What is the recommended treatment approach for Carbapenem-Resistant Enterobacteriaceae (CRE) infections using clavulanic acid and Aztreonam, according to Infectious Diseases Society of America (IDSA) guidelines?

From the Guidelines

The IDSA guidelines recommend combination therapy for Carbapenem-Resistant Enterobacteriaceae (CRE) infections, with a preferred regimen of ceftazidime/avibactam plus aztreonam, as it has shown in vitro synergy and improved clinical outcomes, including lower 30-day mortality rates, compared to other treatment options 1.

Key Considerations

• The combination of ceftazidime/avibactam and aztreonam is particularly effective against metallo-β-lactamase (MBL) producing CRE, which are increasingly reported worldwide 1.
• Aztreonam is not hydrolyzed by MBLs, while ceftazidime/avibactam inhibits other β-lactamases that might otherwise compromise aztreonam's effectiveness, creating a synergistic combination against these highly resistant pathogens 1.
• The use of clavulanic acid with aztreonam is not the preferred regimen, as the evidence supports the use of ceftazidime/avibactam with aztreonam for the treatment of MBL-producing CRE infections 1.

Treatment Approach

• The typical regimen involves ceftazidime/avibactam plus aztreonam, with the specific dosing and duration of treatment depending on the infection site and severity, as well as susceptibility testing results 1.
• For severe infections, this combination should be part of a broader multi-drug regimen that may include agents like polymyxins (colistin), tigecycline, or aminoglycosides based on susceptibility testing 1.
• Monitoring for adverse effects, particularly renal function with certain combination agents, is essential, and treatment duration typically ranges from 7-14 days depending on infection site and severity, with longer courses for complicated infections 1.

Evidence Summary

• A recent observational study including patients with bloodstream CRE infection caused by MBL-producing CRE showed that 30-day mortality was significantly lower in patients treated with ceftazidime/avibactam plus aztreonam compared to patients who received other antibiotics active in vitro, including colistin, tigecycline, and fosfomycin (19.2% vs. 44%; P = 0.007) 1.
• The combination of ceftazidime/avibactam and aztreonam has been shown to have in vitro synergy and improved clinical outcomes, including lower 30-day mortality rates, compared to other treatment options 1.

From the FDA Drug Label

To reduce the development of drug-resistant bacteria and maintain the effectiveness of AZACTAM (aztreonam for injection, USP) and other antibacterial drugs, AZACTAM should be used only to treat or prevent infections that are proven or strongly suspected to be caused by susceptible bacteria AZACTAM is indicated for the treatment of the following infections caused by susceptible Gram-negative microorganisms: Certain antibiotics (eg, cefoxitin, imipenem) may induce high levels of beta-lactamase in vitro in some Gram-negative aerobes such as Enterobacter and Pseudomonas species, resulting in antagonism to many beta-lactam antibiotics including aztreonam.

The FDA drug label does not answer the question.

From the Research

IDSA Guidelines on Treatment of CRE with Clavulanic Acid and Aztreonam

• The Infectious Diseases Society of America (IDSA) guidelines for the treatment of Carbapenem-Resistant Enterobacteriaceae (CRE) infections do not specifically recommend the use of clavulanic acid and Aztreonam as a first-line treatment option 2, 3, 4.
• However, studies have shown that the combination of Aztreonam and amoxicillin-clavulanate has synergistic activity against Enterobacteriaceae-producing class B and/or class D carbapenemases with or without extended-spectrum β-lactamases 5.
• Another study found that the combination of Aztreonam and amoxicillin/clavulanic acid has a synergistic effect against metallo-β-lactamase-producing CR-GNOs, especially Enterobacteriaceae spp. isolates that coproduce ESBLs 6.
• The IDSA guidelines suggest that treatment options for CRE infections are limited and that optimization of dosing regimens and combination therapy are additional treatment strategies being explored 2, 3, 4.
• New antibiotics, such as ceftazidime/avibactam and meropenem/vaborbactam, have shown promise in treating CRE infections, but the development of resistance is a concern 2, 4.

Treatment Approaches

• The combination of Aztreonam and amoxicillin-clavulanate may be considered as an unconventional treatment option for infections due to carbapenemase- and ESBL-producing Enterobacteriaceae 5.
• High-dose and combination strategies that may include new β-lactam/β-lactamase inhibitors should be considered in severe CRE infections to maximize treatment success 2.
• Polymyxins, tigecycline, and aminoglycosides are still important options for low-risk patients with susceptible CRE infections, but also for high-risk patients in regions where metallo-β-lactamase-producing CRE predominate 4.