β-lactams
Summary
β-lactams are a major class of antibiotics characterized by a core β-lactam ring, which inhibits bacterial cell wall synthesis by binding penicillin-binding proteins (PBPs). This class includes penicillins, cephalosporins, carbapenems, and monobactams. Resistance commonly arises via bacterial β-lactamase enzymes that hydrolyze the ring.
Detail
β-lactams work by mimicking the D-Ala-D-Ala terminus of peptidoglycan precursors, allowing them to bind and inhibit transpeptidases (penicillin-binding proteins, PBPs) that cross-link peptidoglycan strands in the bacterial cell wall. This inhibition prevents proper cell wall synthesis, leading to osmotic instability and bacterial lysis, particularly effective against actively dividing bacteria. β-lactams are bactericidal.
Major subclasses: - Penicillins (e.g., penicillin G/V, ampicillin, amoxicillin, nafcillin, piperacillin): vary in spectrum; natural penicillins target gram-positive cocci and spirochetes; aminopenicillins extend to some gram-negatives; antistaphylococcal penicillins resist penicillinase; antipseudomonal penicillins cover Pseudomonas. - Cephalosporins (1st–5th generation): increasing gram-negative coverage with each generation; 5th generation (ceftaroline) covers MRSA. - Carbapenems (imipenem, meropenem, ertapenem): broadest spectrum, reserved for severe/multidrug-resistant infections; imipenem given with cilastatin to prevent renal inactivation. - Monobactams (aztreonam): gram-negative only, safe in penicillin-allergic patients, no cross-reactivity.
Clinical significance: - Resistance mechanisms: β-lactamase production (penicillinase, extended-spectrum β-lactamases [ESBLs], carbapenemases), altered PBPs (e.g., MRSA's PBP2a, Streptococcus pneumoniae resistance), decreased permeability, efflux pumps. - Combination with β-lactamase inhibitors (clavulanic acid, sulbactam, tazobactam) restores efficacy against β-lactamase-producing organisms. - Hypersensitivity reactions range from mild rash to anaphylaxis; cross-reactivity between penicillins and cephalosporins is low (~1-2%) but historically overestimated. - Adverse effects: GI upset, interstitial nephritis, hemolytic anemia (direct Coombs positive), seizures at high doses (especially imipenem), Jarisch-Herxheimer reaction when treating syphilis. - Mechanism exploited clinically: synergy with aminoglycosides (cell wall disruption enhances aminoglycoside entry) is used in treating enterococcal endocarditis.
High-yield board associations: MRSA and penicillin-resistant pneumococcus due to altered PBPs; Pseudomonas coverage requires specific penicillins/cephalosporins/carbapenems; renal dosing adjustments needed since most are renally excreted; probenecid can prolong penicillin half-life by blocking renal tubular secretion.
Sources
- First Aid for the USMLE Step 1
- Katzung's Basic & Clinical Pharmacology
- Sketchy Pharm
- Goodman & Gilman's The Pharmacological Basis of Therapeutics
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