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Pharmacology Antibiotics - NEET PG Notes

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OVERVIEW: CLASSIFICATION OF ANTIBIOTICS

By Mechanism of Action

Bactericidal vs. Bacteriostatic

NEET PG Key Point: Bactericidal agents are MANDATORY in: endocarditis/endovascular infections, bacterial meningitis, neutropenic patients, and immunocompromised hosts.

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1. BETA-LACTAM ANTIBIOTICS

Common Core Structure

Mechanism of Action

• Bind to Penicillin Binding Proteins (PBPs) - transpeptidases on bacterial cell wall
• Inhibit transpeptidation (cross-linking of peptidoglycan chains)
• Result: osmotically fragile cell wall → lysis and cell death
• Bactericidal, time-dependent killing (efficacy depends on time above MIC)

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A. PENICILLINS

Classification & Spectrum

Key Facts for NEET PG

• Amoxicillin is better absorbed orally than ampicillin; equivalent to ampicillin 4x/day when given 3x/day
• Ampicillin is drug of choice for Listeria monocytogenes meningitis
• Nafcillin/Oxacillin - preferred for MSSA endocarditis (superior to vancomycin)
• Piperacillin-tazobactam - covers Pseudomonas, anaerobes, most gram-negatives
• Ampicillin can no longer be used empirically for UTI or typhoid (beta-lactamase producing strains)

Adverse Effects

• Hypersensitivity - most serious: anaphylaxis (IgE-mediated, type I)
• Antigenic determinants: penicilloic acid (major determinant) and alkaline hydrolysis products
• ~5-8% of people report penicillin allergy; <1% of those previously tolerant will react
• Cross-reactivity with cephalosporins: ~1-2% (mainly for same side-chain R groups) - use with caution, not contraindicated
• Ampicillin rash: maculopapular, NOT IgE-mediated (occurs especially with EBV/CMV infections)
• Interstitial nephritis: methicillin (reason it is no longer used clinically)
• Seizures: at very high doses (CNS penetration)

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B. CEPHALOSPORINS

Generational Classification

Key NEET PG Points

• Ceftriaxone: Drug of choice for gonorrhea, meningococcal meningitis, typhoid fever in children, Lyme disease
• Cefazolin: Preferred for surgical prophylaxis; safe in mild penicillin allergy
• Ceftazidime: Anti-pseudomonal cephalosporin (3rd gen)
• Cefoxitin: 2nd gen; covers anaerobes including B. fragilis
• Ceftaroline: MRSA coverage - unique among cephalosporins
• No cephalosporin covers enterococci or Listeria

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C. CARBAPENEMS

• Imipenem: Co-formulated with cilastatin (inhibits renal dihydropeptidase that degrades imipenem; prevents nephrotoxicity)
• Ertapenem: Does NOT cover Pseudomonas or Acinetobacter
• Meropenem: Preferred for meningitis (less seizure risk than imipenem)
• Adverse effects: Imipenem can cause seizures (lower threshold than other carbapenems)
• Carbapenems: drugs of choice for ESBL-producing organisms and Klebsiella pneumoniae carbapenemase (KPC) need alternative (colistin/ceftazidime-avibactam)

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D. MONOBACTAMS

• Active only against aerobic gram-negative rods (including Pseudomonas)
• No activity against gram-positive or anaerobes
• Safe in penicillin-allergic patients (no cross-reactivity)
• Used in penicillin-allergic patients who need gram-negative coverage

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E. BETA-LACTAMASE INHIBITORS

• Sulbactam has intrinsic activity against Acinetobacter baumannii

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2. GLYCOPEPTIDES

VANCOMYCIN

• Poor oral bioavailability; must be given IV for systemic infections
• Exception: oral vancomycin for C. difficile colitis (local action in gut)
• Eliminated by kidneys; dose-adjust in renal failure
• Clearance proportional to creatinine clearance

• MRSA bacteremia and endocarditis (drug of choice)
• MRSA meningitis + ceftriaxone/rifampin (for penicillin-resistant pneumococcal meningitis)
• Alternative for enterococcal endocarditis in penicillin-allergic patients (+ gentamicin)
• Oral: C. difficile (if metronidazole fails; guidelines now prefer fidaxomicin due to lower relapse rates)

• Red man syndrome: Infusion-related flushing due to histamine release - NOT allergic; prevented by slow infusion (>1 hour) or pretreatment with antihistamine
• Nephrotoxicity: Especially at high trough levels or combined with aminoglycosides
• Ototoxicity: Rare; minimize by keeping peak levels <60 mcg/mL
• Phlebitis at injection site

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3. TETRACYCLINES

• Chelate divalent cations (Ca²⁺, Mg²⁺, Fe²⁺, Al³⁺) → absorption reduced by milk, antacids, iron
• Doxycycline: Excreted in feces; safe in renal failure; once or twice daily dosing
• Tigecycline: IV only; glycylcycline derivative of minocycline; evades efflux pump resistance; covers MRSA, VRE, MDR gram-negatives

• Chlamydia (doxycycline - first choice)
• Mycoplasma pneumoniae pneumonia
• Rickettsial infections (RMSF, typhus)
• Brucellosis (doxycycline + rifampin)
• Lyme disease (early: doxycycline)
• Acne vulgaris (tetracycline, doxycycline, minocycline)
• Anthrax (doxycycline - alternative to ciprofloxacin)
• Cholera (doxycycline)
• Malaria (doxycycline as prophylaxis + chloroquine in resistant areas)

• Tooth discoloration and enamel hypoplasia - contraindicated in children <8 years and pregnancy
• Photosensitivity (especially demeclocycline, doxycycline)
• Hepatotoxicity at high doses
• Fanconi syndrome with expired tetracyclines
• Minocycline: Vestibular toxicity (dizziness, ataxia)
• Tigecycline: Nausea/vomiting most common; associated with increased mortality in hospital-acquired pneumonia

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4. AMINOGLYCOSIDES

1. Passive diffusion via porin channels (outer membrane)
2. Active transport into cell (oxygen-dependent; requires electrochemical gradient/proton pump)
3. Bind to 30S ribosomal subunit → three effects:
   • Block formation of initiation complex
   • Misreading of mRNA → incorporation of wrong amino acids → nonfunctional proteins
   • Break polyribosomes into non-functional monosomes
4. Bactericidal, concentration-dependent killing

Key NEET Point: Low pH and anaerobic conditions inhibit aminoglycoside transport (reduced efficacy in abscess cavities). Synergy with cell wall-active antibiotics (penicillin/vancomycin) enhances uptake.

• Not absorbed orally (used topically/locally or IV/IM)
• Once-daily dosing preferred (concentration-dependent killing + post-antibiotic effect)
• Renally eliminated; dose reduction in renal failure

• Gram-negative sepsis, nosocomial pneumonia (often combined with beta-lactam)
• Streptomycin: Tuberculosis (first drug used), Brucellosis, Plague, Tularemia
• Gentamicin: Enterococcal endocarditis (synergy with penicillin/vancomycin)
• Amikacin: Resistant gram-negative infections (least susceptible to acquired resistance enzymes)
• Neomycin: Only topical / bowel decontamination (too toxic for systemic use)
• Tobramycin: Pseudomonas aeruginosa (especially in cystic fibrosis - inhaled formulation)

• Ototoxicity (vestibular > cochlear): Especially streptomycin (vestibular); neomycin (cochlear). Irreversible.
• Nephrotoxicity: Proximal tubular damage; reversible usually. Risk factors: prolonged use, high troughs, concomitant nephrotoxins
• Neuromuscular blockade: Rare; inhibit Ca²⁺-dependent acetylcholine release; treat with calcium gluconate. Risk increased with muscle relaxants.
• Aminoglycoside order for ototoxicity: Neomycin > Amikacin > Tobramycin > Gentamicin > Streptomycin (for cochlear), reversed for vestibular

1. Aminoglycoside-modifying enzymes (acetyltransferases, phosphotransferases, nucleotidyltransferases) - encoded on plasmids
2. Reduced uptake/transport
3. Ribosomal modification (rare)

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5. MACROLIDES

• Erythromycin: short half-life, GI side effects; inhibits CYP3A4
• Azithromycin: Long half-life (~68 h), tissue concentrations >> serum, single-dose regimens possible; does NOT inhibit CYP3A4 significantly
• Clarithromycin: CYP3A4 inhibitor; used in H. pylori triple therapy

• Community-acquired pneumonia (atypical coverage)
• Mycoplasma, Legionella, Chlamydia - macrolide is drug of choice
• MAC prophylaxis/treatment in HIV (azithromycin or clarithromycin + ethambutol)
• H. pylori: Clarithromycin + amoxicillin + PPI (triple therapy)
• Pertussis (azithromycin first choice)
• Diphtheria carrier state (erythromycin)
• Azithromycin single dose: Chlamydia trachomatis (1g), gonorrhea (combined with ceftriaxone)

• Erythromycin: GI motility stimulation (acts as motilin receptor agonist) - nausea, cramping, diarrhea
• QT prolongation - all macrolides (especially azithromycin + erythromycin); avoid with other QT-prolonging drugs
• Erythromycin estolate: Cholestatic hepatitis (most hepatotoxic ester)
• Ototoxicity at high doses of erythromycin (IV)
• Drug interactions (CYP3A4): Erythromycin and clarithromycin increase levels of cyclosporine, statins, warfarin, carbamazepine

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6. CHLORAMPHENICOL

• Excellent CNS penetration (brain tissue levels = serum levels)
• Metabolized by glucuronidation in liver; 10% excreted unchanged in urine
• Parenteral form = prodrug (chloramphenicol succinate) → hydrolyzed in vivo
• Dose in neonates: 25 mg/kg/day (slow glucuronidation; risk of gray baby syndrome)

• Typhoid fever (historically; now replaced by fluoroquinolones/ceftriaxone)
• Rickettsial infections (alternative to doxycycline, used in pregnancy/children)
• Bacterial meningitis in severe penicillin-allergic patients (alternative)
• H. influenzae meningitis (historically)

• Gray baby syndrome: Neonates lack glucuronyl transferase → drug accumulates → cardiovascular collapse, ashen gray color, abdominal distension, vomiting, hypothermia. Dose: keep <25 mg/kg/day in neonates
• Aplastic anemia: Idiosyncratic (not dose-related), irreversible, ~1:25,000 - most feared adverse effect
• Reversible bone marrow suppression: Dose-related, reversible on stopping drug
• Inhibits CYP2C9/CYP3A4 → increases phenytoin, warfarin levels
• Resistance: Chloramphenicol acetyltransferase (CAT enzyme, plasmid-encoded) inactivates drug

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7. FLUOROQUINOLONES

• Ciprofloxacin: Best gram-negative coverage including Pseudomonas; relatively weak gram-positive
• Levofloxacin: Extended gram-positive + atypicals (pneumococcus coverage)
• Moxifloxacin: Broad-spectrum including anaerobes; NO urinary excretion (not for UTI)
• Norfloxacin: Only urinary tract (poor tissue penetration)

• Ciprofloxacin: UTI, typhoid fever, anthrax (drug of choice), traveler's diarrhea, Pseudomonas infections, gonorrhea (resistance now common)
• Levofloxacin/Moxifloxacin: Community-acquired pneumonia (respiratory fluoroquinolones), TB (second-line: levofloxacin, moxifloxacin)
• Ciprofloxacin: Meningococcal prophylaxis (single dose)

• Tendinitis and tendon rupture (Achilles tendon most common) - especially in elderly + corticosteroid users
• QT prolongation
• Cartilage damage in growing animals - contraindicated in children <18 years and pregnancy (generally avoided, though some uses like anthrax are exceptions)
• CNS: Headache, dizziness, seizures (lowers seizure threshold)
• Photosensitivity
• Ciprofloxacin inhibits CYP1A2 → increases theophylline/caffeine levels
• Interactions: Chelation with antacids/iron/calcium (reduce absorption)

• Mutation in genes encoding DNA gyrase (gyrA) or topoisomerase IV (parC)
• Plasmid-mediated resistance (efflux pumps, target protection by Qnr proteins)

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8. CLINDAMYCIN

• Anaerobic infections (aspiration pneumonia, abdominal/pelvic infections)
• MRSA skin and soft tissue infections (community-acquired MRSA)
• Toxin-suppressing effect: Streptococcal toxic shock syndrome, gas gangrene (inhibits toxin production)
• Malaria (in combination with quinine)
• Pneumocystis jirovecii pneumonia (with primaquine, as alternative)
• Toxoplasmosis (alternative)
• Babesiosis (with quinine)

• Pseudomembranous colitis (C. difficile overgrowth) - classic association; highest risk with clindamycin
• Diarrhea (most common)

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9. SULFONAMIDES & TRIMETHOPRIM

• Sulfonamides: Structural analogs of PABA → competitively inhibit dihydropteroate synthase → block folate synthesis. Bacteriostatic.
• Trimethoprim: Inhibits dihydrofolate reductase (selectively for bacterial enzyme) → blocks tetrahydrofolate synthesis
• TMP-SMX (Co-trimoxazole): Sequential blockade of folate synthesis → synergistic bactericidal effect

• Pneumocystis jirovecii pneumonia (PCP): Drug of choice for treatment AND prophylaxis (CD4 <200)
• UTI (E. coli, but resistance increasing)
• Nocardia infections (drug of choice)
• Toxoplasma gondii prophylaxis in HIV (CD4 <100)
• Stenotrophomonas maltophilia (one of few drugs active)
• Community-acquired MRSA soft tissue infections
• Listeria (alternative in penicillin allergy)
• Shigella, Salmonella (where sensitive)
• Traveler's diarrhea

• Hypersensitivity (Stevens-Johnson syndrome, toxic epidermal necrolysis - especially sulfonamides)
• Kernicterus in neonates (displacement of bilirubin from albumin) - contraindicated in neonates
• Folate deficiency/megaloblastic anemia (especially TMP at high doses)
• Hemolytic anemia in G6PD deficiency
• Crystalluria and nephrotoxicity (sulfonamides; maintain adequate hydration)
• Contraindicated in pregnancy (folate antagonism, kernicterus risk at term)

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10. LINEZOLID

• VRE infections (unique oral bioavailability - 100%)
• MRSA pneumonia (preferred by some guidelines over vancomycin for lung tissue penetration)
• MDR-TB (second-line)

• Myelosuppression (thrombocytopenia most common, anemia, neutropenia) - monitor CBC weekly if >2 weeks
• Serotonin syndrome: Linezolid is a weak MAO inhibitor - avoid with SSRIs, TCAs, meperidine
• Peripheral and optic neuropathy with prolonged use
• Lactic acidosis (rare but serious - inhibits mitochondrial protein synthesis)

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11. METRONIDAZOLE

• C. difficile colitis (oral; now second-line to vancomycin/fidaxomicin)
• Anaerobic infections (B. fragilis, abdominal, pelvic infections)
• Bacterial vaginosis (metronidazole first choice)
• Trichomoniasis (single 2g dose)
• Giardiasis (drug of choice)
• Amoebiasis (invasive; drug of choice)
• H. pylori (part of quadruple therapy)
• Guinea worm (anti-inflammatory effect)

• Disulfiram-like reaction with alcohol (acetaldehyde accumulation) - absolute contraindication
• Metallic taste, nausea
• Peripheral neuropathy with prolonged use
• Contraindicated in first trimester of pregnancy

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12. RIFAMPIN (RIFAMPICIN)

• Tuberculosis (always in combination to prevent resistance)
• Meningococcal prophylaxis (2 days)
• H. influenzae meningitis prophylaxis
• Leprosy (rifampin is bactericidal against M. leprae)
• Brucellosis (with doxycycline)
• Adjunct for MRSA infections (prosthetic devices) - adds synergy but NEVER used alone

• Orange-red discoloration of urine, tears, sweat, saliva (harmless but distressing)
• Hepatotoxicity (transaminase elevation common, fulminant rare)
• CYP induction (most potent inducer) → reduces levels of: oral contraceptives, warfarin, phenytoin, cyclosporine, antiretrovirals, methadone → drug interactions are very high yield
• Thrombocytopenia, hemolytic anemia (rare)
• Flu-like syndrome with intermittent therapy

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PHARMACODYNAMIC PRINCIPLES - HIGH YIELD

Concentration-Dependent vs. Time-Dependent Killing

Post-Antibiotic Effect (PAE)

• Defined as persistent suppression of bacterial growth AFTER drug exposure ends
• PAE = T - C (time for test culture to grow 10-fold above baseline minus time for untreated culture)
• Drugs with PAE against gram-negative bacilli: Aminoglycosides, Carbapenems, Quinolones, Rifampin, Tetracyclines

Synergism

• Beta-lactam + aminoglycoside: Beta-lactam disrupts cell wall → enhanced aminoglycoside uptake
• TMP + sulfonamide: Sequential block of same pathway → synergistic bactericidal effect
• Beta-lactamase inhibitor + beta-lactam: Inhibitor blocks enzyme degradation of antibiotic

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QUICK-REFERENCE: DRUG OF CHOICE FOR NEET PG

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CONTRAINDICATIONS SUMMARY

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