 1

Important Clinical Considerations

Dosing and Administration

• For adults, ceftazidime-avibactam is dosed at 2.5 grams (ceftazidime 2 grams and avibactam 0.5 grams) every 8 hours by IV infusion over 2 hours 2
• Dose adjustment is required for patients with renal impairment 2
• Therapeutic drug monitoring should be considered for narrow therapeutic index drugs like polymyxins and aminoglycosides 1

Efficacy and Safety

• Ceftazidime-avibactam has demonstrated clinical and microbiological responses even in critically ill patients with XDR or PDR K. pneumoniae infections 3
• The combination appears to be well-tolerated without significant adverse events 3, 4
• In vitro studies show that ceftazidime-avibactam lowers MICs by a median of 512-fold against KPC-producing K. pneumoniae 5

Resistance Concerns

• KPC-3 variants may have higher MICs to ceftazidime-avibactam compared to KPC-2 variants 5
• Resistance to ceftazidime-avibactam in KPC-producing isolates has been reported (0% to 12.8%) 1
• Mutations in the blaKPC-3 gene (D179Y variants) can confer resistance to ceftazidime-avibactam 1

Carbapenem-Sparing Strategies

• Extended use of carbapenems should be limited to preserve their activity and prevent emergence of carbapenem-resistance 1
• Carbapenem-sparing strategies are desirable in settings with high prevalence of carbapenem-resistant strains 1
• Novel β-lactam/β-lactamase inhibitor combinations (ceftazidime-avibactam, ceftolozane-tazobactam) are valuable for treating MDR gram-negative infections while preserving carbapenems 1

Source Control

• Effective source control is essential alongside appropriate antimicrobial therapy 1
• Surgical or radiological drainage of collections and removal of infected devices are crucial components of treatment 1
• Accurate surgical source control may allow for reduced antibiotic usage and increased effectiveness 1