What is the role of avibactam (a beta-lactamase inhibitor) in treating bacterial infections?

Role of Avibactam in Treating Bacterial Infections

Avibactam is a potent non-β-lactam β-lactamase inhibitor that significantly enhances the efficacy of partner antibiotics against multidrug-resistant Gram-negative bacteria, particularly those producing extended-spectrum β-lactamases (ESBLs), AmpC enzymes, and Klebsiella pneumoniae carbapenemases (KPCs). It plays a crucial role in overcoming bacterial resistance mechanisms that would otherwise render β-lactam antibiotics ineffective.

Mechanism of Action and Spectrum of Activity

• Avibactam is a synthetic non-β-lactam β-lactamase inhibitor that covalently bonds to β-lactamases, preventing them from inactivating partner antibiotics 1
• It effectively inhibits Ambler class A (including ESBLs and KPCs), class C (AmpC), and some class D (OXA-48-like) β-lactamases 2
• Unlike older β-lactamase inhibitors (clavulanic acid, sulbactam, tazobactam), avibactam has expanded activity against a broader range of β-lactamases 3, 4
• Avibactam does not inhibit class B metallo-β-lactamases (MBLs) such as NDM, VIM, or IMP 2

FDA-Approved Indications

When combined with ceftazidime (as AVYCAZ), avibactam is FDA-approved for:

• Complicated intra-abdominal infections (cIAI), used in combination with metronidazole 2
• Complicated urinary tract infections (cUTI), including pyelonephritis 2
• Hospital-acquired bacterial pneumonia and ventilator-associated bacterial pneumonia (HABP/VABP) 2

Clinical Applications in Resistant Infections

Treatment of ESBL-Producing Enterobacteriaceae

• Ceftazidime-avibactam is highly effective against ESBL-producing Enterobacteriaceae that would otherwise be resistant to ceftazidime alone 5, 1
• In settings with high ESBL prevalence, ceftazidime-avibactam provides a carbapenem-sparing option, helping to reduce selective pressure for carbapenem resistance 6
• The addition of avibactam to ceftazidime results in 4-1024-fold reduction in minimum inhibitory concentrations (MICs) against most Enterobacteriaceae species 1

Treatment of Carbapenem-Resistant Enterobacteriaceae (CRE)

• For KPC-producing CRE infections, ceftazidime-avibactam is recommended as a first-line treatment option with strong recommendation and moderate certainty of evidence 6
• For OXA-48-like-producing CRE, ceftazidime-avibactam is also effective, though with lower certainty of evidence 6
• For MBL-producing CRE (e.g., NDM, VIM), ceftazidime-avibactam plus aztreonam is strongly recommended as the preferred treatment 6
• In a study of patients with bloodstream infections caused by MBL-producing CRE, ceftazidime-avibactam plus aztreonam showed significantly lower 30-day mortality (19.2%) compared to other regimens (44%) 6

Treatment of Pseudomonas aeruginosa Infections

• Avibactam improves the activity of ceftazidime against Pseudomonas aeruginosa, including some multidrug-resistant strains, with approximately 4-fold reduction in MICs 1
• Ceftazidime-avibactam may be valuable for treating infections caused by difficult-to-treat P. aeruginosa 6

Limitations and Considerations

• Avibactam does not improve activity against Acinetobacter species or most anaerobic bacteria 1
• Avibactam is not active against metallo-β-lactamases (MBLs), limiting its use as monotherapy for infections caused by MBL-producing organisms 2
• Resistance to ceftazidime-avibactam can emerge, particularly through mutations in KPC enzymes or through other resistance mechanisms 4
• Avibactam is primarily renally excreted, requiring dose adjustment in patients with renal impairment 2

Combination Therapy vs. Monotherapy

• There is insufficient evidence to make strong recommendations for or against using ceftazidime-avibactam as monotherapy versus combination therapy 6
• Some studies suggest no difference in outcomes between monotherapy and combination therapy for most infections 6
• However, combination therapy may be beneficial in specific scenarios such as severe lower respiratory tract infections, particularly ventilator-associated pneumonia 6

Role in Antimicrobial Stewardship

• Ceftazidime-avibactam and other avibactam combinations represent important carbapenem-sparing options in settings with high carbapenem resistance rates 6
• Carbapenem-sparing treatment is strongly recommended in settings with high incidence of carbapenem-resistant K. pneumoniae to reduce selective pressure 6
• Avibactam-containing combinations should be used judiciously to preserve their effectiveness and prevent development of resistance 4

Future Developments

• Aztreonam-avibactam is a promising combination for treating infections caused by carbapenem-resistant Enterobacteriaceae, including MBL producers 7
• Other avibactam combinations (with ceftaroline, aztreonam) are being investigated to address specific resistance patterns 5

In conclusion, avibactam represents a significant advancement in combating antimicrobial resistance, particularly against ESBL and carbapenemase-producing Gram-negative bacteria. Its strategic use as part of combination therapy provides effective treatment options for infections with limited alternatives while supporting antimicrobial stewardship efforts to preserve the effectiveness of carbapenems.