Monobactams / beta-lactamase inhibitors

I. Introduction

Monobactams combined with beta-lactamase inhibitors represent a specialized subclass of beta-lactam antibiotics, designed to target Gram-negative bacterial infections, including those caused by extended-spectrum beta-lactamase (ESBL)-producing and carbapenem-resistant Enterobacteriaceae (CRE). This subclass offers a strategic solution to the increasing threat of antimicrobial resistance by restoring or enhancing the activity of monobactams against resistant pathogens.

Monobactams, particularly aztreonam, are characterized by their monocyclic beta-lactam ring, in contrast to the bicyclic structure found in penicillins, cephalosporins, and carbapenems. Alone, aztreonam is vulnerable to hydrolysis by metallo-beta-lactamases (MBLs) and some serine beta-lactamases. However, when paired with beta-lactamase inhibitors (e.g., avibactam), these combinations become potent against multi-drug resistant Gram-negative bacteria, including MBL-expressing strains.

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II. Components of the Class

A. Monobactam Agent

• Aztreonam

  • First and only monobactam approved for clinical use

  • Active primarily against Gram-negative aerobic bacteria (e.g., Pseudomonas aeruginosa, Enterobacteriaceae)

  • No activity against Gram-positive organisms or anaerobes

  • Resistant to most serine beta-lactamases, but hydrolyzed by MBLs

B. Beta-lactamase Inhibitors (Used in Combination)

• Avibactam (a non-beta-lactam diazabicyclooctane [DBO] inhibitor)

• Vaborbactam (cyclic boronic acid derivative; not yet used with aztreonam)

• Relebactam (another DBO inhibitor)

• Zidebactam (a novel PBP2 inhibitor with dual action)

• Nacubactam (DBO class)

• Enmetazobactam, Tazobactam, and Clavulanic acid have little effect on MBLs, so less commonly paired

Only aztreonam/avibactam has shown promising efficacy against MBL-producing organisms, making it a key investigational or compassionate-use therapy in areas with high antimicrobial resistance.

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III. Mechanism of Action

A. Aztreonam

• Binds to penicillin-binding protein 3 (PBP3) in susceptible Gram-negative bacteria

• Inhibits bacterial cell wall synthesis → leads to lysis and death (bactericidal)

• Stable against hydrolysis by most class A and C beta-lactamases, but susceptible to class B (MBLs)

B. Beta-lactamase Inhibitors

• Inhibit specific beta-lactamase enzymes that degrade aztreonam

• Avibactam inhibits class A (KPC), class C (AmpC), and some class D enzymes

• Does not inhibit class B (metallo-beta-lactamases) directly, but protects aztreonam from co-produced class A or D enzymes

C. Combination Strategy

• Aztreonam/Avibactam combination restores aztreonam activity against organisms co-producing MBLs and serine beta-lactamases

• Aztreonam resists MBLs → avibactam inhibits other beta-lactamases → synergy

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IV. Clinical Indications

Infection Type	Utility of Monobactam/BLI Combination
Complicated UTIs	CRE and MBL-producing E. coli, Klebsiella
Hospital-acquired pneumonia (HAP/VAP)	Effective against resistant Gram-negative rods
Intra-abdominal infections	When MDR organisms are present
Bloodstream infections (BSI/sepsis)	Especially those caused by MBL-producing Enterobacteriaceae
Cystic fibrosis-associated infections	P. aeruginosa in CF patients (aztreonam alone or in combo)

V. Available Combinations and Developmental Agents

1. Aztreonam/Avibactam (Investigational as of 2024)

• Phase 3 trials completed (REVISIT, ALLIUM, REJUVENATE)

• Developed by Pfizer/AstraZeneca

• Proposed indications: cUTI, cIAI, HAP/VAP, bacteremia

• Administered IV

• Expected to be a game-changer for MBL-mediated resistance

2. Aztreonam + Ceftazidime/Avibactam (off-label combo)

• Co-administration of separately approved drugs (not co-formulated)

• Strategy: aztreonam resists MBLs, ceftazidime-avibactam inhibits other enzymes

• Used in compassionate settings or MDR outbreak management

3. Aztreonam/Nacubactam, Aztreonam/Zidebactam (preclinical/clinical development)

• Advanced investigational therapies

• Show enhanced PBP inhibition and beta-lactamase inhibition

• Goal: broaden aztreonam spectrum and overcome resistance

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VI. Pharmacokinetics and Administration

A. Aztreonam

• Route: Intravenous (IV), Intramuscular (IM), Inhalation (for CF)

• Bioavailability (IV): 100%

• Protein binding: ~56-60%

• Half-life: ~1.7 hours (prolonged in renal impairment)

• Renal excretion: ~70-80% unchanged

• Dosing adjustment required in renal insufficiency

B. Beta-lactamase Inhibitors (e.g., Avibactam)

• IV administration

• Dose matched with companion beta-lactam

• Renal excretion; dose adjustment required in renal dysfunction

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VII. Spectrum of Activity

Pathogen	Aztreonam Alone	Aztreonam/Avibactam
E. coli, K. pneumoniae (non-ESBL)	✓	✓
ESBL-producing Enterobacteriaceae	±	✓
Carbapenem-resistant Enterobacteriaceae	×	✓
Pseudomonas aeruginosa	✓	✓
Acinetobacter baumannii	×	×
Anaerobes	×	×
Gram-positives	×	×

✓ = active; × = not active; ± = variable depending on beta-lactamase expression

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VIII. Adverse Effects

System	Potential Adverse Effects
Gastrointestinal	Nausea, vomiting, diarrhea, pseudomembranous colitis
Dermatologic	Rash, pruritus, urticaria
Hematologic	Eosinophilia, neutropenia, thrombocytopenia
Renal	Elevated creatinine, nephrotoxicity (rare)
Hepatic	Elevated liver enzymes
Local	Injection site pain, thrombophlebitis
Hypersensitivity	Cross-reactivity with other beta-lactams is low (~1%)

IX. Contraindications and Precautions

• Known hypersensitivity to aztreonam or avibactam

• Use caution in patients with a history of severe allergic reactions to beta-lactams

• Adjust dose in renal impairment

• Avoid unnecessary use in infections where Gram-positive/anaerobic coverage is needed

• Monitor for signs of superinfection with prolonged use

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X. Drug Interactions

Interacting Agent	Effect / Concern
Probenecid	May increase aztreonam levels (renal clearance reduction)
Other nephrotoxic drugs	Additive nephrotoxicity (e.g., aminoglycosides)
Valproate (with Avibactam)	Decreased valproate levels → seizure risk
Live vaccines (oral typhoid)	Avoid during antibiotic therapy

XI. Advantages of Monobactam/BLI Combinations

• Selective Gram-negative activity (sparing gut flora from collateral damage)

• No Gram-positive or anaerobic activity – ideal for de-escalation

• Low cross-allergenicity with penicillins/cephalosporins

• Aztreonam stable against MBLs, providing a unique treatment option

• Enhanced efficacy when paired with advanced BLIs

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XII. Limitations and Considerations

• Lack of activity against Gram-positives and anaerobes

• Cost and availability may limit use

• Formulary restrictions in some hospitals

• Investigational status of aztreonam/avibactam in many countries

• Emergence of resistance during therapy possible; use stewardship principles

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XIII. Stewardship and Clinical Use

• Reserve for confirmed or suspected MDR infections, particularly MBL-producing Gram-negatives

• Use susceptibility testing to guide therapy

• Consider combination therapy in critical illness (e.g., with colistin or tigecycline)

• Monitor closely for resistance development during treatment

• Avoid empirical use unless strong suspicion of target pathogens