🦠 ANTIMICROBIAL DRUGS - Complete Pharmacology Lecture

PART 1: THE CONCEPT - What Are Antimicrobial Drugs?

"Antimicrobial drugs take advantage of biochemical differences that exist between microorganisms and human beings." - Lippincott Pharmacology

PART 2: CLASSIFICATION OF ANTIMICROBIAL DRUGS

A. By Mechanism of Action (Most Important!)

Think of this as attacking different parts of the bacteria's factory: cell wall construction, outer skin, protein-making machines, DNA copying machines, and vitamin factory.

B. By Spectrum of Activity

• Narrow Spectrum - kills only a limited type (e.g., Penicillin G kills mainly gram-positive organisms)
• Extended Spectrum - covers gram-positive + some gram-negative (e.g., Ampicillin)
• Broad Spectrum - effective against a wide variety of bacteria (e.g., Carbapenems, Tetracyclines)

C. By Type of Killing

Remember: Bactericidal = Killer. Bacteriostatic = Stopper. In immunocompromised patients, you always prefer bactericidal drugs because their immune system cannot do the finishing work.

PART 3: HOW TO SELECT AN ANTIMICROBIAL (The Clinical Logic)

1. What organism is causing the infection? - Gram stain + culture
2. Is the organism susceptible to the drug? - MIC (Minimum Inhibitory Concentration) testing
3. Where is the infection? - The drug must reach that site (e.g., some drugs don't cross into the CSF/brain)
4. What are the patient factors? - Age, pregnancy, kidney/liver function, immune status
5. Is the drug safe and effective? - Adverse effect profile
6. What is the cost? - Affordability and availability

Empiric vs Definitive Therapy

• Empiric Therapy = you start antibiotics immediately based on clinical judgment BEFORE culture results come back. This is the most common scenario - you can't wait 48-72 hours for culture results when a patient is deteriorating.
• Definitive Therapy = once culture + sensitivity results come, you narrow down to the most specific antibiotic.

PART 4: PHARMACODYNAMICS - HOW DO ANTIBIOTICS KILL?

Two Killing Patterns (Very Important for Dosing!)

• The more drug you give = the more bacteria you kill
• Dosing strategy: Give a large single daily dose to create a high peak concentration
• Examples: Aminoglycosides, Fluoroquinolones
• Key parameter: Cmax/MIC ratio (peak concentration / minimum inhibitory concentration)

• It doesn't matter HOW HIGH the concentration is - what matters is how LONG the drug stays above the MIC
• Dosing strategy: Give frequent small doses or continuous infusion
• Examples: Penicillins, Cephalosporins
• Key parameter: Time above MIC

• Some antibiotics continue to suppress bacterial growth EVEN AFTER the drug concentration has fallen below the MIC
• Aminoglycosides and Fluoroquinolones have a long PAE - this allows once-daily dosing

PART 5: THE MAJOR DRUG CLASSES - One by One

CLASS 1: BETA-LACTAM ANTIBIOTICS (The Biggest Family)

• Bacteria need to build their cell wall using an enzyme called transpeptidase (also called Penicillin-Binding Protein or PBP)
• Beta-lactam drugs BIND to this PBP and BLOCK it - so the cell wall cannot be completed
• Without a complete cell wall, bacteria undergo osmotic lysis (they swell and burst) - death!
• This is why beta-lactams are bactericidal

A. PENICILLINS

• Spectrum: Mainly gram-positive cocci (Streptococcus, Pneumococcus), Neisseria meningitidis, Treponema pallidum (syphilis)
• Penicillin G - given IV, short half-life (30 min), needs dosing every 4 hours
  • Benzathine Penicillin G = long-acting IM form - used for syphilis, rheumatic fever prophylaxis
  • Procaine Penicillin G = medium-acting IM form
• Penicillin V - oral form, but lower blood levels limit use
• Uses: Streptococcal infections, meningococcal infections, neurosyphilis, rheumatic fever
• Adverse Effects: Hypersensitivity (most common - from mild rash to anaphylactic shock), seizures at high doses

• Why needed? Many Staphylococci produce an enzyme called beta-lactamase that breaks the beta-lactam ring and inactivates ordinary penicillin. These drugs have bulky side chains that PROTECT the beta-lactam ring from this enzyme.
• Spectrum: Mainly penicillinase-producing Staphylococci (MSSA)
• Nafcillin/Oxacillin - IV use
• Cloxacillin/Dicloxacillin - oral use
• Important: They do NOT work against MRSA (Methicillin-Resistant Staphylococcus aureus) because MRSA changes the PBP itself (mecA gene encodes PBP-2a), making all beta-lactams ineffective

• Why extended? They have a free amino group on the side chain - this allows them to penetrate the outer membrane of gram-negative bacteria
• Spectrum: Gram-positive + gram-negative (H. influenzae, E. coli, Salmonella, H. pylori)
• Amoxicillin - better oral absorption than ampicillin (food does not affect it)
• Uses: UTI, URTI, otitis media, typhoid, H. pylori eradication (with clarithromycin + PPI)
• Amoxicillin-Clavulanate (Augmentin) - adding clavulanate (a beta-lactamase inhibitor) restores activity against beta-lactamase-producing organisms

• Broadest spectrum penicillins
• Active against Pseudomonas aeruginosa (a notoriously resistant hospital bug)
• Piperacillin/Tazobactam - the combination is widely used for hospital-acquired infections
• Dose: 3.375-4.5 g IV every 4-6 hours

• These are NOT antibiotics themselves - they have no or weak antibacterial activity on their own
• They SACRIFICE themselves to beta-lactamase - the enzyme destroys the inhibitor, leaving the antibiotic unharmed
• Always given in combination: Amoxicillin + Clavulanate, Piperacillin + Tazobactam, Ampicillin + Sulbactam

B. CEPHALOSPORINS

• 1st Gen Cefazolin = Gold standard for surgical prophylaxis (given 30-60 min before incision)
• 3rd Gen Ceftriaxone = Community-acquired pneumonia, meningitis, gonorrhea, typhoid
• 3rd Gen Ceftazidime = Pseudomonas infections
• 3rd Gen Ceftriaxone = Preferred in children for meningitis (excellent CSF penetration, once-daily dosing)

• 1st and 2nd gen: do NOT penetrate CNS - cannot treat meningitis
• 3rd gen and above: cross blood-brain barrier - can treat meningitis
• Cross-allergy with penicillins: Only 1-2% of penicillin-allergic patients react to cephalosporins. Can use cephalosporins in mild penicillin allergy (rash); AVOID in immediate hypersensitivity (anaphylaxis).

C. CARBAPENEMS (Imipenem, Meropenem, Ertapenem, Doripenem)

• Broadest spectrum beta-lactams - the last resort antibiotics in many cases
• Resistant to most beta-lactamases
• Imipenem is given with Cilastatin (a renal tubular enzyme inhibitor that prevents breakdown of imipenem in the kidney)
• Spectrum: Almost everything - gram-positive, gram-negative, anaerobes, Pseudomonas
• Uses: Severe hospital-acquired infections, polymicrobial infections, ESBL-producing organisms
• Adverse effects: Seizures (especially imipenem in patients with renal failure or seizure history - meropenem is less epileptogenic)
• Resistance: Carbapenem-Resistant Enterobacteriaceae (CRE) - a major public health threat

D. MONOBACTAMS (Aztreonam)

• Only active against aerobic gram-negative bacteria (including Pseudomonas)
• No activity against gram-positives or anaerobes
• Key advantage: Safe in patients with penicillin allergy - structurally distinct, no cross-reactivity
• Used for gram-negative infections in penicillin-allergic patients

E. VANCOMYCIN (Not a beta-lactam, but a cell wall inhibitor)

• Inhibits cell wall synthesis by binding to D-Ala-D-Ala terminal of peptidoglycan precursors - a different step than beta-lactams
• Spectrum: Gram-positive ONLY (especially MRSA, Enterococcus)
• The drug of choice for MRSA
• "Red Man Syndrome" - if infused too fast, causes flushing, erythema, and hypotension due to histamine release. Prevented by slow infusion over 60 minutes.
• Adverse Effects: Nephrotoxicity, ototoxicity (especially with aminoglycosides)
• Monitoring: Serum trough levels must be monitored

CLASS 2: AMINOGLYCOSIDES (Gentamicin, Amikacin, Tobramycin, Streptomycin, Neomycin)

1. Nephrotoxicity - reversible, affects proximal tubules. Risk increased by volume depletion, other nephrotoxic drugs.
2. Ototoxicity - both cochlear (hearing loss, irreversible) and vestibular (balance problems). Aminoglycosides accumulate in the inner ear fluid.
3. Neuromuscular Blockade - at very high doses, can cause respiratory paralysis (important in patients on muscle relaxants or with myasthenia gravis)

• Gentamicin - gram-negative hospital infections (often combined with beta-lactams for synergy)
• Amikacin - reserved for gentamicin-resistant organisms
• Streptomycin - tuberculosis (second-line), plague, brucellosis, tularemia
• Neomycin - topical use only, bowel sterilization before surgery (not absorbed orally)
• Tobramycin - Pseudomonas (especially in cystic fibrosis, as inhaled tobramycin)

CLASS 3: TETRACYCLINES (Tetracycline, Doxycycline, Minocycline, Tigecycline)

• Mycoplasma pneumonia
• Rickettsia (Rocky Mountain spotted fever)
• Chlamydia (STIs, PID, psittacosis, trachoma)
• Acne vulgaris (long-term doxycycline)
• Spirochetes - Lyme disease (Borrelia) - Doxycycline is drug of choice
• Tularemia, Brucellosis, Cholera

• GI disturbance - nausea, vomiting, diarrhea (take with food, but not with milk/antacids)
• Teeth staining and bone growth inhibition in children under 8 - tetracyclines bind calcium, depositing in developing teeth and bones. Permanent yellow-gray discoloration.
• Photosensitivity - sunburn easily while on tetracyclines
• Fanconi syndrome - outdated tetracycline is nephrotoxic
• Esophageal ulceration - take with plenty of water, remain upright

CLASS 4: MACROLIDES (Erythromycin, Azithromycin, Clarithromycin, Roxithromycin)

CLASS 5: CHLORAMPHENICOL

1. Aplastic Anemia - the most feared. Rare (1 in 25,000-40,000) but IRREVERSIBLE. Idiosyncratic reaction - not dose-related. Causes death. This has severely limited its use.
2. Grey Baby Syndrome - in neonates/premature infants. They lack the glucuronyl transferase enzyme to conjugate chloramphenicol. Drug accumulates - causes vomiting, abdominal distension, grey color, cardiovascular collapse, death. Contraindicated in neonates.
3. Bone marrow suppression - dose-related, reversible. Monitor CBC during therapy.

CLASS 6: CLINDAMYCIN

CLASS 7: FLUOROQUINOLONES (Ciprofloxacin, Levofloxacin, Moxifloxacin, Ofloxacin, Norfloxacin)

• Ciprofloxacin - best anti-Pseudomonas activity among oral antibiotics; gram-negative focus
• Levofloxacin - extended gram-positive coverage; "respiratory quinolone" (covers Streptococcus pneumoniae)
• Moxifloxacin - best anaerobic coverage; "respiratory quinolone"

• UTI (especially complicated, or resistant organisms)
• Respiratory tract infections (levofloxacin/moxifloxacin for community-acquired pneumonia)
• Anthrax prophylaxis/treatment
• Typhoid fever
• Tuberculosis (second-line)
• Pseudomonas infections
• Gonorrhoea (but resistance is increasing)
• Traveller's diarrhea

1. Tendinopathy and tendon rupture - especially Achilles tendon. Risk increased in elderly, steroid users. Black box warning.
2. CNS effects - headache, dizziness, insomnia, rarely seizures and psychosis
3. QTc prolongation - cardiac arrhythmias
4. Photosensitivity
5. Cartilage/Joint damage in growing animals - hence avoid in children and pregnancy (theoretical, but caution maintained)
6. Hyperglycemia/hypoglycemia - especially with diabetic medications

CLASS 8: SULFONAMIDES (Sulfamethoxazole, Sulfadiazine, Sulfacetamide)

• UTI - most common indication. Drug of choice for uncomplicated UTI where organism is susceptible.
• PCP (Pneumocystis jirovecii Pneumonia) - drug of choice in HIV/AIDS patients (both treatment and prophylaxis)
• Shigellosis, Salmonellosis
• Toxoplasmosis (with pyrimethamine)
• MRSA skin infections (TMP-SMX is surprisingly effective)
• Nocardiosis

1. Hypersensitivity - rash, fever, Stevens-Johnson syndrome (severe, life-threatening skin reaction)
2. Kernicterus in neonates - sulfonamides displace bilirubin from albumin, causing bilirubin to deposit in infant's brain. Contraindicated in neonates and near term pregnancy.
3. Hemolytic anemia in G6PD-deficient patients
4. Crystalluria - crystals form in urine, blocking kidney tubules. Prevent by drinking plenty of water and alkalinizing urine.
5. Bone marrow suppression

CLASS 9: RIFAMPICIN (Rifampin)

• Leprosy (in combination regimens)
• Meningococcal prophylaxis (contacts of meningitis patients)
• MRSA (always in combination - never alone due to rapid resistance development)
• Brucellosis

• Oral contraceptives (use barrier contraception!)
• Warfarin (increase dose during rifampicin therapy)
• HIV antiretrovirals
• Corticosteroids
• Many other drugs

CLASS 10: METRONIDAZOLE (The Anaerobe Killer + Antiprotozoal)

• Anaerobic infections (intra-abdominal, pelvic, dental, brain abscess)
• C. difficile colitis (oral metronidazole, though vancomycin is now preferred for severe cases)
• Giardiasis (drug of choice)
• Amoebiasis (drug of choice for invasive, systemic amoeba - but not luminal - add diloxanide furoate)
• Trichomoniasis (treat both partners!)
• H. pylori eradication (in combination regimens)
• Bacterial vaginosis

• Disulfiram-like reaction with alcohol - MUST warn patients to avoid alcohol completely during therapy and 48 hours after (causes severe flushing, nausea, vomiting, headache)
• Metallic taste in mouth
• Peripheral neuropathy (with prolonged use)
• CNS effects (dizziness, headache)
• Nausea, GI upset

PART 6: ANTIMICROBIAL RESISTANCE - The Modern Crisis

PART 7: DRUG COMBINATIONS IN ANTIMICROBIALS

• Bacteriostatic + Bactericidal can ANTAGONIZE each other
• Classic example: Tetracyclines/Chloramphenicol (bacteriostatic) + Penicillin (bactericidal) - the static drug prevents bacterial growth, so penicillin (which needs actively growing cells to work) becomes ineffective

PART 8: SPECIAL PATIENT CONSIDERATIONS

PART 9: COMPLICATIONS OF ANTIMICROBIAL THERAPY - Summary

1. Hypersensitivity - most with penicillins. Spectrum from rash → urticaria → anaphylaxis → Stevens-Johnson syndrome
2. Superinfection - killing normal flora allows resistant organisms to overgrow. Classic example: C. difficile after clindamycin; Candida oral thrush after broad-spectrum antibiotics
3. Organ toxicity - kidney (aminoglycosides, vancomycin), liver (rifampicin, isoniazid), bone marrow (chloramphenicol), ear (aminoglycosides), tendon (fluoroquinolones)
4. Drug interactions - especially rifampicin (CYP inducer) and erythromycin/azithromycin (CYP inhibitors)

PART 10: QUICK MEMORY TABLES FOR EXAMS

"Drugs to Avoid in Pregnancy" - FAST MNEMONIC

• M - Metronidazole (1st trimester)
• A - Aminoglycosides
• T - Tetracyclines
• T - TMP-SMX (near term - kernicterus)
• Plus Fluoroquinolones, Chloramphenicol

Sites of Action - Quick Reference

CELL WALL:         Beta-lactams (Penicillin, Cephalosporins, Carbapenems)
                   Vancomycin, Bacitracin, Cycloserine

CELL MEMBRANE:     Polymyxins, Amphotericin B (antifungal)

30S RIBOSOME:      Aminoglycosides (bactericidal)
                   Tetracyclines (bacteriostatic)

50S RIBOSOME:      Macrolides, Chloramphenicol, Clindamycin, Linezolid

DNA GYRASE:        Fluoroquinolones

RNA POLYMERASE:    Rifampicin

FOLATE SYNTHESIS:  Sulfonamides (DHPS step)
                   Trimethoprim (DHFR step)

DNA DAMAGE:        Metronidazole, Nitrofurantoin

The "Last Resort" Antibiotics

• MRSA: Vancomycin, Linezolid, Daptomycin, Ceftaroline, Teicoplanin
• VRE: Linezolid, Daptomycin
• Pseudomonas: Ceftazidime, Ciprofloxacin, Piperacillin-Tazobactam, Meropenem, Colistin
• CRE/Pan-resistant: Colistin (Polymyxin E), Tigecycline - the absolute last resorts

Sources: Katzung's Basic and Clinical Pharmacology, 16th Edition (Chapters 43-47) and Lippincott Illustrated Reviews: Pharmacology (Unit VI, Chapters 28-36). These cover the same core content as Gobind Rai Garg and Bhalani Pharmacology used in Indian medical colleges - the mechanisms, classifications, and clinical points are identical across all standard pharmacology texts.