⚕️ Principles of Antimicrobial Therapy
- Bactericidal — directly kill organisms
- β-lactams, vancomycin, aminoglycosides, fluoroquinolones, metronidazole, rifampin
- Bacteriostatic — inhibit growth; host immune system clears infection
- Tetracyclines, macrolides, clindamycin, chloramphenicol, sulfonamides, trimethoprim, linezolid
- Combination therapy
- Additive — effects sum (e.g., sulfamethoxazole + trimethoprim)
- Synergistic — effect > sum of parts (e.g., penicillin + aminoglycoside for enterococci)
- Antagonistic — effect < sum (e.g., penicillin + tetracycline; bacteriostatic impairs cell-wall synthesis)
- Key mechanisms of action
- Cell-wall synthesis — β-lactams, vancomycin
- Protein synthesis — aminoglycosides, tetracyclines, macrolides, chloramphenicol, clindamycin, linezolid
- Nucleic acid synthesis — fluoroquinolones (DNA gyrase), rifampin (RNA polymerase)
- Folate synthesis — sulfonamides, trimethoprim, pyrimethamine
📌 High-Yield
- Bactericidal drugs are preferred in immunocompromised patients and in life-threatening infections.
| Mechanism | Drug Class | Examples |
|---|---|---|
| Cell-wall inhibition | β-lactams, glycopeptides | Penicillins, cephalosporins, vancomycin |
| Protein synthesis (30S) | Aminoglycosides, tetracyclines | Gentamicin, doxycycline |
| Protein synthesis (50S) | Macrolides, chloramphenicol, clindamycin, streptogramins | Azithromycin, linezolid |
| DNA/RNA synthesis | Fluoroquinolones, rifamycins | Ciprofloxacin, rifampin |
| Folate synthesis | Sulfonamides, dihydrofolate reductase inhibitors | Sulfamethoxazole, trimethoprim |
🧫 Cell-Wall Synthesis Inhibitors
Penicillins
- Mechanism
- Bind penicillin-binding proteins (PBPs) on bacterial cell membrane
- Inhibit transpeptidase → prevent cross-linking of peptidoglycan
- Activate autolytic enzymes → cell lysis (bactericidal)
- Resistance
- β-lactamase production — cleaves β-lactam ring (e.g., staphylococci, many Gram-negatives)
- Altered PBPs — reduced binding affinity (e.g., MRSA, penicillin-resistant pneumococci)
- Porin changes — reduced drug entry (e.g., Pseudomonas)
- Subgroups
- Antistaphylococcal — nafcillin, oxacillin, methicillin; narrow, β-lactamase-resistant; not MRSA
- Natural — penicillin G, penicillin V; narrow, β-lactamase-sensitive; Strep, Treponema
- Aminopenicillins — ampicillin, amoxicillin; broad, β-lactamase-sensitive; Listeria, E. coli, H. pylori
- Antipseudomonal — piperacillin; very broad, β-lactamase-sensitive; Pseudomonas, Gram-negatives
- Pharmacokinetics
- Most renal clearance (active tubular secretion); probenecid blocks secretion → ↑ levels
- Nafcillin/oxacillin — biliary elimination
- Benzathine penicillin G — repository form; half-life ≈ 2 weeks
- Adverse effects
- Hypersensitivity (5–7%) — types I–IV; urticaria, anaphylaxis, Stevens–Johnson
- Complete cross-allergenicity among penicillins
- GI distress — especially ampicillin
- Jarisch–Herxheimer reaction — during syphilis treatment (fever, chills, myalgia)
Cephalosporins
- Mechanism & resistance — identical to penicillins
- Generations
- 1st — cefazolin, cephalexin; Gram+ cocci (not MRSA), E. coli, Klebsiella, Proteus; surgical prophylaxis
- 2nd — cefotetan, cefoxitin, cefuroxime; ↑ Gram− coverage, some anaerobes
- 3rd — ceftriaxone, cefotaxime, cefdinir, cefixime, ceftazidime; broad Gram−, Neisseria, Pseudomonas (ceftazidime); penetrate CNS
- 4th — cefepime; wider spectrum incl. Pseudomonas; resistant to many β-lactamases; penetrates CNS
- Pharmacokinetics
- Renal clearance (probenecid blocks secretion); ceftriaxone — biliary
- Dose reduction in renal dysfunction
- Adverse effects
- Hypersensitivity (~2%) — rashes, drug fever
- Positive Coombs test (hemolysis rare)
- Partial cross-allergenicity with penicillins (~5%)
Carbapenems & Monobactams
- Imipenem / Meropenem
- Broadest spectrum — Gram+, Gram−, anaerobes; resistant to β-lactamases
- Imipenem + cilastatin (renal dehydropeptidase inhibitor) prevents nephrotoxic metabolite
- Renal elimination; dose reduction in renal failure
- SE: GI distress, drug fever, CNS (seizures — imipenem, especially with renal dysfunction)
- Aztreonam
- Monobactam; active only against Gram− rods
- Resistant to β-lactamases
- No cross-allergenicity with penicillins or cephalosporins
Vancomycin
- Mechanism
- Binds D-Ala-D-Ala terminus of muramyl pentapeptide
- Sterically hinders transglycosylation → prevents peptidoglycan elongation
- Does not bind PBPs
- Spectrum — MRSA, enterococci, C. difficile (oral for colitis)
- Resistance
- VRE / VRSA — change in muramyl pentapeptide: D-Ala replaced by D-Lactate → reduced binding
- Pharmacokinetics
- IV for systemic; oral for colitis (not absorbed)
- Enters bone, most tissues; poor CNS penetration
- Renal clearance; dose reduction in renal dysfunction
- Adverse effects
- Red man syndrome — histamine release (infusion-related)
- Ototoxicity — usually permanent; additive with other agents
- Nephrotoxicity — mild, additive with aminoglycosides, amphotericin B, cisplatin
⚠️ Exam Trap
- Vancomycin is not a β-lactam; it binds D-Ala-D-Ala, not PBPs.
- MRSA resistance is due to altered PBPs (not β-lactamase).
🧬 Protein Synthesis Inhibitors
30S Ribosomal Subunit
- Aminoglycosides — bactericidal
- Gentamicin, tobramycin, amikacin, streptomycin
- O₂-dependent uptake → anaerobes innately resistant
- Spectrum: Gram− rods; synergistic with β-lactams for enterococci & Pseudomonas
- SE: nephrotoxicity, ototoxicity (irreversible), neuromuscular blockade
- Once-daily dosing leverages post-antibiotic effect; toxicity is total-dose dependent
- Tetracyclines — bacteriostatic
- Doxycycline, minocycline, tigecycline
- Broad: Chlamydia, Mycoplasma, Rickettsia, Borrelia, H. pylori, Brucella
- Doxycycline — prostatitis (high prostatic fluid levels)
- Minocycline — meningococcal carrier state
- Tigecycline — resistant Gram+ (MRSA, VRE), Gram−, anaerobes
- SE: tooth enamel dysplasia, bone growth inhibition (children), phototoxicity, GI distress, vestibular (minocycline)
- Absorption reduced by divalent cations (Ca²⁺, Mg²⁺, Fe²⁺)
50S Ribosomal Subunit
- Macrolides — bacteriostatic
- Erythromycin, azithromycin, clarithromycin
- Spectrum: Gram+ cocci (not MRSA), atypical (Chlamydia, Mycoplasma, Legionella), Campylobacter, MAC, H. pylori
- SE: GI distress (motilin receptor stimulation), reversible deafness (high dose), QT prolongation
- Cytochrome P450 inhibition
- Clindamycin — bacteriostatic
- Spectrum: Gram+ cocci (incl. CA-MRSA), anaerobes (incl. B. fragilis)
- Concentrates in bone → osteomyelitis
- SE: pseudomembranous colitis (C. difficile) — most common cause
- Chloramphenicol — bacteriostatic
- Wide spectrum; backup for Salmonella typhi, B. fragilis, Rickettsia, meningitis
- Hepatic glucuronidation; dose reduction in neonates/liver dysfunction
- SE: dose-dependent marrow suppression, aplastic anemia (1:35,000), gray baby syndrome
- Linezolid — bacteriostatic
- Inhibits initiation complex (50S)
- Spectrum: VRSA, VRE, drug-resistant pneumococci
- SE: bone marrow suppression (platelets), MAO-A/B inhibition
- Quinupristin-Dalfopristin — bacteriostatic
- Spectrum: VRSA, drug-resistant Gram+
- Active against E. faecium (including VRE), not E. faecalis
- SE: diarrhea, jaundice, severe headache
📌 High-Yield
- Aminoglycosides are concentration-dependent killers; macrolides are time-dependent.
- Linezolid is effective against both E. faecium and E. faecalis VRE; quinupristin-dalfopristin covers only E. faecium.
| Drug | Ribosomal Target | Key Spectrum | Distinctive SE |
|---|---|---|---|
| Gentamicin | 30S | Gram− rods | Nephrotoxicity, ototoxicity |
| Doxycycline | 30S | Chlamydia, Rickettsia, Lyme | Phototoxicity, tooth discoloration |
| Azithromycin | 50S | Atypicals, Legionella | QT prolongation, GI distress |
| Clindamycin | 50S | Anaerobic, CA-MRSA | Pseudomembranous colitis |
| Linezolid | 50S | VRE, VRSA | Marrow suppression, MAO inhibition |
🧪 Nucleic Acid & Folate Synthesis Inhibitors
Folate Synthesis Inhibitors
- Sulfonamides
- Competitive inhibitors of p-aminobenzoic acid (PABA) → block dihydropteroate synthase
- Bacteriostatic
- Resistance: altered enzyme, ↑ PABA production, exogenous folate use
- Sulfasalazine — prodrug; active in ulcerative colitis & rheumatoid arthritis
- Ag sulfadiazine — burns
- Trimethoprim / Pyrimethamine
- Inhibit dihydrofolate reductase (DHFR)
- Synergy with sulfonamides — sequential blockade
- Trimethoprim-Sulfamethoxazole (TMP-SMX, cotrimoxazole)
- Bacterial — Nocardia (DOC), Listeria (backup), Gram− (E. coli, Salmonella, Shigella), Staph (incl. CA-MRSA)
- Fungal — Pneumocystis jirovecii (DOC; alternatives: pentamidine, atovaquone)
- Protozoal — Toxoplasma (sulfadiazine + pyrimethamine)
- Pharmacokinetics
- Sulfonamides — hepatic acetylation; renal excretion; crystalluria (older agents)
- High protein binding → kernicterus risk (avoid in 3rd trimester)
- Adverse effects (sulfonamides)
- Hypersensitivity (Stevens–Johnson, rashes)
- Hemolysis in G6PD deficiency
- Phototoxicity
- Trimethoprim — bone marrow suppression (leukopenia)
Fluoroquinolones
- Mechanism
- Inhibit topoisomerase II (DNA gyrase) and topoisomerase IV → prevent DNA replication
- Bactericidal
- Spectrum
- UTIs, Gram− infections (ciprofloxacin)
- Drug-resistant pneumococci (levofloxacin)
- Bacillus anthracis (anthrax)
- Pharmacokinetics
- Absorption reduced by iron/calcium
- Renal clearance (filtration + secretion); probenecid inhibits secretion
- Dose reduction in renal dysfunction
- Adverse effects
- Tendonitis / tendon rupture (black box warning)
- Peripheral neuropathy
- Phototoxicity, rashes
- CNS: insomnia, dizziness, headache
- Contraindicated in pregnancy & children (chondrogenesis inhibition)
⚠️ Exam Trap
- Fluoroquinolones are contraindicated in pregnancy and children < 18 years due to cartilage damage.
- TMP-SMX is the DOC for Pneumocystis jirovecii and Nocardia.
💊 Other Antimicrobial Agents
Metronidazole
- Mechanism
- Converted to reactive free radicals by ferredoxin in anaerobic organisms
- Binds DNA → strand breakage (bactericidal)
- Spectrum
- Antiprotozoal — Giardia, Trichomonas, Entamoeba
- Antibacterial — anaerobes (Bacteroides, Clostridium), Gardnerella, H. pylori
- DOC for pseudomembranous colitis (C. difficile)
- Adverse effects
- Metallic taste
- Disulfiram-like reaction with alcohol
β-Lactamase Inhibitors
- Clavulanic acid, sulbactam, tazobactam
- Used in combination with penicillins to extend spectrum
- Examples: amoxicillin-clavulanate, piperacillin-tazobactam
📌 Clinical Pearl
- Metronidazole is the drug of choice for C. difficile colitis and most anaerobic infections above the diaphragm.
🫁 Antitubercular Drugs
- Combination therapy is mandatory
- Delays/prevents resistance
- Provides additive / synergistic effects
- Standard regimen: 2–4 drugs from the first-line list
- First-line agents
- Isoniazid (INH), rifampin, ethambutol, pyrazinamide
- Prophylaxis
- Isoniazid 9 months or rifampin 4 months
- May be combined
- MAC (Mycobacterium avium-intracellulare)
- Prophylaxis: azithromycin or clarithromycin
- Treatment: clarithromycin + ethambutol + rifabutin
| Drug | Mechanism | Key Adverse Effects |
|---|---|---|
| Isoniazid (INH) | Inhibits mycolic acid synthesis (prodrug; activated by catalase) | Hepatitis (age-dependent), peripheral neuritis (use B6), sideroblastic anemia, SLE (slow acetylators) |
| Rifampin | Inhibits DNA-dependent RNA polymerase | Hepatitis, P450 induction, red-orange secretions (urine, tears, sweat) |
| Ethambutol | Inhibits arabinogalactan synthesis (cell wall) | Dose-dependent retrobulbar neuritis → ↓ visual acuity, red-green color discrimination |
| Pyrazinamide | Unknown (acidic environment activity) | Hepatitis, hyperuricemia (gout) |
| Streptomycin | 30S protein synthesis inhibition (aminoglycoside) | Deafness (irreversible), vestibular dysfunction, nephrotoxicity |
⚠️ Exam Trap
- Isoniazid resistance is often due to katG gene deletion (catalase needed for prodrug activation).
- Rifampin causes P450 induction → reduces efficacy of oral contraceptives, warfarin, etc.
- Ethambutol toxicity is dose-dependent and affects red-green color vision first.
📌 High-Yield
- Always give pyridoxine (vitamin B6) with isoniazid to prevent peripheral neuropathy.
- Rifampin metabolites cause orange-red discoloration of body fluids — reassure patients.
INH
+
Rifampin
+
Ethambutol
+
Pyrazinamide
→
Standard 4-drug regimen
⭐ Clinical Pearls & High-Yield Facts
Drugs to Avoid in Pregnancy
- Aminoglycosides — ototoxicity, nephrotoxicity
- Fluoroquinolones — cartilage damage
- Sulfonamides — kernicterus risk (3rd trimester)
- Tetracyclines — tooth/bone effects
Phototoxic Agents
- Tetracyclines (especially demeclocycline, doxycycline)
- Sulfonamides
- Fluoroquinolones
Community-Acquired Pneumonia (CAP)
- Most common pathogens in patients with no comorbidity: M. pneumoniae, C. pneumoniae, viruses
- In smokers: Streptococcus pneumoniae more frequent
- Macrolides cover most of these (except viruses) → first-line empiric therapy
H. pylori Eradication Regimens
- Classic "BMT" — bismuth, metronidazole, tetracycline
- Alternative: clarithromycin, amoxicillin, omeprazole (triple therapy)
Key Resistance Mechanisms
- β-lactams — β-lactamase, altered PBPs, porin changes
- Aminoglycosides — acetyl/phosphoryl/adenylyl transferases (conjugation inactivation)
- Macrolides — methyltransferases (50S alteration), efflux pumps
- Tetracyclines — efflux pumps
- Fluoroquinolones — altered topoisomerases, efflux
- Chloramphenicol — acetyltransferase
- Vancomycin — D-Ala → D-Lactate change (VRE/VRSA)
- INH — katG deletion (loss of catalase activation)
📌 Clinical Pearl
- For MRSA: vancomycin, linezolid, daptomycin, or ceftaroline (depending on site).
- For Pseudomonas: antipseudomonal penicillins, ceftazidime, cefepime, carbapenems, or aminoglycosides.
- For UTIs: TMP-SMX, fluoroquinolones, nitrofurantoin (reserve quinolones for complicated cases).
- For STIs: ceftriaxone (gonorrhea), doxycycline or azithromycin (chlamydia), penicillin G (syphilis).
⚠️ Exam Trap
- Bacteriostatic + bactericidal combinations can be antagonistic — e.g., tetracycline + penicillin.
- Probenecid prolongs the half-life of penicillins, cephalosporins, and fluoroquinolones by blocking renal tubular secretion.