What are the antibiotic choices for treating carbapenem (Carbapenam)-resistant Enterobacteriaceae (CRE) infections?

Antibiotic Choices for Carbapenem-Resistant Enterobacteriaceae (CRE) Infections

For CRE infections, ceftazidime-avibactam 2.5 g IV every 8 hours infused over 3 hours is the preferred first-line treatment, particularly for KPC and OXA-48 producers, with meropenem-vaborbactam 4 g IV every 8 hours or imipenem-cilastatin-relebactam 1.25 g IV every 6 hours as equally effective alternatives. 1, 2

First-Line Treatment Selection Based on Carbapenemase Type

The carbapenemase type fundamentally determines optimal therapy, and rapid molecular testing should be performed immediately to guide treatment selection. 1, 2

For KPC-Producing CRE (Most Common Globally)

• Ceftazidime-avibactam 2.5 g IV every 8 hours (infused over 2-3 hours) is the preferred agent, demonstrating significantly higher microbiological eradication and clinical cure rates compared to traditional regimens. 1, 3
• Meropenem-vaborbactam 4 g IV every 8 hours (infused over 3 hours) is equally effective and may be preferred for pneumonia due to superior lung penetration. 1, 2
• Imipenem-cilastatin-relebactam 1.25 g IV every 6 hours is an additional first-line option with 83.8% susceptibility rates against CRE. 1

For OXA-48-Like Producing CRE

• Ceftazidime-avibactam 2.5 g IV every 8 hours remains the first-line choice, as avibactam inhibits Class D β-lactamases. 1, 4, 3

For Metallo-β-Lactamase (MBL) Producers (NDM, VIM, IMP)

• Mandatory combination therapy: Ceftazidime-avibactam 2.5 g IV every 8 hours PLUS aztreonam is required, as avibactam lacks activity against Class B enzymes but protects aztreonam from co-produced ESBLs. 2, 4
• This combination reduces 30-day mortality from 44% to 19.2% compared to other active agents. 2

Combination Therapy Strategies

When to Use Combination Therapy

Polymyxin-based combination therapy should be used for severe CRE infections with sepsis or septic shock, as it reduces mortality from 55.5% to 35.7% (OR 0.46,95% CI 0.30-0.69) compared to monotherapy. 1, 2, 5

The most effective combinations include:

• Colistin plus tigecycline (most commonly used combination for CRE bloodstream infections). 1
• Colistin plus carbapenem (particularly for high INCREMENT-CPE mortality scores). 1
• Aminoglycoside-containing combinations reduce clinical treatment failures by 417 per 1000 patients compared to non-aminoglycoside combinations. 1, 2

Colistin Dosing

For patients with normal renal function: loading dose of 300 mg colistimethate sodium (9 MU) infused over 0.5-1 hour, followed by maintenance dose of 300-360 mg CMS (9-10.9 MU) divided in two doses. 1

Important Caveat on Combination Therapy

For newer β-lactam/β-lactamase inhibitors (ceftazidime-avibactam, meropenem-vaborbactam), routine combination therapy is NOT recommended for uncomplicated CRE infections, as studies show no mortality benefit over monotherapy except in severely ill patients. 1, 4

Alternative and Salvage Options

Tigecycline

• High-dose tigecycline (loading dose 200 mg, maintenance 100 mg every 12 hours) in combination therapy reduces mortality (OR 0.44,95% CI 0.30-0.66) compared to standard dosing. 1
• Tigecycline is only appropriate when MIC ≤0.5 mg/L and should be used in combination, not as monotherapy. 1

Aminoglycosides

• Amikacin or gentamicin-containing combinations are recommended for patients without contraindications, with therapeutic drug monitoring essential. 1, 2
• Single-dose aminoglycoside is an alternative for uncomplicated CRE urinary tract infections, as urinary concentrations remain therapeutic for days. 1, 4

High-Dose Extended-Infusion Carbapenems

• Meropenem may be considered when MICs are ≤8 mg/L, typically in combination therapy. 2, 6

Treatment Duration

• Bloodstream infections: 7-14 days after source control and clinical improvement. 2, 5
• Complicated urinary tract infections: 7-14 days individualized to clinical response. 4, 3
• Complicated cases with endocarditis or persistent bacteremia: 4-6 weeks. 5

Critical Pitfalls to Avoid

Never Use These Approaches:

• Never use tigecycline monotherapy for CRE bloodstream infections due to poor plasma concentrations and documented treatment failures. 1, 2, 4
• Never use ceftazidime-avibactam monotherapy for MBL producers, as avibactam completely lacks activity against Class B metallo-β-lactamases. 2, 4
• Never combine amikacin with colistin due to extreme synergistic nephrotoxicity. 5
• Never use tigecycline for meningitis due to poor CSF penetration. 2
• Never use first or second-generation cephalosporins against Enterobacter species due to intrinsic resistance. 4

Monitoring Requirements

• Therapeutic drug monitoring (TDM) is mandatory for polymyxins, aminoglycosides, and high-dose carbapenems when available. 1, 2
• Follow-up blood cultures at 48-72 hours after starting therapy to detect persistent bacteremia. 5
• Monitor for nephrotoxicity with polymyxins and aminoglycosides through serial creatinine measurements. 1, 2

Special Considerations for Specific Infection Sites

Urinary Tract Infections

• Plazomicin 15 mg/kg IV every 12 hours is specifically approved for complicated UTI due to CRE. 4
• Single-dose aminoglycosides achieve sufficient urinary concentrations for simple cystitis. 4

Pneumonia

• Meropenem-vaborbactam is preferred over ceftazidime-avibactam due to better lung tissue penetration. 2

Catheter-Related Bloodstream Infections

• Immediate catheter removal is mandatory for successful treatment, as antibiotic therapy alone results in 5-fold higher treatment failure rates. 5