What is the recommended treatment for carbapenem‑resistant Klebsiella pneumoniae infection in hospitalized adults?

Treatment of Carbapenem-Resistant Klebsiella pneumoniae (CRKP)

For hospitalized adults with CRKP infection, initiate ceftazidime-avibactam 2.5g IV every 8 hours (infused over 3 hours) as first-line monotherapy for non-severe infections, or combine with a second active agent for critically ill patients with septic shock or high APACHE scores. 1

First-Line Treatment Options

Preferred Agents for KPC-Producing CRKP

• Ceftazidime-avibactam 2.5g IV every 8 hours (3-hour infusion) is the primary first-line option, achieving 81.6% clinical success in complicated intra-abdominal infections and reducing 28-day mortality to 18.3% versus 40.8% with other agents. 1, 2

• Meropenem-vaborbactam 4g IV every 8 hours provides equivalent efficacy and is specifically preferred for pneumonia due to superior epithelial lining fluid penetration, with concentrations remaining several-fold higher than the MIC90 of KPC-producing isolates. 1

• Imipenem-cilastatin-relebactam 1.25g IV every 6 hours serves as an alternative when first-line agents are unavailable or contraindicated. 1

Critical Diagnostic Step

• Obtain rapid molecular testing immediately to identify the specific carbapenemase type (KPC versus OXA-48 versus MBL), as each confers different susceptibility profiles requiring distinct treatment strategies. 1

• KPC remains the most common carbapenemase (47.4%), followed by MBLs (20.6%) and OXA-48-like enzymes (19.0%). 1

Special Resistance Scenarios

Metallo-β-Lactamase (MBL) Producers

• For MBL-producing strains, use ceftazidime-avibactam 2.5g IV every 8 hours PLUS aztreonam as the combination shows 70-90% efficacy where other options fail. 1, 2

• This combination reduces 30-day mortality (HR 0.37,95% CI 0.13-0.74) in prospective studies. 1

OXA-48-Like Producers

• Ceftazidime-avibactam should be first-line treatment for OXA-48-like producing CRE. 1

Combination Therapy Indications

When to Use Combination Therapy

• Mandatory combination of ≥2 in-vitro active agents for patients with septic shock, bloodstream infections with high APACHE III scores, or critically ill ICU patients reduces 30-day mortality (adjusted HR 0.56,95% CI 0.34-0.91). 1, 3

• Combination therapy is particularly important when using polymyxin or tigecycline-based regimens. 2

Effective Combination Regimens

• High-dose extended-infusion meropenem (6g/day as 3-hour infusions) plus polymyxin is effective when meropenem MIC is ≤8-16 mg/L, showing lower 14-day mortality compared to non-carbapenem combinations. 1, 2

• Double-carbapenem therapy (ertapenem plus another carbapenem) may be considered when options are limited, with in vitro synergy demonstrated in 78.6% of isolates, though clinical evidence remains limited. 1, 4

Treatment Duration by Infection Site

• Bloodstream infections: 7-14 days 1
• Complicated urinary tract infections: 5-7 days 1
• Complicated intra-abdominal infections: 5-7 days 1
• Hospital-acquired/ventilator-associated pneumonia: 10-14 days 1

Therapeutic Drug Monitoring (TDM)

• Perform TDM whenever feasible for narrow therapeutic index drugs including polymyxins, aminoglycosides, and carbapenems in critically ill patients or those with renal dysfunction. 2, 1

• Monitor renal function closely throughout polymyxin treatment and avoid concomitant nephrotoxic or ototoxic medications. 1

• Use prolonged infusion (3 hours) for all β-lactams when treating high-MIC pathogens to maximize time above MIC and optimize pharmacodynamics. 1

Critical Pitfalls to Avoid

• Colistin monotherapy shows poor efficacy with approximately 33% mortality and <70% clinical/microbiological response, and should only be used in combination for severe infections. 1

• Ceftazidime-avibactam resistance emergence occurs in 0-12.8% of KPC-producing isolates during treatment, especially with prior exposure; if resistance develops, switch to meropenem-vaborbactam. 1

• Inadequate empirical antimicrobial therapy independently predicts 14-day mortality (OR 1.48,95% CI 1.01-2.18). 3

• Time to active antibiotic therapy influences outcomes in critically ill patients with KPC-producing K. pneumoniae bloodstream infections. 1

Infection Control Measures

• Place all patients with CRE on contact precautions and implement aggressive infection control strategies including hand hygiene reinforcement and patient cohorting. 2

• Perform active surveillance cultures of patients with epidemiologic links to persons from whom CRE have been recovered. 2

• Infectious disease consultation is highly recommended for all CRKP infections. 1