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Antimicrobial Agents - BDS 1st Year Pharmacology (Kathmandu University)

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Q1. Classify Antifungal Drugs. Write down the MOA and Uses of Amphotericin B

Classification of Antifungal Drugs

Amphotericin B - Mechanism of Action

• It binds selectively to ergosterol in the fungal cell membrane (ergosterol is the principal sterol in fungi, unlike cholesterol in human cells - this is the basis of selectivity)
• After binding, it forms transmembrane pores (channels) through hydrophobic interactions
• These pores increase membrane permeability, causing leakage of potassium ions and other small molecules from the fungal cell
• This results in disruption of electrochemical gradients and cell death (fungicidal)
• At low concentrations it may be fungistatic

Uses of Amphotericin B

1. Drug of choice for most life-threatening systemic mycoses:

• Cryptococcal meningitis (especially in HIV patients)
• Invasive aspergillosis
• Candidiasis (systemic/disseminated)
• Histoplasmosis, Coccidioidomycosis, Blastomycosis
• Mucormycosis

1. Leishmaniasis (liposomal form)
2. Oral/esophageal candidiasis (nystatin preferred orally; amphotericin used for severe cases)

Formulations

• Conventional (sodium deoxycholate) - more toxic
• Liposomal (AmBisome) - less nephrotoxic, preferred in renal impairment

Adverse Effects

• Fever and chills (infusion reaction - most common, 1-3 hrs after IV)
• Nephrotoxicity (most serious - azotemia, hypokalemia, hypomagnesemia)
• Hypotension
• Thrombophlebitis at IV site
• Anemia (decreased erythropoietin)

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Q2. List Fluoroquinolones. Write the MOA, Indications, and Important Adverse Effects

List of Fluoroquinolones

Mechanism of Action

• DNA gyrase (main target in gram-negatives): introduces negative supercoils into DNA, essential for DNA replication, transcription, and repair. Fluoroquinolones bind the enzyme-DNA complex, blocking re-ligation of cut DNA strands → double strand DNA breaks → bactericidal effect
• Topoisomerase IV (main target in gram-positives): responsible for separating daughter chromosomes after replication
• Human cells have topoisomerase II but fluoroquinolones have much higher affinity for bacterial enzymes - basis of selectivity
• Bactericidal, concentration-dependent killing

Indications

1. Urinary tract infections (UTI) - especially Norfloxacin, Ciprofloxacin
2. Respiratory tract infections - community-acquired pneumonia (Levofloxacin, Moxifloxacin)
3. Enteric fever / typhoid (Ciprofloxacin)
4. Gonorrhea, Chlamydia (Ofloxacin)
5. Anthrax prophylaxis/treatment (Ciprofloxacin - drug of choice)
6. Bone and joint infections (osteomyelitis)
7. Tuberculosis (Levofloxacin, Moxifloxacin - 2nd line)
8. Intra-abdominal infections (with metronidazole)
9. Dental relevance: Severe odontogenic infections with gram-negative involvement

Important Adverse Effects

1. GI disturbances - nausea, vomiting, diarrhea (most common)
2. CNS effects - headache, dizziness, insomnia; rarely seizures (avoid in epileptics)
3. Phototoxicity - avoid sun exposure (especially sparfloxacin)
4. Tendinitis and tendon rupture (Achilles tendon) - important black box warning
5. Cartilage damage - avoid in children <18 years and pregnancy (teratogenic in animals)
6. QT prolongation - especially moxifloxacin (avoid with other QT-prolonging drugs)
7. Dysglycemia - hyperglycemia/hypoglycemia (Gatifloxacin)

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Q3. Short Notes: Rationale of Combination of Sulfamethoxazole and Trimethoprim (Co-trimoxazole)

The Drugs

Rationale for Combination

• Each drug alone is bacteriostatic
• The combination is bactericidal
• Synergism allows use of lower doses of each drug → reduced toxicity
• Reduces emergence of resistance (a mutation must affect both targets simultaneously)
• Broad spectrum coverage is expanded

Uses

1. UTI (first-line for uncomplicated UTI)
2. Pneumocystis jirovecii pneumonia (PCP) - prophylaxis and treatment in HIV
3. Typhoid fever
4. Shigellosis
5. Otitis media
6. Oral thrush / Superinfection - SMX has no antifungal activity; co-trimoxazole use can predispose to oral candidiasis (relevant to dentistry)

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Q4. Classify Cephalosporins with Examples. Write MOA, Common Therapeutic Uses, and Adverse Effects

Classification

Mechanism of Action

1. Binding to Penicillin-Binding Proteins (PBPs) - enzymes (transpeptidases, carboxypeptidases) located on the bacterial cell wall
2. Inhibiting transpeptidation - the cross-linking of peptidoglycan chains that gives the cell wall rigidity
3. This prevents synthesis of a structurally sound cell wall
4. The bacteria activate their own autolytic enzymes → cell lysis and death → bactericidal
5. Effective only against dividing bacteria (because cell wall synthesis only occurs during division)

Common Therapeutic Uses

1. Dental infections / oral surgery prophylaxis (1st generation - Cefalexin)
2. Respiratory tract infections (pneumonia - Ceftriaxone)
3. Meningitis (3rd generation - Ceftriaxone, crosses BBB)
4. UTIs (Cefalexin, Cefuroxime)
5. Skin and soft tissue infections
6. Gonorrhea (Ceftriaxone - drug of choice)
7. Typhoid fever
8. Surgical prophylaxis (Cefazolin)

Adverse Effects

1. Hypersensitivity reactions - most common (rash, urticaria, anaphylaxis); ~10% cross-reactivity with penicillin
2. GI disturbances - nausea, vomiting, diarrhea
3. Nephrotoxicity (especially 1st generation in high doses)
4. Bleeding tendencies - some 3rd generation agents (e.g., cefoperazone) contain MTT side chain → inhibit Vitamin K-dependent clotting factors + disulfiram-like reaction with alcohol
5. Superinfections - Clostridium difficile diarrhea (pseudomembranous colitis)
6. Pain at injection site (IM)

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Q5. Classify Penicillins. Write MOA, Uses, and Adverse Effects

Classification of Penicillins

Mechanism of Action

1. The beta-lactam ring binds irreversibly to PBPs (transpeptidases) on the inner surface of the bacterial cell membrane
2. Inhibits transpeptidation → prevents cross-linking of peptidoglycan
3. Inhibits carboxypeptidase → cannot complete cell wall synthesis
4. Activates autolysins → lysis of the bacterium
5. Bactericidal, time-dependent killing (efficacy depends on time above MIC)
6. Effective only against growing organisms

Uses

1. Dental infections - most common use in dentistry (Amoxicillin is first-line for dental abscess)
2. Streptococcal pharyngitis, tonsillitis (Pen V)
3. Pneumococcal pneumonia
4. Syphilis (Penicillin G - drug of choice)
5. Gonorrhea (Amoxicillin)
6. Staphylococcal infections - use Cloxacillin (penicillinase-resistant)
7. H. pylori eradication (Amoxicillin in triple therapy)
8. Prophylaxis of infective endocarditis (dental procedures)

Adverse Effects

1. Hypersensitivity - most important adverse effect:

• Immediate (Type I, IgE-mediated): urticaria, bronchospasm, anaphylaxis (life-threatening)
• Delayed (Type III/IV): serum sickness, maculopapular rash

1. GI disturbances - nausea, diarrhea (especially ampicillin/amoxicillin)
2. Superinfection - oral candidiasis (important in dentistry!), C. difficile colitis
3. Neurotoxicity - seizures in very high doses or renal failure
4. Diarrhea - Ampicillin causes it in up to 10% patients

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Q6. Classify Aminoglycosides. Write MOA, Uses, and Adverse Effects

Classification

Mechanism of Action

1. Aminoglycosides are polycations - they penetrate the outer membrane of gram-negative bacteria via aqueous channels (porins)
2. Transport across the inner (cytoplasmic) membrane is energy-dependent (driven by electron transport / transmembrane electrical gradient) - this is why they are ineffective against anaerobes
3. Inside the cell, they bind to the 30S ribosomal subunit (specifically the 16S rRNA)
4. This causes misreading of mRNA (incorrect amino acids are inserted) and premature termination of translation
5. The abnormal proteins insert into the cell membrane, increasing permeability → more drug enters → amplifies the killing
6. Bactericidal, concentration-dependent killing (higher peak = more killing) with post-antibiotic effect (PAE)

Uses

1. Severe gram-negative infections (Gentamicin, Tobramycin, Amikacin)
2. Tuberculosis - Streptomycin (1st-line in some regimens), Amikacin (2nd-line/MDR-TB)
3. Plague, tularemia - Streptomycin
4. Infective endocarditis - synergism with penicillin (e.g., Gentamicin + Penicillin for enterococcal endocarditis)
5. Intestinal amoebiasis - Paromomycin (oral, not absorbed)
6. Bowel prep before surgery - Neomycin (oral)
7. Pseudomonal infections - Tobramycin, Amikacin

Adverse Effects

1. Ototoxicity - most important:

• Auditory (cochlear damage) - especially Neomycin, Amikacin → irreversible sensorineural hearing loss
• Vestibular - Streptomycin, Gentamicin → vertigo, nystagmus

1. Nephrotoxicity - acute tubular necrosis (usually reversible); monitor serum creatinine
2. Neuromuscular blockade - rare; risk increased with anesthetics; can cause respiratory paralysis
3. Teratogenicity (8th cranial nerve damage in fetus) - contraindicated in pregnancy

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Q7. Classify Antimicrobial Agents on the Basis of Mechanism of Action. Write MOA and Uses of Ciprofloxacin

Classification by Mechanism of Action

Ciprofloxacin - MOA and Uses

• Inhibits DNA gyrase (topoisomerase II) in gram-negatives and topoisomerase IV in gram-positives
• Prevents DNA replication and transcription → bactericidal, concentration-dependent

1. UTI (including complicated UTI)
2. Anthrax - drug of choice (prophylaxis and treatment)
3. Typhoid fever
4. Gonorrhea
5. Traveler's diarrhea (E. coli, Shigella)
6. Respiratory infections (hospital-acquired pneumonia, Pseudomonas infections)
7. Bone and joint infections (osteomyelitis)
8. Meningococcal prophylaxis (though Rifampicin preferred)

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Q8. Short Notes on Amphotericin B

• Class: Polyene antifungal, from Streptomyces nodosus
• MOA: Binds ergosterol → forms pores → K+ leaks → cell death
• Spectrum: Candida, Cryptococcus, Histoplasma, Aspergillus, Coccidioides, Blastomyces, Mucor
• Route: IV slow infusion (conventional or liposomal)
• Adverse effects: Fever/chills (infusion reaction), nephrotoxicity, hypokalemia, hypotension, thrombophlebitis, anemia
• Liposomal form: Less toxic, used in renal impairment

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Q9. MOA and Two Important Adverse Effects of Amoxicillin

Mechanism of Action

1. Amoxicillin is a broad-spectrum aminopenicillin (beta-lactam)
2. Binds to Penicillin-Binding Proteins (PBPs) - transpeptidases and carboxypeptidases
3. Inhibits transpeptidation → prevents cross-linking of peptidoglycan in the cell wall
4. Cell wall becomes structurally defective → osmotic lysis → bactericidal
5. Time-dependent killing

Two Important Adverse Effects

1. Hypersensitivity reactions - ranging from maculopapular rash (common with amoxicillin, especially in patients with infectious mononucleosis/EBV infection who receive ampicillin/amoxicillin - "ampicillin rash") to severe anaphylaxis (IgE-mediated). Cross-reactivity with other penicillins.
2. Gastrointestinal disturbances + Superinfection (Oral candidiasis) - nausea, diarrhea, and disruption of normal flora leading to oral/vaginal candidiasis. Highly relevant in dentistry as amoxicillin is the most commonly prescribed antibiotic for dental infections.

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Q10. Pharmacological Basis of Amoxicillin + Clavulanic Acid in Management of Staphylococcus aureus Infection

The Problem

The Solution - Clavulanic Acid (Clavulanate)

• It has weak intrinsic antibacterial activity but acts as a "suicide inhibitor" or progressive inhibitor
• It binds irreversibly to beta-lactamase at its active site, forming a stable complex → permanently inactivates the enzyme
• This protects amoxicillin from enzymatic degradation
• Amoxicillin is now free to bind PBPs and kill the bacteria

Pharmacological Basis (Summary)

1. Clavulanate "shields" amoxicillin from beta-lactamase
2. Amoxicillin exerts bactericidal action via PBP inhibition
3. The combination is synergistic - effective against beta-lactamase-producing S. aureus
4. Ratio: Amoxicillin 500mg + Clavulanate 125mg (trade name: Augmentin, Co-amoxiclav)
5. Also effective against ESBL-producing strains (to some extent)

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Q11. Mechanism of Action of Cloxacillin

Mechanism of Action

1. Same as all penicillins: Binds PBPs (transpeptidases) → inhibits peptidoglycan cross-linking → bactericidal
2. Resistance to penicillinase: The bulky isoxazolyl side chain creates steric hindrance around the beta-lactam ring, physically preventing beta-lactamase enzymes from accessing and hydrolyzing the ring. This is why it is effective against penicillinase-producing S. aureus where regular penicillin G fails.

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Q12. Role of Clotrimazole (SAQ) / Role of Cotrimoxazole in Oral Thrush / Superinfection

Clotrimazole in Oral Thrush (Oral Candidiasis)

• Clotrimazole is an imidazole antifungal
• MOA: Inhibits fungal CYP450 enzyme 14α-demethylase → blocks conversion of lanosterol to ergosterol → ergosterol depletion in fungal cell membrane → increased membrane permeability → cell death
• Use for oral thrush: Available as oropharyngeal troches/lozenges (10mg, dissolved slowly in mouth 5x/day) - high local concentration with minimal systemic absorption → ideal for oral candidiasis
• Also available as topical cream for angular cheilitis (Candida-associated)
• Dental relevance: Oral candidiasis is a superinfection commonly seen after prolonged antibiotic use (which disrupts normal oral flora)

Superinfection

• Superinfection = emergence of a new infection during/after treatment of a primary infection, due to disruption of normal flora
• Broad-spectrum antibiotics (especially tetracyclines, cephalosporins, clindamycin) kill commensal bacteria, allowing resistant organisms (Candida albicans, C. difficile, Pseudomonas) to proliferate
• Common oral superinfection in dentistry: Oral candidiasis - treated with clotrimazole lozenges or nystatin

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Q13. Azithromycin (Short Note / Compare with Erythromycin - MOA)

Azithromycin

• Class: Azalide (derivative of erythromycin, macrolide-like)
• MOA: Binds to the 50S ribosomal subunit (23S rRNA) → inhibits translocation (prevents movement of peptidyl-tRNA from acceptor to donor site) → inhibits protein synthesis → bacteriostatic (bactericidal at high concentrations)

Comparison with Erythromycin

1. Atypical pneumonias (Mycoplasma, Chlamydia, Legionella)
2. STIs - Chlamydia (single 1g dose)
3. Dental use: Prophylaxis of infective endocarditis (alternative to amoxicillin in penicillin-allergic patients)
4. H. pylori eradication (in combination)
5. Traveler's diarrhea

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Summary Table of Key Points for Exam

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Note on Q1 - "Classify antianginal drugs + Digoxin MOA": This appears on your sheet but under the "Antimicrobial Agents" heading, suggesting it may be a separate topic from a different section. Digoxin is a cardiac glycoside that works by inhibiting the Na+/K+ ATPase pump in cardiac muscle cells, increasing intracellular Ca2+ → positive inotropy. Antianginals include nitrates (GTN), beta-blockers, and calcium channel blockers. Let me know if you want that topic covered in full.