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B. Pharm 7th Semester - Pharmacology

Chapter: Chemotherapy / Antimicrobials

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UNIT 1: INTRODUCTION TO ANTIMICROBIAL CHEMOTHERAPY

1.1 Definition

1.2 Goals of Antimicrobial Therapy

Key principle: Primary prophylaxis should use the narrowest appropriate spectrum drug for the shortest appropriate duration.

1.3 Classification of Antibiotics

1. Type of microorganism - Antibacterial, antiviral, antifungal, antiparasitic
2. Biochemical pathway inhibited - Cell wall synthesis, membrane function, ribosomal translation, nucleic acid metabolism, folate synthesis, etc.
3. Chemical structure - Beta-lactam, aminoglycoside, macrolide, tetracycline, etc.
4. Spectrum - Narrow spectrum vs. broad spectrum
5. Action - Bactericidal vs. bacteriostatic

1.4 Bactericidal vs. Bacteriostatic

1.5 Key Pharmacokinetic/Pharmacodynamic (PK/PD) Concepts

• MIC (Minimum Inhibitory Concentration): Lowest drug concentration that prevents visible bacterial growth
• MBC (Minimum Bactericidal Concentration): Lowest drug concentration that kills 99.9% of organisms
• PAE (Post-Antibiotic Effect): Continued bacterial suppression after drug concentration falls below MIC
• AUC/MIC ratio: Key PD parameter for concentration-dependent drugs (e.g., aminoglycosides, fluoroquinolones)
• Time above MIC (T>MIC): Key PD parameter for time-dependent drugs (e.g., beta-lactams)

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UNIT 2: MECHANISMS OF ACTION

2.1 Sites of Action (Summary Table)

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UNIT 3: MECHANISMS OF RESISTANCE

3.1 Types of Resistance

1. Reduced drug concentration at target site
   • Decreased permeability (loss of outer membrane porins)
   • Active efflux pumps (pump drug out of cell)
2. Alteration or destruction of antibiotic
   • Enzymatic inactivation: beta-lactamases hydrolyze beta-lactam ring; aminoglycoside-modifying enzymes
   • Acetylation, phosphorylation, adenylation of aminoglycosides
3. Altered target structure
   • Modified PBPs (Penicillin Binding Proteins) - MRSA mechanism
   • Ribosomal RNA methylation (aminoglycoside resistance)
   • Altered DNA gyrase (fluoroquinolone resistance)

3.2 Genetic Basis of Resistance

• Mutation selection: Spontaneous mutations selected by antibiotic pressure
• External acquisition: Horizontal gene transfer via plasmids, transposons, integrons (most clinically important)

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UNIT 4: BETA-LACTAM ANTIBIOTICS

4.1 General Features

• Contain the beta-lactam ring - essential for activity
• Mechanism: Bind to and inhibit transpeptidases (PBPs - Penicillin Binding Proteins) → block peptidoglycan cross-linking → cell wall weakened → cell lysis
• Bactericidal, time-dependent killing (T>MIC is key PD parameter)
• Resistance primarily by beta-lactamases (hydrolysis of the ring)

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4.2 Penicillins

Structure & Classification

Pharmacokinetics of Penicillins

• Penicillin G: IV preferred (IM painful); serum level 20-50 mcg/mL after 1 g IV dose; t½ = 30 min (normal renal function), up to 10 hours in renal failure; 90% excreted by renal tubular secretion
• Oral penicillins (ampicillin, amoxicillin, dicloxacillin): Acid-stable; absorbed well (amoxicillin better absorbed than ampicillin); food impairs absorption of most except amoxicillin
• Benzathine penicillin (IM): Depot formulation; single 1.2 million unit dose maintains levels >0.02 mcg/mL for 10 days; used for Group A strep pharyngitis, syphilis prevention
• Procaine penicillin (IM): 600,000 units gives useful levels for 12-24 hours
• Distribution: Widely distributed; poor CNS penetration normally; good penetration with inflamed meninges (1-5 mcg/mL with 18-24 million units/day IV)
• Dose adjustment: Required in renal failure - give 1/4 to 1/3 normal dose if CrCl ≤10 mL/min
• Nafcillin: Erratic oral absorption; primarily biliary (not renal) clearance - no renal dose adjustment needed

Adverse Effects of Penicillins

• Hypersensitivity (most common): Urticaria, rashes, anaphylaxis (IgE-mediated); ~1-5% patients
• Cross-reactivity between penicillins and cephalosporins: <1-2% (much less than previously thought)
• Seizures: High doses, especially in renal failure
• GI: Diarrhea, C. difficile colitis (especially ampicillin)

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4.3 Cephalosporins

Generation-Based Classification

Key Points Per Generation

• Cefazolin: Most commonly used for surgical prophylaxis; good for Staph/Strep soft tissue infections
• Does NOT penetrate CNS - cannot treat meningitis
• Cannot use for Pseudomonas or enterococci

• Cefuroxime: Active against H. influenzae; useful for community-acquired pneumonia
• Cefoxitin/Cefotetan: Cover anaerobes (B. fragilis); used for intra-abdominal infections
• None active against Pseudomonas or enterococci

• Ceftriaxone: Long half-life (8 h); once-daily dosing; drug of choice for bacterial meningitis, gonorrhea, typhoid fever
• Ceftazidime: Only 3rd gen with anti-Pseudomonal activity
• Beware: Enterobacter strains can develop resistance during therapy (inducible chromosomal beta-lactamase)

• Stable against many beta-lactamases
• Used for febrile neutropenia, hospital-acquired pneumonia, Pseudomonas infections

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4.4 Carbapenems

• Resistant gram-negative infections (Pseudomonas, ESBL-producing Enterobacteriaceae)
• Mixed aerobic-anaerobic infections
• Febrile neutropenia (imipenem/meropenem ± aminoglycoside)
• Enterobacter infections (resistant to other beta-lactams)

• Nausea, vomiting, diarrhea
• Seizures - most common with imipenem (CNS toxicity at high levels/renal failure)
• Meropenem and ertapenem: much lower seizure risk
• Cross-reactivity with penicillin allergy: <1%

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4.5 Monobactams

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4.6 Vancomycin (Glycopeptide)

• MRSA infections (drug of choice)
• Serious Staph epidermidis infections
• Enterococcal endocarditis (combined with aminoglycoside)
• C. difficile colitis (oral vancomycin - not absorbed)
• Patients with serious beta-lactam allergy

• Nephrotoxicity - monitor serum creatinine
• Ototoxicity - tinnitus, hearing loss (dose-related)
• Red man syndrome: Infusion-related flushing, erythema, hypotension of neck/upper body - due to histamine release; prevented by slowing infusion rate or pre-treating with antihistamine (NOT a true allergy)
• Thrombophlebitis at infusion site

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UNIT 5: AMINOGLYCOSIDES

• Poorly absorbed orally; given IV or IM
• Not significantly metabolized
• Excreted unchanged by glomerular filtration; dose adjustment required in renal failure
• Poor CNS penetration
• Streptomycin: used for tuberculosis (2nd line), plague, tularemia

• Serious gram-negative infections (sepsis, pneumonia, UTI)
• Pseudomonas aeruginosa (usually combined with beta-lactam)
• Synergy with penicillin/vancomycin for enterococcal endocarditis
• Streptomycin: tuberculosis (SHRZ regimen), brucellosis
• Neomycin: topical; bowel decontamination (not systemic)
• Amikacin: infections resistant to gentamicin/tobramycin (less susceptible to aminoglycoside-modifying enzymes)

• Aminoglycoside-modifying enzymes (acetylation, phosphorylation, adenylation) - most common
• Efflux pumps
• Reduced permeability

• Nephrotoxicity: Proximal tubular damage; reversible usually; increased risk with dehydration, concurrent nephrotoxins; monitor serum creatinine/BUN
• Ototoxicity: Auditory (cochlear - high-frequency hearing loss, usually irreversible) and vestibular toxicity; accumulate in inner ear
• Neuromuscular blockade: Rare; risk with anesthetics or myasthenia gravis; avoid in myasthenia
• Dose adjustment: Required in renal failure; therapeutic drug monitoring recommended

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UNIT 6: TETRACYCLINES

• Good oral absorption (except chelation with divalent cations - Ca2+, Mg2+, Al3+, Fe2+; avoid antacids, milk, iron supplements)
• Doxycycline: best absorbed; long half-life (18h); biliary/fecal excretion - safe in renal failure
• Minocycline: excellent tissue penetration; vestibular side effects
• Widely distributed including bone, teeth, CSF (variable)

• Atypical pneumonia (Mycoplasma, Chlamydia, Legionella)
• Rickettsial diseases (Rocky Mountain Spotted Fever, typhus) - drug of choice
• Chlamydia (urogenital infections) - doxycycline
• Lyme disease - doxycycline
• Acne vulgaris (topical and systemic)
• Brucellosis, cholera, plague (prophylaxis), anthrax

• Teeth discoloration and enamel hypoplasia in children; contraindicated in pregnancy and children <8 years
• Photosensitivity - avoid sun exposure
• GI: nausea, vomiting, esophageal ulceration (take with full glass of water, stay upright)
• Hepatotoxicity (high doses)
• Anti-anabolic effects (increase urea nitrogen)

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UNIT 7: CHLORAMPHENICOL

• Well absorbed orally; widely distributed; excellent CNS penetration
• Hepatic glucuronidation; renal excretion of inactive metabolites
• Dose adjustment in liver disease; NOT renal failure

• Meningitis (when penicillin/cephalosporins contraindicated)
• Typhoid fever (replaced by fluoroquinolones)
• Rickettsial disease in patients who cannot take tetracyclines
• Brain abscesses (anaerobic coverage + CNS penetration)

• Bone marrow suppression: Two types:
  • Dose-related, reversible: anemia, leukopenia (common)
  • Idiosyncratic, irreversible aplastic anemia (~1:30,000; life-threatening) - limits its use
• Gray baby syndrome: In neonates - inadequate glucuronidation; accumulation leads to cardiovascular collapse, gray cyanosis, vomiting, death
• Drug interactions: Inhibits CYP2C9/CYP3A4 - increases levels of warfarin, phenytoin

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UNIT 8: MACROLIDES

• Atypical pneumonia (Mycoplasma, Chlamydia, Legionella) - drugs of choice
• Community-acquired pneumonia (combined with beta-lactam)
• Pertussis (Whooping cough) - azithromycin or erythromycin
• H. pylori eradication - clarithromycin + amoxicillin + PPI (triple therapy)
• STIs: Chlamydia (azithromycin single 1g dose)
• MAC (Mycobacterium avium complex) in AIDS - clarithromycin/azithromycin

• GI: Most common - nausea, vomiting, diarrhea, abdominal cramps (especially erythromycin - also a motilin receptor agonist → prokinetic effect)
• QT prolongation: Risk of cardiac arrhythmia (azithromycin, clarithromycin) - avoid in patients with existing QT prolongation
• Hepatotoxicity: Cholestatic jaundice (erythromycin estolate - most common)
• Drug interactions: Erythromycin and clarithromycin are potent CYP3A4 inhibitors (increase levels of statins, warfarin, cyclosporine) - azithromycin much safer

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UNIT 9: FLUOROQUINOLONES

• Excellent oral bioavailability (~70-90%) - oral = IV equivalent
• Wide tissue distribution; good intracellular penetration
• Chelation with divalent cations (antacids, dairy, calcium, iron) reduces absorption - take 2h apart
• Renal excretion (ciprofloxacin, levofloxacin) - dose adjust in renal failure
• Moxifloxacin: hepatic metabolism - no renal dose adjustment

• UTI and pyelonephritis - ciprofloxacin, norfloxacin
• Typhoid fever - ciprofloxacin (drug of choice)
• Traveler's diarrhea - ciprofloxacin
• Community/hospital-acquired pneumonia - levofloxacin, moxifloxacin ("respiratory quinolones")
• Pseudomonas infections - ciprofloxacin
• Gonorrhea - ciprofloxacin (resistance now widespread; ceftriaxone preferred)
• Anthrax - ciprofloxacin (prophylaxis and treatment)
• TB (2nd line) - levofloxacin, moxifloxacin

• GI: Nausea, vomiting (most common)
• CNS: Headache, dizziness, insomnia; rarely seizures (especially in elderly)
• QT prolongation (moxifloxacin > levofloxacin > ciprofloxacin)
• Tendinopathy / Tendon rupture: Achilles tendon most common; risk increases with age, steroids, renal failure - Black box warning (FDA)
• Cartilage damage: In growing cartilage - contraindicated in children and pregnancy (teratogenic)
• Photosensitivity
• Drug interactions: Inhibit CYP1A2 (theophylline toxicity with ciprofloxacin)

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UNIT 10: SULFONAMIDES & TRIMETHOPRIM

10.1 Sulfonamides

10.2 Trimethoprim

10.3 Co-trimoxazole (TMP-SMX: Trimethoprim + Sulfamethoxazole)

• Sequential blockade of folate pathway (at two steps) → synergistic, bactericidal effect

• UTI - TMP-SMX (first-line for uncomplicated UTI in many guidelines)
• PCP (Pneumocystis jirovecii pneumonia) prophylaxis and treatment - first choice in HIV/AIDS
• Toxoplasmosis prophylaxis
• Nocardiosis
• Traveler's diarrhea
• MRSA skin infections (TMP-SMX)

• Hypersensitivity (rash, Stevens-Johnson syndrome - especially sulfonamides)
• Bone marrow suppression - megaloblastic anemia, neutropenia
• Crystalluria/nephrolithiasis - maintain adequate hydration
• Kernicterus in neonates - sulfonamides displace bilirubin from albumin; contraindicated in neonates and late pregnancy
• Hemolytic anemia in G6PD deficiency

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UNIT 11: ANTITUBERCULAR DRUGS

11.1 First-Line Drugs (HRZE Regimen)

11.2 Standard TB Regimen

• Intensive phase (2 months): HRZE daily
• Continuation phase (4 months): HR daily (or 3x/week supervised)
• Total: 6 months (new pulmonary TB)

11.3 Isoniazid (INH) - Detailed Notes

• Bactericidal against actively dividing mycobacteria
• Prodrug - activated by KatG (mycobacterial catalase-peroxidase)
• Resistance: KatG mutations (most common), InhA mutations
• Metabolized by N-acetyltransferase (NAT2) - genetic polymorphism:
  • Slow acetylators: Higher drug levels, more toxicity (neuropathy, hepatotoxicity)
  • Fast acetylators: Lower drug levels, may need higher doses; common in Japanese, Eskimos
• Pyridoxine (B6) supplementation mandatory in: pregnancy, malnutrition, HIV, slow acetylators, alcoholics, diabetics, renal failure

11.4 Rifampicin - Detailed Notes

• Bactericidal; kills dormant organisms in macrophages
• Most powerful CYP inducer - reduces levels of: oral contraceptives, warfarin, antiretrovirals, steroids, methadone, antifungals → adjust doses
• Orange-red discoloration of urine, sweat, tears, saliva (warn patients, stains contact lenses)
• Resistance: Single-step (point mutations in rpoB gene) - develops rapidly if used alone

11.5 Second-Line TB Drugs

• Fluoroquinolones (levofloxacin, moxifloxacin)
• Injectable agents: Amikacin, Kanamycin, Capreomycin
• Cycloserine (D-alanine analog, CNS toxicity)
• Ethionamide (nausea, hepatotoxicity)
• Bedaquiline (ATP synthase inhibitor - new drug for MDR-TB)
• Delamanid (DprE1 inhibitor - MDR-TB)

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UNIT 12: ANTIFUNGAL DRUGS

12.1 Polyenes

• Drug of choice for life-threatening systemic fungal infections
• Active against: Candida, Cryptococcus, Aspergillus, Histoplasma, Coccidioides, Blastomyces, Mucor
• Given IV (lipid formulations reduce toxicity)
• Adverse Effects: Nephrotoxicity (dose-limiting; tubular damage, renal tubular acidosis), infusion-related reactions (fever, chills, rigors - "shake and bake"), hypokalemia and hypomagnesemia (tubular loss), anemia

12.2 Azoles

12.3 Echinocandins

12.4 Allylamines

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UNIT 13: ANTIVIRAL DRUGS

13.1 Anti-Herpetic Drugs

13.2 Antiretroviral Drugs (HIV)

• Zidovudine (AZT): Bone marrow suppression, anemia, lactic acidosis
• Tenofovir: Nephrotoxicity, bone demineralization
• Efavirenz: CNS effects (vivid dreams, dizziness), teratogenic
• PI: Lipodystrophy, metabolic syndrome, inhibit CYP3A4

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UNIT 14: ANTIPARASITIC DRUGS

14.1 Antimalarials

14.2 Antihelminthics

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QUICK SUMMARY: MECHANISMS OF ACTION AT A GLANCE

CELL WALL SYNTHESIS:
  Beta-lactams → PBP (transpeptidase) inhibition
  Vancomycin  → D-Ala-D-Ala binding
  Cycloserine → D-alanine synthesis inhibition
  Isoniazid   → mycolic acid synthesis (MTB)
  Ethambutol  → arabinogalactan synthesis (MTB)

CELL MEMBRANE:
  Polymyxins   → disrupt gram-negative membranes
  Amphotericin → bind ergosterol (fungi)

PROTEIN SYNTHESIS (30S):
  Aminoglycosides → misreading (bactericidal)
  Tetracyclines   → block tRNA attachment (bacteriostatic)

PROTEIN SYNTHESIS (50S):
  Chloramphenicol → inhibit peptidyl transferase
  Macrolides      → block translocation
  Clindamycin     → block translocation
  Linezolid       → block initiation complex

DNA/RNA:
  Fluoroquinolones → DNA gyrase/topoisomerase IV
  Rifampin         → RNA polymerase (rpoB)
  Metronidazole    → DNA strand breaks (anaerobes)

FOLATE SYNTHESIS:
  Sulfonamides  → DHPS inhibition
  Trimethoprim  → DHFR inhibition

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KEY MNEMONICS

• Bactericidal drugs: "Very Finely Proficient At Killing Organisms" - Vancomycin, Fluoroquinolones, Penicillins, Aminoglycosides, Ketoconazole (fungi), Others (metronidazole)
• 30S inhibitors: "AT 30" - Aminoglycosides (cidal), Tetracyclines (static)
• 50S inhibitors: "CLEM at 50" - Chloramphenicol, Linezolid, Erythromycin (macrolides), clindaMycin
• TB first-line drugs: "RIPE" - Rifampicin, Isoniazid, Pyrazinamide, Ethambutol
• Penicillin allergy: Cross-reactivity with cephalosporins <1-2%; with carbapenems <1%
• Gray baby syndrome: Chloramphenicol in neonates (no glucuronidation)
• Red man syndrome: Vancomycin (not allergy - slow the infusion)

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FREQUENTLY ASKED EXAM QUESTIONS

1. Drug of choice for MRSA → Vancomycin
2. Drug of choice for invasive Aspergillus → Voriconazole
3. Peripheral neuropathy in TB treatment → Isoniazid (prevent with Pyridoxine/B6)
4. Optic neuritis in TB treatment → Ethambutol
5. Most potent CYP inducer among antibiotics → Rifampicin
6. Contraindicated in children and pregnancy (antibiotic) → Fluoroquinolones, Tetracyclines
7. Gray baby syndrome → Chloramphenicol (neonates)
8. Red man syndrome → Vancomycin (slowed infusion, antihistamines)
9. Beta-lactam with no gram-positive activity → Aztreonam
10. Only carbapenem without Pseudomonas coverage → Ertapenem
11. Concentration-dependent antibiotics → Aminoglycosides, Fluoroquinolones
12. Time-dependent antibiotics → Beta-lactams, Vancomycin
13. G6PD check before use → Primaquine (hemolytic anemia risk)
14. Disulfiram-like reaction with alcohol → Metronidazole, Cephalosporins with MTT side chain (cefamandole)
15. Aminoglycoside least susceptible to enzymatic inactivation → Amikacin

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