Beta-Lactam Antibiotics
Beta-lactam antibiotics inhibit bacterial cell wall synthesis by irreversibly binding penicillin-binding proteins, causing osmotic lysis.
Overview
Beta-lactam antibiotics are the largest and most widely used class of antibiotics. Their defining feature is the beta-lactam ring, which inhibits bacterial transpeptidases (penicillin-binding proteins, PBPs) that cross-link peptidoglycan chains in the bacterial cell wall. Inhibition leads to cell wall weakness and osmotic lysis in growing bacteria.
Mechanism of Action
Beta-lactams mimic the D-Ala-D-Ala terminus of peptidoglycan precursors, binding covalently to PBPs and inhibiting transpeptidation (cross-linking). Cell wall integrity fails, causing lysis. Beta-lactams are bactericidal and time-dependent (efficacy depends on T>MIC).
Penicillins
- Natural penicillins (penicillin G/V): Gram-positive cocci (streptococci), syphilis, enterococci. Penicillin G IV for meningococcal meningitis, syphilis, endocarditis.
- Anti-staphylococcal penicillins (nafcillin, oxacillin, dicloxacillin): MSSA infections; bulky side chain protects against staphylococcal beta-lactamase.
- Aminopenicillins (amoxicillin, ampicillin): Extended gram-negative coverage (H. influenzae, E. coli, Listeria). Often combined with beta-lactamase inhibitors (amoxicillin-clavulanate).
- Antipseudomonal penicillins (piperacillin-tazobactam): Broad-spectrum including Pseudomonas, Bacteroides; used for empiric hospital-acquired infections.
Cephalosporins
Successive generations expand gram-negative coverage and reduce gram-positive activity:
- 1st gen (cefazolin): Gram-positive, MSSA; surgical prophylaxis
- 2nd gen (cefuroxime, cefoxitin): Added gram-negative (Enterobacteriaceae), anaerobes (cefoxitin)
- 3rd gen (ceftriaxone, cefotaxime, ceftazidime): Broad gram-negative including Neisseria meningitidis; ceftazidime adds Pseudomonas
- 4th gen (cefepime): Gram-negative including Pseudomonas + gram-positive (less MRSA)
- 5th gen (ceftaroline): MRSA activity (binds PBP2a)
Carbapenems and Monobactams
Carbapenems (meropenem, imipenem, ertapenem) are the broadest-spectrum beta-lactams, covering ESBL-producing gram-negatives, anaerobes, and most gram-positives (not MRSA). Reserved for MDR organisms. Imipenem is metabolized by renal dehydropeptidase; formulated with cilastatin (inhibitor) to prevent nephrotoxicity.
Aztreonam (monobactam) covers only gram-negative aerobes; safe in penicillin-allergic patients with true IgE-mediated allergy (cross-reactivity ~1-2%).
Resistance
Beta-lactamase production (hydrolysis of the beta-lactam ring) is the primary resistance mechanism. Extended-spectrum beta-lactamases (ESBLs) and carbapenemases (KPC, NDM, OXA) represent escalating resistance threats.
Key Takeaways
- Beta-lactams inhibit PBPs, preventing peptidoglycan cross-linking; bactericidal, time-dependent killing
- Cephalosporin generations progressively expand gram-negative coverage; ceftaroline covers MRSA
- Carbapenems are last-resort agents for ESBL and MDR gram-negative infections
- Beta-lactamase inhibitor combinations (amoxicillin-clavulanate, piperacillin-tazobactam) restore activity against producers