What is the approach to treating carbapenem-resistant Enterobacteriaceae (CRE) infections?

Treatment Approach to Carbapenem-Resistant Enterobacteriaceae (CRE)

Ceftazidime-avibactam 2.5 g IV every 8 hours infused over 3 hours is the preferred first-line treatment for CRE infections, particularly for KPC and OXA-48 producers. 1, 2, 3

Initial Assessment and Carbapenemase Typing

Determine the carbapenemase type (KPC, NDM, OXA-48, etc.) whenever possible to guide optimal therapy. 2 This is critical because treatment selection differs substantially:

• KPC producers: Ceftazidime-avibactam is first-line 3
• OXA-48-like producers: Ceftazidime-avibactam remains effective 3
• Metallo-β-lactamase (MBL) producers: Mandatory combination therapy with ceftazidime-avibactam PLUS aztreonam is required, as avibactam lacks activity against Class B enzymes 3, 2

Perform susceptibility testing immediately to guide therapy, especially for determining MICs to carbapenems. 2

First-Line Treatment Options (in order of preference)

For KPC and OXA-48 Producers:

1. Ceftazidime-avibactam 2.5 g IV every 8 hours (infused over 3 hours) 1, 2, 3

   • Treatment duration: 7-14 days for bloodstream infections, individualized based on clinical response 2, 3
   • Adjust dose for renal impairment 2

2. Meropenem-vaborbactam 4 g IV every 8 hours (infused over 3 hours) 1, 2, 3

   • Particularly effective for KPC producers 4
   • May be preferred for pneumonia due to better lung penetration 3

3. Imipenem-cilastatin-relebactam 1.25 g IV every 6 hours 1, 2, 3

   • Requires dose adjustment based on creatinine clearance in renal dysfunction 3

For Metallo-β-Lactamase Producers:

Ceftazidime-avibactam 2.5 g IV every 8 hours PLUS aztreonam is the preferential choice, with significantly lower 30-day mortality (19.2% vs 44%) compared to other active antimicrobial agents. 2 Never use ceftazidime-avibactam monotherapy for MBL producers. 3

Combination Therapy for Severe Infections

For severe CRE infections with sepsis or septic shock, polymyxin-based combination therapy is recommended, as it reduces mortality compared to monotherapy (35.7% vs 55.5%). 1, 5, 3

Polymyxin-Based Regimen:

• Colistin loading dose: 300 mg CMS (9 million units) IV infused over 0.5-1 hour 1, 5
• Maintenance dose: 300-360 mg CMS (9-10.9 million units) IV divided in two doses 1, 5
• Combined with tigecycline: 100 mg IV loading dose, then 50 mg IV every 12 hours 2

The most frequently prescribed combinational agent for CRE bloodstream infections is tigecycline. 1 However, combination antimicrobial therapy must be based on susceptibility testing results. 1, 5

Aminoglycoside-Containing Combinations:

Combination therapies containing amikacin or other aminoglycosides are suggested for CRE infections in patients without contraindications. 1 Aminoglycoside-containing combination therapy showed 417 fewer clinical treatment failures per 1000 patients compared to combinations without aminoglycosides. 1

• Monitor closely for nephrotoxicity and ototoxicity 1, 5
• Avoid other nephrotoxic drugs in the combination regimen 1, 5
• Perform therapeutic drug monitoring (TDM) when available, especially with high doses 1, 5
• CRE isolates show significantly higher susceptibility to amikacin than gentamicin 1

Alternative Strategies When New Agents Unavailable

High-Dose Carbapenem Strategy:

Consider high-dose extended-infusion meropenem when MICs are ≤8 mg/L. 2 Double carbapenem therapy (typically ertapenem plus another carbapenem) may be considered for highly resistant strains when other options are limited, with observational studies suggesting improved survival in patients with invasive KPC infections. 2

Carbapenem-Sparing Approach:

In settings with high incidence of carbapenem-resistant K. pneumoniae, carbapenem-sparing treatment should be recommended to reduce selective pressure. 1 Inappropriate use of carbapenems should be avoided to reduce their association with the increase in CRE. 1

Critical Pitfalls to Avoid

• Never use tigecycline monotherapy for CRE bloodstream infections - it has poor plasma concentrations and performs poorly in bacteremic patients, with much higher risk of failing to clear bacteremia 1, 5, 3
• Avoid tigecycline for meningitis - it has poor CSF penetration 5
• Do not use ceftazidime-avibactam monotherapy for MBL producers - avibactam lacks activity against Class B enzymes 3
• Avoid first or second-generation cephalosporins against Enterobacteriaceae due to intrinsic resistance 3

Site-Specific Considerations

Bloodstream Infections:

• Treatment duration: 7-14 days, individualized based on clinical response 2, 3
• Avoid tigecycline monotherapy; use newer β-lactam/β-lactamase inhibitors or combination therapy 3

Respiratory Tract Infections:

• Ceftazidime-avibactam 2.5 g IV every 8 hours with prolonged infusion (3 hours) is preferred 2
• Meropenem-vaborbactam may be preferred due to better lung penetration 3
• Treatment duration: typically 7 days for uncomplicated cases 3

Urinary Tract Infections:

• Single-dose aminoglycosides can be considered as alternative for complicated UTI 3

Intra-Abdominal Infections:

• Ceftazidime-avibactam combined with metronidazole may be valuable for treating infections caused by Gram-negative MDROs 1

Monitoring and Follow-Up

• Perform therapeutic drug monitoring (TDM) for polymyxins, aminoglycosides, and carbapenems when available 5
• Follow-up cultures are recommended in case of treatment failure to detect resistance development 2
• Monitor for nephrotoxicity with polymyxins and aminoglycosides 1, 5
• Ensure source control as a priority to optimize outcomes and shorten antibiotic treatment durations 2