Treatment of Klebsiella pneumoniae After Failure of Meropenem and Ceftazidime-Avibactam
For Klebsiella pneumoniae infections that have failed both meropenem and ceftazidime-avibactam, the next antibiotic choice depends critically on the carbapenemase type: for metallo-β-lactamase (MBL)-producing strains, use ceftazidime-avibactam plus aztreonam; for KPC-producing strains with ceftazidime-avibactam resistance, use meropenem-vaborbactam or cefiderocol; for OXA-48-like producers, consider cefiderocol. 1
Critical First Step: Identify the Carbapenemase Type
- Rapid molecular testing to identify the specific carbapenemase mechanism is essential before selecting salvage therapy, as each enzyme class requires a different treatment strategy 1, 2
- The three main carbapenemase classes in Klebsiella pneumoniae are:
Treatment Algorithm Based on Carbapenemase Type
For MBL-Producing Klebsiella pneumoniae (NDM, VIM, IMP)
Primary Recommendation:
- Ceftazidime-avibactam 2.5g IV every 8 hours PLUS aztreonam is the strongly recommended first-line therapy 1, 2
- This combination showed 30-day mortality of 19.2% versus 44% with other regimens (colistin, tigecycline, fosfomycin) in bloodstream infections 1
- The combination works because aztreonam is stable against MBLs, while ceftazidime-avibactam inhibits co-produced ESBLs and AmpC enzymes that would otherwise inactivate aztreonam 1, 3, 4
Alternative Option:
- Cefiderocol may be used as an alternative, with clinical cure rates of 75% in MBL-producing CRE infections 1
- Recent data shows 70.8% clinical cure rates and 12.5% 28-day mortality with cefiderocol against MBL-producers 1
Avoid:
- Do not use colistin-containing regimens as they showed the highest mortality rates in MBL infections 1
For KPC-Producing Klebsiella pneumoniae with Ceftazidime-Avibactam Resistance
Primary Recommendation:
- Meropenem-vaborbactam 4g IV every 8 hours (infused over 3 hours) is the preferred option 1, 2
- KPC variants (particularly D179Y mutations in blaKPC-3) that confer ceftazidime-avibactam resistance often remain susceptible to meropenem-vaborbactam 1
- Meropenem-vaborbactam showed higher clinical cure rates and decreased mortality compared to best available therapy in the TANGO II trial 1
Alternative Option:
- Cefiderocol can be considered for KPC-producing strains resistant to ceftazidime-avibactam 1
Combination Strategy (if monotherapy fails):
- Ceftazidime-avibactam plus meropenem showed remarkable synergistic activity in vitro and in vivo against KPC-producing strains, even those with elevated MICs 5, 6, 7
- This combination restored susceptibility to both partnering antibiotics and prevented emergence of resistance mutations 6
- Consider this combination particularly when ceftazidime-avibactam MICs are near the susceptibility breakpoint (≥8/4 mg/L) 5
For OXA-48-Like Producing Klebsiella pneumoniae
Primary Recommendation:
- Cefiderocol should be considered as the first-line option 1
- Limited clinical data exists for OXA-48 producers, but ceftazidime-avibactam showed promising results in small observational studies 1
Site-Specific Considerations
For Pneumonia
- Meropenem-vaborbactam is preferred due to superior lung penetration, with epithelial lining fluid concentrations 63% for meropenem and 65% for vaborbactam, remaining several-fold higher than MIC90 1
For Bloodstream Infections
- Avoid tigecycline due to low serum concentrations and poor outcomes in bacteremia 1, 2
- Time to active antibiotic therapy critically influences outcomes in critically ill patients with bloodstream infections 1, 2
For Urinary Tract Infections (Non-severe)
- Aminoglycosides (including plazomicin) are suggested over tigecycline for complicated UTIs caused by CRE 1
Combination Therapy Considerations
- For severe infections with limited options, combination therapy with more than one in vitro active drug is suggested when only polymyxins, aminoglycosides, tigecycline, or fosfomycin are available 1
- Fosfomycin-containing combinations showed reduced mortality (RR 0.55) compared to other regimens in CRKP infections, though evidence quality is very low 1
- Therapeutic drug monitoring (TDM) should be performed when using polymyxins, aminoglycosides, or carbapenems, especially in critically ill patients 1
Critical Pitfalls to Avoid
- Never delay appropriate therapy while awaiting susceptibility results; empiric therapy should be based on local epidemiology and rapid molecular diagnostics 1, 2
- Avoid tigecycline monotherapy for bloodstream infections and pneumonia due to poor outcomes 1, 2
- Do not use carbapenem-based combinations unless meropenem MIC is ≤8 mg/L with high-dose extended-infusion dosing 1
- Resistance to ceftazidime-avibactam ranges from 0-12.8% in KPC-producing isolates and can emerge during therapy, necessitating alternative strategies 1