25. Antimicrobial Drugs - INH Cell Wall Synth

What is the final step in bacterial cell wall synthesis and why is it important?

Transpeptidation: cross-linking of peptidoglycan (PPG) strands for structural integrity of the cell wall.

How do penicillins and cephalosporins inhibit cell wall synthesis?

They mimic the PPG strand terminus and bind to penicillin-binding proteins (PBPs), blocking transpeptidation → weak cell wall → bacterial lysis.

What is the effect of blocking PBPs on bacteria?

Creates a structurally weakened cell wall, oddly shaped bacteria, and ultimately cell death (bactericidal).

Why must bacteria be actively growing for β-lactam antibiotics to work?

Active cells constantly synthesize new peptidoglycan and transport it to the cell envelope; β-lactams only act during this process.

How does resistance to β-lactams develop?

Through production of β-lactamase enzymes, which inactivate β-lactams antibiotics by opening the β-lactam ring. 

What is penicillin and what is it typically used against?

It is a mold that is the DOC for syphilis. 

What is amoxicillin (amoxil)?

A aminopenicillin that affects most gram + and some gram - (E. coli and H. influenzae). It is deactivated by penicillinase. 

What is Augmentin?

A combination of amoxicillin and clavulanate (a beta-lactamase inhibitor) to protect penicillins from inactivation. 

What are the major clinical indications for penicillins?

• Pneumonia

• Meningitis

• Endocarditis

• Syphilis (Is the DOC for it)

• Acute oral infections (e.g., amoxicillin)

How are most penicillins absorbed and excreted?

• Excreted renally via tubular secretion (except nafcillin, which is hepatic).

• Absorption impaired by food, except amoxicillin, which is acid-stable and can be taken with food.

What is Probenecid (Benemid)?

It is a drug that blocks penicillins from being excreted by tubular secretion.

What are the adverse reactions to penicillin?

• Hypersensitivity (potentail for anaphylaxis 0.05%)/allergic manifestation

• GI upset with oral medications

• Diarrhea

• Secondary infections

• Topical (ocular) synthetic penicillins can result in itching & redness

What is MRSA and why is it clinically important?

Methicillin-Resistant Staphylococcus aureus is a strain of S. aureus resistant to many antibiotics, including methicillin and most β-lactams. It is a major cause of nosocomial infections.

What are common risk factors for MRSA infection?

Most MRSA infections occur after invasive procedures or device use, such as surgeries, IV tubing, or artificial joints.

Why does penicillin work better on Gram-positive bacteria than Gram-negative?

• Gram-positive: Thick peptidoglycan layer, no outer membrane → PBPs easily accessible → penicillin inhibits transpeptidation effectively.

• Gram-negative: Outer membrane acts as a barrier; PBPs are harder to reach and β-lactamases in periplasm degrade penicillin.

What is the mechanism of action of cephalosporins?

• Same as penicillins: bind to penicillin-binding proteins (PBPs) at the active site of transpeptidase enzyme.

• This blocks cross-linking of peptidoglycan strands → weak cell wall → lysis and death.

• Bactericidal and effective only on actively growing bacteria.

What makes cephalosporins clinically useful?

• Better CNS penetration 

• Broad-spectrum, well tolerated, easy to administer

• Bactericidal

What is Cephalexin (Keflex)?

A first generation Cephalosporin. Good against Gram +, but sensitive to beta-lactamases.

What is Cefdinir (Omnicef)?

A 3rd generation cephalosporin that is broad spectrum and resistant to beta-lactamases.

What is Ceftaroline?

A 5th gen cephalosporin. Active against MRSA and gram + bacteria.

What is the most common adverse reaction to cephalosporins?

• Allergy, similar to penicillins

• Anti-vitamin K effect → bleeding risk

• Local irritation → pain after IM injection

• Diarrhea

• Seizures at high doses, especially for patients with kidney disease

What is the structure and resistance profile of monobactams?

• Monocyclic β-lactam ring

• Highly resistant to β-lactamases

What is the spectrum of activity of monobactams?

• Narrow spectrum

• Active only against aerobic Gram-negative bacteria (e.g., Neisseria, Pseudomonas)

• High affinity for PBP-3 of Gram-negative organisms

• Poor activity against Gram-positive and anaerobes

Name a specific monobactam drug and its clinical uses.

• Aztreonam (Azactam)

• Used for pneumonia, meningitis, and sepsis

• Safe in penicillin-allergic patients

What are the adverse effects of aztreonam?

• Rash

• Liver function abnormalities

What are carbapenems and what makes them unique among β-lactams?

• Class of β-lactam antibiotics

• Broadest spectrum and greatest potency of all β-lactams

• Inhibit β-lactamase enzymes, making them highly resistant to degradation

Name a common carbapenems and their key features.

Imipenem: Hydrolyzed by renal dipeptidase and must be given with cilastatin. (Primaxin IV)

Why is cilastatin co-administered with imipenem?

Cilastatin inhibits renal dipeptidase, preventing imipenem breakdown and reducing toxic metabolite formation.

What are the main indications for carbapenems?

Severe infections resistant to other drugs.

What is the mechanism of action of glycopeptide antibiotics?

They bind to peptidoglycan precursors, preventing assembly and cross-linking → weak cell wall → bactericidal.

What are the main clinical uses of glycopeptides like vancomycin?

• MRSA infections

• Enterococcal infections resistant to β-lactams

• Infections in β-lactam–allergic patients

Why are glycopeptides not absorbed orally?

They have poor lipophilicity, so systemic absorption is minimal; oral use is only for GI infections (C. difficile).

Why does vancomycin only treat Gram-positive infections?

It cannot cross the outer membrane of Gram-negative bacteria, so it is effective only against Gram-positive organisms.

How is vancomycin administered and why?

IV route for systemic infections due to poor GI absorption.

What causes vancomycin resistance?

Alteration of the NAM side chain in peptidoglycan prevents vancomycin binding, reducing its effectiveness.

What are the major adverse effects of vancomycin?

• Red Man Syndrome (flushing with rapid infusion)

• Nephrotoxicity

• Ototoxicity

• Hypotension

• Hypersensitivity reactions

What is the mechanism of action of Bacitracin?

Bacitracin binds to the lipid carrier that transports peptidoglycan precursors to the cell wall and blocks the enzyme that cleaves the lipid-diphosphate bond. This depletes the carrier molecule, causing peptidoglycan precursors to accumulate in the cytoplasm.

Why is Bacitracin limited to topical use?

Systemic use is avoided because Bacitracin is nephrotoxic.

What is the typical combination of Bacitracin in OTC ointments, and what is it called?

Bacitracin + Polymyxin B + Neomycin = Neosporin.

What is Bacitracin’s spectrum of activity?

Narrow spectrum, mainly effective against Gram-positive bacteria.

What is the mechanism of action of Fosfomycin?

Fosfomycin inhibits an early step in peptidoglycan biosynthesis, interfering with cell wall synthesis in both Gram-positive and Gram-negative bacteria. It is bactericidal.

What is the main clinical use of Fosfomycin?

Treatment of urinary tract infections (UTIs).

What is the primary mechanism of resistance to Fosfomycin?

Inadequate transport of the drug into the bacterial cell.

What is Fosfomycin’s spectrum of activity?

Broad, active against both Gram-positive and Gram-negative bacteria.

What is the structure of Polymyxins and how does it relate to their function?

Polymyxins are polypeptides with a positively charged polar head (lipophobic) and a long-chain fatty acid tail (lipophilic). This amphipathic structure allows interaction with bacterial membranes.

What is the mechanism of action of Polymyxins?

They interact with bacterial cell membranes: the polar head binds to membrane proteins, and the lipophilic tail inserts into lipids, causing distortion and loss of membrane integrity. Result: bactericidal effect.

Which bacteria are Polymyxins most effective against, and why?

Gram-negative bacteria, because they have thick outer membranes rich in lipids, which Polymyxins disrupt effectively.

How do Polymyxins differ from antibiotics that affect cell wall synthesis?

Cell wall synthesis inhibitors (e.g., Bacitracin) target Gram-positive bacteria (thick peptidoglycan wall), while Polymyxins target Gram-negative bacteria (thick lipid membrane).

What is the spectrum of activity of Polymyxins and their typical use in formulations?

Narrow spectrum against Gram-negative bacteria. Commonly combined with other antibiotics or steroids for superficial skin lesions or eyelid infections.

What are two common OTC combinations containing Polymyxin B?

• Polymyxin B + Bacitracin = Polysporin

• Polymyxin B + Bacitracin + Neomycin = Neosporin

What are the major systemic adverse effects of Polymyxins?

Neurotoxicity (vertigo, confusion, muscle weakness) and nephrotoxicity.

What is the mechanism of action of Gramicidin?

Gramicidin inserts into bacterial cell membranes, causing membrane disruption and eventual cell death. It is bactericidal.

What is Gramicidin’s spectrum of activity and why is its use limited?

Mostly effective against Gram-positive bacteria (and some Gram-negative). Limited to topical use because it induces hemolysis before bacterial death if used systemically.

What are common clinical applications of Gramicidin?

• Mixed with antibiotics like Polymyxin B or Neomycin in topical solutions for eye infections

• Used in medicinal lozenges for sore throat

• Topical medicines for infected wounds

What is the mechanism of action of Daptomycin?

Daptomycin is a lipopeptide antibiotic that inserts its lipid tail into the bacterial membrane, causing depolarization via K⁺ efflux. Loss of membrane potential leads to bacterial death.

What is the spectrum of activity of Daptomycin?

Active against Gram-positive bacteria only. Not effective against Gram-negative bacteria because it cannot penetrate the outer membrane.

What are the main clinical applications of Daptomycin?

• Skin and soft tissue infections

• Bacteremia

• Endocarditis