Treatment of Carbapenem-Resistant Klebsiella pneumoniae
For carbapenem-resistant Klebsiella pneumoniae infections, ceftazidime-avibactam 2.5g IV q8h or meropenem-vaborbactam 4g IV q8h should be used as first-line therapy, with strong recommendation and moderate certainty of evidence. 1, 2, 3
First-Line Treatment Options
Novel β-Lactam Agents (Preferred)
Ceftazidime-avibactam 2.5g IV q8h infused over 3 hours is the primary first-line option for KPC-producing carbapenem-resistant K. pneumoniae, with clinical success rates of 81.6% in complicated intra-abdominal infections and 70.1% combined clinical/microbiological cure in complicated urinary tract infections. 1, 4
Meropenem-vaborbactam 4g IV q8h is equally effective as first-line therapy and may be preferred for pneumonia due to superior epithelial lining fluid penetration (63% for meropenem, 65% for vaborbactam), with higher clinical cure rates and decreased mortality compared to traditional therapies. 2, 3
Imipenem-cilastatin-relebactam 1.25g IV q6h is an alternative when first-line options are unavailable (conditional recommendation, low certainty). 1, 2
Site-Specific Treatment Duration
Bloodstream infections: 7-14 days of appropriate therapy, with longer courses (14-21 days) for complicated bacteremia with metastatic foci. 2, 3
Complicated urinary tract infections: 5-7 days of treatment. 2
Complicated intra-abdominal infections: 5-7 days of treatment. 2
Hospital-acquired/ventilator-associated pneumonia: 10-14 days of treatment. 2
Combination Therapy Considerations
For severe CRKP infections with high mortality risk, combination therapy with two or more in vitro active antibiotics is recommended, with adjusted hazard ratio of 0.56 (95% CI 0.34-0.91) for lower 14-day mortality compared to monotherapy. 2
Monotherapy with newer agents (ceftazidime-avibactam, meropenem-vaborbactam) is sufficient for non-severe infections. 2
Polymyxin-based combination therapy is recommended for bloodstream infections due to CRE when newer agents are unavailable, though this carries weak recommendation with very low quality evidence. 1
Special Resistance Scenarios
MBL-Producing Strains
- For metallo-β-lactamase (MBL)-producing strains, the combination of ceftazidime-avibactam plus aztreonam is recommended with 70-90% efficacy, as MBLs hydrolyze all β-lactams except monobactams and are not inhibited by classic serine β-lactamase inhibitors. 1, 2
Ceftazidime-Avibactam Resistance Emergence
Ceftazidime-avibactam resistance can emerge in 0-12.8% of KPC-producing isolates during treatment, often with restoration of carbapenem susceptibility due to KPC mutations (such as KPC-48 variant with L169P-A172T). 2, 5, 6
When ceftazidime-avibactam resistance emerges with restored carbapenem susceptibility, carbapenem-based combination therapy (imipenem-cilastatin or meropenem with tigecycline and/or aminoglycoside) can be used, though clinical cure rates are only 62.5% with 50% all-cause mortality. 5, 6
Critical Diagnostic Requirements
Rapid molecular testing should be obtained immediately to identify specific carbapenemase types (KPC vs OXA-48 vs MBL) to guide appropriate therapy, as each class confers different susceptibility profiles requiring distinct treatment strategies. 1, 2, 3
KPC remains the most common carbapenemase (47.4%), followed by MBLs (20.6%) and OXA-48-like β-lactamases (19.0%). 1
Time from blood culture collection to active antibiotic therapy initiation influences outcomes in critically ill patients with KPC-producing K. pneumoniae bloodstream infections. 1
Alternative Agents (When First-Line Options Unavailable)
Cefiderocol may be considered as an alternative (conditional recommendation, low certainty), though increased all-cause mortality was observed in critically ill patients with carbapenem-resistant Gram-negative infections compared to best available therapy (24.8% vs 18.4% at Day 28). 1, 7
Tigecycline 100mg IV loading dose then 50mg IV q12h is recommended for complicated intra-abdominal infections caused by CRE, but is NOT recommended as monotherapy for pneumonia. 1
Critical Pitfalls to Avoid
Traditional carbapenems are generally not effective against KPC-producing organisms and should not be used as monotherapy unless susceptibility is confirmed and resistance emergence is monitored. 8
Colistin monotherapy has shown poor efficacy and unfavorable toxicity profiles compared to newer agents, with approximately one in three patients dying and <70% achieving clinical/microbiological response. 1
In high-risk patients (acute myeloid leukemia, neutropenia) colonized with CRKP, initial adequate antibiotic therapy is the only independent factor protecting against death (p=0.02), making empiric coverage with CRKP-active agents critical in febrile neutropenia. 9
Infectious disease consultation is highly recommended in the management of all MDRO infections. 1
Prolonged infusion of β-lactams is recommended for pathogens with high minimum inhibitory concentrations. 1