Beta-lactamase inhibitors

Beta-lactamase inhibitors (BLIs) are a critical adjunct class of agents used in combination with beta-lactam antibiotics to combat bacterial resistance. These agents function by inhibiting bacterial enzymes—beta-lactamases—that would otherwise hydrolyze and inactivate the beta-lactam ring essential to the antibiotic's mechanism of action. Their role is particularly significant in the treatment of infections caused by beta-lactamase–producing organisms, including multidrug-resistant (MDR) Gram-negative bacteria.

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1. Background and Rationale

Beta-lactam antibiotics (penicillins, cephalosporins, carbapenems, monobactams) exert their antibacterial activity by binding to penicillin-binding proteins (PBPs) and inhibiting bacterial cell wall synthesis. However, bacteria have developed beta-lactamase enzymes that hydrolyze the beta-lactam ring, rendering the antibiotic ineffective.

Beta-lactamase inhibitors:

• Do not have significant antibacterial activity on their own (except for avibactam and relebactam)

• Are co-administered with beta-lactam agents to restore or expand their activity

• Protect the beta-lactam component from enzymatic degradation

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2. Classification of Beta-Lactamase Inhibitors

BLIs are grouped based on chemical structure and enzyme inhibitory profile:

A. Classical (older) inhibitors – beta-lactam core:

• Clavulanic acid

• Sulbactam

• Tazobactam

B. Non-beta-lactam inhibitors – diazabicyclooctane (DBO) or boronic acid derivatives:

• Avibactam (DBO)

• Relebactam (DBO)

• Vaborbactam (cyclic boronic acid)

• Zidebactam (DBO; under investigation)

• Enmetazobactam (DBO; newer agent)

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3. Mechanism of Action

Beta-lactamase inhibitors function by binding to the active site of beta-lactamase enzymes, either reversibly or irreversibly, and preventing the hydrolysis of beta-lactam antibiotics.

Types of beta-lactamase enzymes:

• Class A: ESBLs (e.g., TEM, SHV, CTX-M), KPC (Klebsiella pneumoniae carbapenemase)

• Class B: Metallo-beta-lactamases (e.g., NDM, VIM, IMP) – not inhibited by current BLIs

• Class C: AmpC beta-lactamases – resistant to older BLIs, inhibited by avibactam, relebactam

• Class D: Oxacillinases (e.g., OXA-type carbapenemases)

Spectrum of inhibition:

Inhibitor	Class A	Class B	Class C	Class D
Clavulanic acid	Yes	No	Weak	No
Sulbactam	Yes	No	No	Weak
Tazobactam	Yes	No	Weak	No
Avibactam	Yes	No	Yes	Some
Relebactam	Yes	No	Yes	No
Vaborbactam	Yes	No	Yes	No

4. Approved Beta-Lactam/BLI Combinations

Combination	Brand Name	Partner Antibiotic	Spectrum	Indications
Amoxicillin + Clavulanate	Augmentin	Penicillin	Broad-spectrum β-lactamase	RTIs, UTIs, SSTIs, otitis media
Ampicillin + Sulbactam	Unasyn	Penicillin	Broad-spectrum β-lactamase	Intra-abdominal, gynecologic infections
Piperacillin + Tazobactam	Zosyn	Antipseudomonal penicillin	Pseudomonas, anaerobes, ESBLs	Nosocomial infections, sepsis
Ceftazidime + Avibactam	Avycaz	3rd-gen cephalosporin	KPC, ESBLs, AmpC	CRE infections, complicated UTI/IAI
Imipenem + Relebactam	Recarbrio	Carbapenem	KPC, AmpC	Resistant Gram-negatives
Meropenem + Vaborbactam	Vabomere	Carbapenem	KPC-producing Enterobacterales	cUTIs, CRE
Cefepime + Zidebactam	(Investigational)	4th-gen cephalosporin	MDR Gram-negatives	Under development

5. Clinical Indications

Beta-lactam/BLI combinations are used in the treatment of infections caused by beta-lactamase–producing organisms, including:

• Urinary tract infections (complicated and uncomplicated)

• Respiratory tract infections (e.g., CAP, HAP/VAP)

• Intra-abdominal infections (e.g., diverticulitis, peritonitis)

• Skin and soft tissue infections

• Bone and joint infections

• Sepsis and bloodstream infections

• Infections due to multidrug-resistant Gram-negative bacteria (CRE, ESBL, KPC)

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6. Resistance Mechanisms

Resistance to BLIs may occur through:

• Production of metallo-beta-lactamases (e.g., NDM) – unaffected by current BLIs

• Overexpression or mutation of beta-lactamase genes

• Porin loss reducing antibiotic uptake

• Efflux pump overexpression

• Biofilm formation

• Target modification (e.g., altered PBPs)

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7. Adverse Effects

Common:

• Diarrhea

• Nausea

• Vomiting

• Rash

• Injection site reactions (IV forms)

Serious:

• Clostridioides difficile infection (CDI)

• Hypersensitivity reactions (e.g., anaphylaxis, urticaria)

• Liver enzyme elevation

• Thrombocytopenia or neutropenia (rare)

Specific Notes:

• Piperacillin/tazobactam can cause hypokalemia

• Avibactam combinations may lead to seizures (with ceftazidime in renal impairment)

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8. Contraindications

• Known hypersensitivity to beta-lactams or beta-lactamase inhibitors

• History of severe allergic reactions (e.g., Stevens–Johnson syndrome)

• Hepatic dysfunction (caution with clavulanate)

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9. Precautions

• Monitor renal function (dose adjustment for combinations like Avycaz, Vabomere)

• Hepatic function tests in prolonged use (especially with clavulanate)

• Consider resistance testing in CRE infections before initiating therapy

• Pregnancy Category B for most agents but limited data for newer combinations

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10. Drug Interactions

• Methotrexate: Increased toxicity with beta-lactams

• Oral contraceptives: May reduce efficacy with amoxicillin/clavulanate

• Allopurinol: Increased rash risk with ampicillin

• Probenecid: Decreases renal excretion of penicillins

• Anticoagulants: Warfarin’s effect may be enhanced (especially with tazobactam)

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11. Summary of Key BLIs

Inhibitor	Partner Antibiotics	Targets	Notes
Clavulanate	Amoxicillin	Class A β-lactamases	Oral; oldest agent
Sulbactam	Ampicillin	Class A, some Class D	Injectable; some intrinsic activity
Tazobactam	Piperacillin	Class A	Injectable; high activity vs ESBLs
Avibactam	Ceftazidime	Class A, C, some D	Broadest of all approved inhibitors
Relebactam	Imipenem	Class A, C	Used for MDR Gram-negatives
Vaborbactam	Meropenem	Class A	No activity vs MBLs

12. Emerging and Investigational BLIs

• Zidebactam + Cefepime – promising activity against CRE, Pseudomonas

• Nacubactam – in combination with meropenem

• Enmetazobactam – paired with cefepime; FDA fast track

• Taniborbactam – a boronate BLI targeting class A, C, D, and even some class B enzymes (in late-stage trials)