What are beta-lactam (β-lactam) antibiotics?

What Are Beta-Lactam Antibiotics?

Beta-lactam antibiotics are a large family of antimicrobial agents characterized by a beta-lactam ring structure that exert their bactericidal effect by inhibiting bacterial cell wall synthesis through binding to penicillin-binding proteins (PBPs). 1, 2

Structural Characteristics

• All beta-lactam antibiotics contain a four-membered beta-lactam ring as their core structural feature, which is essential for their antimicrobial activity 2, 3
• The beta-lactam ring binds to and inhibits penicillin-binding proteins (PBPs) in the bacterial cell wall, preventing the final step of peptidoglycan synthesis 4, 1
• This mechanism produces autolysis and bacterial cell death, making beta-lactams bactericidal agents 1

Major Classes of Beta-Lactam Antibiotics

Beta-lactams encompass several distinct structural classes, each with different spectra of activity:

Penicillins

• Include penicillin G, ampicillin, amoxicillin, and extended-spectrum penicillins like piperacillin 1, 5
• Amoxicillin is the most active oral beta-lactam against streptococci, including pneumococci, due to its intrinsic activity and excellent bioavailability 1
• Penicillin G has a relative pro-convulsive activity of 100 (used as the reference standard) 1

Cephalosporins

• Include multiple generations: cefazolin, cefuroxime, ceftriaxone, ceftazidime, cefepime, and others 1, 5
• Cephalosporins are inherently less active than penicillin/amoxicillin against S. pneumoniae, with baseline MICs typically fourfold higher 1
• Cefazolin has the highest seizure risk among beta-lactams with a relative pro-convulsive activity of 294 1, 6
• Cefepime has the second highest seizure risk at 160 relative pro-convulsive activity 1, 6
• Cefoxitin has the lowest seizure risk at only 1.8 relative pro-convulsive activity 1, 6, 7

Carbapenems

• Include imipenem, meropenem, and ertapenem 5, 3
• Meropenem has a relative pro-convulsive activity of 16, making it significantly less neurotoxic than many other beta-lactams 1, 6
• Carbapenems have the broadest spectrum of activity among beta-lactams and are reserved for serious infections 4, 3
• Patients with penicillin or cephalosporin allergy histories can receive carbapenems without prior testing, as long as the reaction was not a severe delayed cutaneous or organ-involved reaction 1

Monobactams

• Aztreonam is the only clinically available monobactam 1, 3
• Aztreonam has a relative pro-convulsive activity of 42 1
• There is no cross-reactivity for IgE- or T-cell-mediated hypersensitivity between penicillin and aztreonam, except for ceftazidime due to shared R1 side chain 1
• Patients who are penicillin- and cephalosporin-allergic may safely receive aztreonam without prior testing, except those confirmed allergic to ceftazidime 1

Pharmacodynamic Properties

• Beta-lactams exhibit time-dependent killing with relatively slow bactericidal action that is independent of plasma concentration 4
• The key pharmacodynamic parameter is the percentage of time that free drug concentrations remain above the minimum inhibitory concentration (fT>MIC) 1
• Target concentrations should maintain free plasma concentrations at least 4 times the MIC, though avoiding exceeding 8 times the MIC to prevent neurotoxicity 1

Clinical Utility

• Beta-lactams are the most widely used and extensively prescribed antimicrobial class globally 8, 3
• They have little toxicity and a broad therapeutic margin 4
• Penicillin remains the treatment of choice for numerous classic infections 4
• Cephalosporins are widely used in surgical prophylaxis and severe community-acquired infections 4
• Carbapenems are the choice for mixed nosocomial and multiresistant bacterial infections 4

Important Safety Considerations

Neurotoxicity Risk

• Renal failure is the main risk factor for beta-lactam neurotoxicity due to drug accumulation 1, 6
• Neurological manifestations may include acute confusional state, encephalopathy, myoclonus, seizures, and status epilepticus 1
• Specific toxic thresholds exist: cefepime >22 mg/L (trough) or >35 mg/L (steady-state), meropenem >64 mg/L (trough), piperacillin >360 mg/L without tazobactam or >157 mg/L with tazobactam 1

Hypersensitivity

• Serious and occasionally fatal anaphylactic reactions have been reported with beta-lactams 9
• These reactions are more likely in individuals with a history of sensitivity to multiple allergens 9
• Severe cutaneous adverse reactions (Stevens-Johnson syndrome, toxic epidermal necrolysis, DRESS) have been reported 9

Resistance Mechanisms

• The primary resistance mechanism is bacterial production of beta-lactamase enzymes that hydrolyze the beta-lactam ring 8, 2, 3
• Beta-lactamase inhibitors (such as clavulanate, tazobactam, sulbactam) are combined with beta-lactams to overcome this resistance 8, 2, 3