Lecture #120: Pharmacology of Beta-lactam Antibiotics, Other Cell Wall Inhibitors, and Cell Membrane-Active Antibiotics, Part 1: Penicillins & Beta Lactamase Inhibitors

What is the primary mechanism of action of β-lactam antibiotics?

They covalently bind to transpeptidases (penicillin-binding proteins, PBPs), inhibiting the final step of bacterial cell wall synthesis and causing autolysis and cell death.

What structural feature is essential for β-lactam antibiotic activity?

An intact β-lactam ring is required for antibacterial activity; hydrolysis by β-lactamases inactivates the drug.

What are the main pharmacodynamic properties of β-lactam antibiotics?

They are bactericidal and exhibit time-dependent killing, where efficacy is related to the duration that drug concentration remains above the MIC (T>MIC).

What bacterial growth phase is required for β-lactam antibiotics to be effective?

Beta-lactams kill bacteria only when they are actively growing and synthesizing cell walls.

What are the major mechanisms of bacterial resistance to β-lactams?

Production of β-lactamases, modification of PBPs, reduced drug penetration via porin loss, efflux pump expression, and intrinsic resistance in wall-less or intracellular bacteria.

What is the mnemonic for β-lactam resistance mechanisms?

“6 Ps”: Penicillinases, PBPs, Porins, Pumps, Penetration, and Peptidoglycan.

What are Ambler classes of β-lactamases?

Class A, B, C, and D enzymes that differ by mechanism and structure; Class A includes ESBLs and KPCs, Class B are metallo-β-lactamases, Class C are AmpC, and Class D are oxacillinases.

What are β-lactamase inhibitors and why are they important?

They inhibit β-lactamase enzymes that degrade β-lactam antibiotics, restoring antibiotic activity against resistant bacteria.

What are examples of β-lactamase inhibitors?

Irreversible inhibitors: clavulanic acid, sulbactam, tazobactam; reversible inhibitors: avibactam, vaborbactam, relebactam, and durlobactam.

Which β-lactamase inhibitors are effective against Class A and C β-lactamases?

Avibactam, relebactam, vaborbactam, and durlobactam inhibit Class A and some Class C β-lactamases, expanding β-lactam activity.

What is the structure-activity relationship of β-lactam antibiotics?

R-group side chains determine spectrum of action, β-lactamase stability, and pharmacokinetic behavior such as absorption and distribution.

What is the PK-PD profile of β-lactam antibiotics?

Time above MIC (T>MIC) predicts efficacy; higher dosing frequency or continuous infusion maintains concentrations above MIC longer.

What are the subclasses of penicillins?

Natural penicillins, penicillinase-resistant penicillins, aminopenicillins, and antipseudomonal penicillins.

What are the natural penicillins and their uses?

Penicillin G (parenteral) and Penicillin V (oral) treat susceptible gram-positive cocci, anaerobes, and Treponema pallidum; Penicillin G is preferred for syphilis.

What are penicillinase-resistant penicillins used for?

Nafcillin, oxacillin, and dicloxacillin are used to treat infections caused by methicillin-sensitive Staphylococcus aureus (MSSA) and Streptococcus species.

Why are methicillin-resistant Staphylococcus aureus (MRSA) strains resistant to β-lactams?

MRSA expresses a modified PBP2a encoded by the mecA gene, which has low affinity for β-lactam antibiotics.

What are aminopenicillins and their uses?

Ampicillin and amoxicillin have extended spectra covering certain gram-negative bacteria (e.g., E. coli, H. influenzae, Salmonella) and gram-positive pathogens like Listeria monocytogenes.

What is the significance of combining aminopenicillins with β-lactamase inhibitors?

Combinations like amoxicillin-clavulanate and ampicillin-sulbactam restore activity against β-lactamase-producing strains, expanding coverage to resistant gram-negative bacteria.

What are the antipseudomonal penicillins?

Piperacillin (used with tazobactam) and ticarcillin (with clavulanate); piperacillin-tazobactam has the broadest spectrum, including Pseudomonas aeruginosa.

What are key pharmacokinetic features of penicillins?

They are widely distributed in body water but poorly penetrate the CNS unless meninges are inflamed; most are renally excreted except nafcillin and oxacillin (biliary elimination).

What is the major adverse effect of all β-lactam antibiotics?

Hypersensitivity reactions, ranging from rash and urticaria to anaphylaxis; cross-reactivity can occur with other β-lactams due to similar side chains.

What immune mechanism underlies penicillin hypersensitivity?

Penicillins act as haptens, binding to proteins on red blood cells and forming complexes that elicit IgE-mediated allergic responses or hemolytic anemia.

What are other adverse effects of β-lactam antibiotics?

Diarrhea, nausea, Clostridioides difficile-associated colitis, Candida overgrowth (thrush, vaginal yeast infection), and injection site phlebitis.

What is a common non-allergic rash associated with aminopenicillins?

A maculopapular rash, often occurring with viral infections (e.g., mononucleosis) or when given with allopurinol.

What special populations require dose adjustment?

Patients with renal impairment require lower doses; neonates have prolonged half-life due to immature renal function.

Which route of administration should be avoided for β-lactams?

Intrathecal administration, due to risk of CNS irritation, seizures, and arachnoiditis.

What are examples of drug interactions involving β-lactams?

Probenecid inhibits renal tubular secretion, increasing β-lactam plasma levels; antibiotics may reduce oral contraceptive effectiveness by disrupting enterohepatic cycling.

Why should β-lactams not be used to treat viral infections?

They are ineffective against viruses and unnecessary use promotes resistance, adverse effects, and additional cost.

What are the two most common secondary infections from antibiotic use?

Clostridioides difficile infection and Candida overgrowth.

Why is knowledge of normal microbiota important in pharmacology?

Commensal bacteria can become opportunistic pathogens if barriers are breached; understanding flora helps predict infection sources.

What is the general principle for antibiotic selection?

Choose an antibiotic active against the suspected pathogen that achieves therapeutic levels at the infection site without contraindications.

Which penicillin has the broadest spectrum of activity?

Piperacillin-tazobactam, which covers gram-positive, gram-negative, and anaerobic bacteria, including Pseudomonas aeruginosa.

Which penicillin is preferred for Treponema pallidum infections?

Penicillin G (benzathine form), given as a single intramuscular dose for early syphilis.

Which penicillin has 100% oral bioavailability and extended spectrum?

Amoxicillin, which has excellent oral absorption and activity against many gram-negative respiratory pathogens.

Which penicillin is used for Listeria monocytogenes infections?

Ampicillin, often in combination with gentamicin for synergistic bactericidal activity.

Why is understanding β-lactamase classification clinically important?

It helps determine which β-lactam/β-lactamase inhibitor combinations are effective against resistant organisms.