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Complete Guide to Antibiotics: Mechanisms, Uses, ADRs, Contraindications

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Overview: How Antibiotics Work (4 Main Mechanisms)

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1. BETA-LACTAMS

A. Penicillins

• Penicillin G/V: Streptococcal pharyngitis, pneumococcal pneumonia, syphilis, meningococcal meningitis, gas gangrene, actinomycosis, Lyme disease (mild), rheumatic fever prophylaxis
• Ampicillin/Amoxicillin: UTIs, otitis media, sinusitis, Listeria meningitis, Enterococcal infections, H. pylori (triple therapy)
• Piperacillin/tazobactam: Hospital-acquired pneumonia, febrile neutropenia, intra-abdominal infections, complicated skin infections

• Hypersensitivity (most important): Maculopapular rash, urticaria, fever, serum sickness, angioedema, anaphylaxis (0.004-0.04%; death in 0.001%)
  • IgE-mediated (immediate): Anaphylaxis, urticaria - respond to minor determinants
  • IgG-mediated: Serum sickness (after >1 week of therapy)
  • Ampicillin rash: 9% incidence; nearly 100% in infectious mononucleosis (EBV) - NOT a true allergy in this context
• Hematologic: Reversible neutropenia (especially nafcillin at high doses >8-12 g for >21 days), Coombs-positive hemolytic anemia (rare), eosinophilia
• Renal: Interstitial nephritis (especially antistaphylococcal penicillins, piperacillin)
• Neurologic: High-dose penicillin G can cause seizures (especially in renal failure)
• GI: Diarrhea, nausea (especially amoxicillin/clavulanate - clavulanate causes GI distress); C. difficile colitis
• Electrolyte: Hypernatremia/hyperkalemia from high doses of sodium/potassium salts

• History of IgE-mediated (anaphylactic) penicillin allergy - absolute contraindication
• Use with caution in renal failure (dose adjust)
• Cross-reactivity with cephalosporins: ~1-2% in true penicillin allergy (older data overstated at 10%)

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B. Cephalosporins

• Cefazolin: Surgical prophylaxis (standard of care), MSSA bacteremia, cellulitis, UTIs
• Ceftriaxone (IM/IV): Community-acquired pneumonia, meningitis, gonorrhea, Lyme disease (late), gram-negative bacteremia - widely used due to once-daily dosing
• Ceftazidime: Pseudomonal infections (pneumonia, UTI, bacteremia)
• Cefepime: Febrile neutropenia empiric therapy, hospital-acquired gram-negative infections
• Ceftaroline: MRSA infections (skin, pneumonia)

• Hypersensitivity: Rash, urticaria, anaphylaxis (less common than penicillins; ~1-2% cross-reactivity in penicillin allergy)
• Cefoperazone, Cefamandole, Cefotetan - contain MTT (methylthiotetrazole) side chain - causes disulfiram-like reaction with alcohol and inhibits Vitamin K-dependent clotting factors causing hypoprothrombinemia/bleeding
• Ceftriaxone: Biliary sludge/pseudolithiasis (especially in neonates/children - can cause cholestasis), displaces bilirubin from albumin - avoid in neonates
• Nephrotoxicity: Mild; increases risk when combined with aminoglycosides
• C. difficile colitis
• Cefepime: Neurotoxicity (confusion, encephalopathy, myoclonus) in renal impairment

• Known severe allergy to cephalosporins
• Ceftriaxone: Avoid in neonates with hyperbilirubinemia, concurrent calcium-containing IV solutions (precipitation risk)
• MTT-containing cephalosporins: Avoid alcohol

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C. Carbapenems

• Imipenem: Seizures (especially in renal failure, high doses, CNS pathology, elderly) - 1.5-2% incidence
• Meropenem: Fewer seizures than imipenem - preferred when CNS infection or seizure risk
• Drug interaction: Carbapenems (especially meropenem) significantly reduce valproic acid levels by up to 60-90% - do NOT coadminister; can precipitate seizures in epilepsy
• Nausea, vomiting, diarrhea
• Hypersensitivity reactions (cross-reactivity with penicillins ~1%)
• C. difficile colitis
• Neutropenia, thrombocytopenia (rare)

• Concurrent valproic acid use (major drug interaction - use alternative antibiotic if possible)
• Imipenem: Caution in patients with seizure history, renal failure
• Adjust dose in renal impairment (all carbapenems)

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D. Monobactams

• Gram-negative infections in patients with serious penicillin/cephalosporin allergy (no cross-reactivity with penicillins/carbapenems)
• UTIs, pneumonia, sepsis due to gram-negative bacilli
• Note: Cross-reactivity with ceftazidime due to identical R1 side chain - avoid in ceftazidime allergy

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2. GLYCOPEPTIDES

Vancomycin

• MRSA infections: bacteremia, endocarditis, osteomyelitis, pneumonia, skin/soft tissue (drug of choice)
• Penicillin-allergic patients with serious streptococcal/enterococcal infections
• Oral: C. difficile colitis (non-absorbable - acts locally in GI tract)
• Empiric coverage in febrile neutropenia (with gram-negative coverage)

• "Red Man Syndrome": Flushing, erythema, urticaria, hypotension of face, neck, upper chest - caused by non-immunologic mast cell degranulation due to rapid infusion; NOT a true allergy. Prevented by slow infusion (>60 min), premedication with antihistamines. Rate-related, not dose-related.
• Nephrotoxicity: Important - especially with aminoglycosides (synergistic nephrotoxicity), high trough levels, prolonged courses. Monitor serum creatinine, vancomycin AUC/MIC (AUC-guided dosing preferred over trough monitoring now)
• Ototoxicity: Tinnitus, hearing loss - especially with aminoglycosides, high serum levels, renal failure
• Neutropenia, thrombocytopenia (rare)
• Phlebitis at IV site

• Renal failure: Reduce dose/extend interval (renally cleared)
• Avoid combination with other nephrotoxic/ototoxic agents when possible
• VRE (Vancomycin-Resistant Enterococcus): Resistance via VanA/VanB gene - use linezolid or daptomycin

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Teicoplanin

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3. AMINOGLYCOSIDES

• Enter bacterial cell via oxygen-dependent active transport (requires electron transport chain - therefore INACTIVE against strict anaerobes)
• Bind irreversibly to 30S ribosomal subunit (specifically 16S rRNA of 30S subunit)
• Cause misreading of mRNA codon - incorporation of wrong amino acids into proteins
• Also disrupt cell membrane integrity
• Bactericidal and concentration-dependent (higher peak concentrations = greater killing) - once-daily dosing (ODD) exploits this

• Pseudomonas aeruginosa (tobramycin and amikacin preferred)
• Enterobacterales: E. coli, Klebsiella, Proteus, Serratia, Enterobacter
• Streptomycin: Mycobacterium tuberculosis (second-line), Yersinia pestis (plague), Francisella tularensis, Brucella
• Synergy with beta-lactams/glycopeptides for: Enterococcus, Viridans streptococci (endocarditis), Listeria monocytogenes
• Neomycin: Topical only (too toxic systemically); bowel prep pre-surgery

• Severe gram-negative infections (bacteremia, pneumonia, UTI, sepsis) - usually in combination with beta-lactams
• Endocarditis synergistic therapy (Enterococcal, Streptococcal)
• TB: Streptomycin (second-line), Amikacin (MDR-TB)
• Tobramycin inhalation: Cystic fibrosis (Pseudomonal lung infections)
• Gentamicin eye/ear drops: Local infections

• Nephrotoxicity: Most common serious ADR. Acute tubular necrosis (proximal tubular injury). Accumulation in cortical tubular cells. Risk increased with prolonged courses, high troughs, concurrent nephrotoxins (NSAIDs, vancomycin, cisplatin, amphotericin B), pre-existing renal disease, hypovolemia. Monitor creatinine and drug levels. Usually reversible.
• Ototoxicity: Dose-related, often irreversible
  • Cochlear: High-frequency hearing loss progressing to deafness (amikacin > neomycin > kanamycin > gentamicin)
  • Vestibular: Vertigo, ataxia, nausea (gentamicin, tobramycin > streptomycin)
  • Toxicity results from accumulation in perilymph/endolymph of cochlea - damages outer hair cells
  • Risk factors: High cumulative dose, renal failure, elderly, concurrent loop diuretics (furosemide), prior aminoglycoside use
• Neuromuscular blockade: Rare - can cause respiratory paralysis especially if given with muscle relaxants or in myasthenia gravis. Calcium gluconate reverses this.
• Contraindicated in pregnancy - crosses placenta - fetal ototoxicity (Category D)

• Myasthenia gravis (neuromuscular blockade risk)
• Pregnancy (fetal ototoxicity - Category D; streptomycin documented to cause congenital deafness)
• Severe renal failure without dose adjustment
• Concurrent furosemide (ototoxicity), vancomycin (nephrotoxicity + ototoxicity)
• Do NOT use for anaerobic infections (inactive)

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4. TETRACYCLINES

• Bind reversibly to 30S ribosomal subunit
• Block attachment of aminoacyl-tRNA to the ribosomal acceptor (A) site
• Inhibit protein synthesis - bacteriostatic
• Enter gram-negative bacteria via outer membrane porins (OmpF/C) - concentration inside cell exceeds outside by active transport

• Atypical pneumonia (Mycoplasma, Chlamydophila) - doxycycline or macrolides
• Rickettsia infections: RMSF (Rocky Mountain spotted fever), epidemic typhus - doxycycline drug of choice
• STIs: Chlamydia, lymphogranuloma venereum
• Lyme disease (early)
• Acne vulgaris (tetracycline, doxycycline, minocycline - inhibit lipase-producing P. acnes)
• Malaria prophylaxis (doxycycline)
• Cholera (single dose doxycycline)

• Photosensitivity: Sunburn-like reactions with sun exposure - especially doxycycline, demeclocycline; advise sun avoidance
• GI: Nausea, vomiting, esophageal ulceration (especially if taken lying down, without water - "pill esophagitis"); doxycycline - take with full glass of water, remain upright
• Teeth and bone: Chelates calcium - causes yellow-brown discoloration of developing teeth and inhibits bone growth in children under 8 years; deposits in growing bones causing retarded growth
• Hepatotoxicity: Rare but serious, especially in pregnant women given IV tetracycline - fatty liver necrosis
• Benign intracranial hypertension (pseudotumor cerebri) - minocycline especially
• Vestibular toxicity (minocycline): Dizziness, vertigo, ataxia, tinnitus - dose-related, reversible
• Anti-anabolic effect: Azotemia in renal failure patients (doxycycline is exception - safe in renal failure)
• Superinfections: C. difficile, oral/vaginal candidiasis (broad-spectrum suppression of normal flora)

• Pregnancy (crosses placenta - discolors fetal teeth, inhibits bone growth) - Category D
• Children under 8 years (tooth discoloration - exception: RMSF where benefits outweigh risks)
• Renal failure (use doxycycline only - it is excreted via GI tract, safe in renal failure; other tetracyclines accumulate)
• Drug interactions: Antacids, calcium, iron, magnesium, dairy products chelate tetracyclines and reduce oral absorption by up to 50% - take 1-2 hours before or after

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5. MACROLIDES

• Bind reversibly to 23S rRNA of 50S ribosomal subunit (peptidyl transferase center)
• Block translocation step - prevent movement of ribosome along mRNA (transpeptidation)
• Also inhibit ribosome assembly
• Bacteriostatic (can be bactericidal at high concentrations vs some organisms)
• Tissue concentrations >> serum concentrations (especially azithromycin - concentrates in macrophages, neutrophils - long tissue half-life ~68 hours, allows Z-pack dosing)

• CAP (community-acquired pneumonia): Covers both typical (pneumococcus) and atypical (Mycoplasma, Chlamydophila, Legionella)
• Atypical pneumonia: Drug of choice
• STIs: Chlamydia (azithromycin 1 g single dose)
• Pertussis (whooping cough): Azithromycin or erythromycin
• Penicillin allergy alternative for streptococcal infections
• MAC infection in HIV/AIDS: Clarithromycin + ethambutol (± rifabutin)
• H. pylori: Clarithromycin + amoxicillin + PPI (standard triple therapy) or bismuth quadruple therapy
• GI motility: Erythromycin is motilin receptor agonist - low-dose used for gastroparesis

• GI: Most common - nausea, vomiting, abdominal cramps, diarrhea (especially erythromycin - due to motilin receptor agonism stimulating GI motility); often limits compliance
• Hepatotoxicity: Cholestatic jaundice (especially erythromycin estolate salt) - avoid in liver disease; estolate is most hepatotoxic form
• QT prolongation: All macrolides prolong QT interval - risk of torsades de pointes (TdP); especially azithromycin + erythromycin. Avoid in patients with pre-existing QT prolongation, concurrent QT-prolonging drugs (antipsychotics, amiodarone, quinolones), hypokalemia, hypomagnesemia
• Drug interactions: Erythromycin and clarithromycin are potent CYP3A4 inhibitors - inhibit metabolism of many drugs: statins (myopathy), warfarin (bleeding), cyclosporine, tacrolimus, digoxin, benzodiazepines, theophylline. Azithromycin is NOT a CYP3A4 inhibitor (fewer drug interactions)
• Ototoxicity: High-dose IV erythromycin (rare, reversible)
• Telithromycin (ketolide): Hepatotoxicity (rare but severe, including liver failure) - now very limited use

• Pre-existing QT prolongation, hypokalemia/hypomagnesemia (risk of TdP)
• Concurrent QT-prolonging drugs
• Erythromycin estolate: Liver disease, pregnancy
• CYP3A4 interactions: Caution with statins, warfarin, ergot alkaloids

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6. FLUOROQUINOLONES (QUINOLONES)

• Generation 1: Nalidixic acid (urinary only - no systemic use)
• Generation 2: Ciprofloxacin, Norfloxacin, Ofloxacin, Lomefloxacin
• Generation 3 (Respiratory): Levofloxacin
• Generation 4 (Respiratory + Anaerobic): Moxifloxacin, Gemifloxacin

• Inhibit bacterial type II topoisomerases:
  • DNA gyrase (topoisomerase II): Primary target in gram-negative bacteria - introduces negative supercoils needed for DNA replication/transcription
  • Topoisomerase IV: Primary target in gram-positive bacteria - separates interlocked daughter chromosomes after replication
• Fluoroquinolones stabilize the enzyme-DNA complex (cleavable complex), causing double-strand DNA breaks - bactericidal, concentration-dependent killing

• UTIs (uncomplicated and complicated): Ciprofloxacin, levofloxacin, norfloxacin
• CAP (community-acquired pneumonia): Levofloxacin, moxifloxacin (respiratory quinolones)
• Bacterial gastroenteritis (Salmonella, Shigella, Campylobacter): Ciprofloxacin
• Anthrax (inhalational): Ciprofloxacin or doxycycline - post-exposure prophylaxis and treatment
• Gonorrhea: Ciprofloxacin (but high resistance - ceftriaxone now preferred)
• TB: Levofloxacin/moxifloxacin in MDR-TB regimens
• Prostatitis: Ciprofloxacin (excellent prostate penetration)
• Osteomyelitis: Oral ciprofloxacin (good bioavailability - only oral drug for bone gram-negative infections)

• Tendinopathy and tendon rupture: Black box warning - Achilles tendon most common; risk with age >60, concurrent corticosteroids, renal failure. Can occur during or weeks after therapy. Also tendinitis in shoulder, hand.
• Peripheral neuropathy: Black box warning - burning, tingling, numbness, weakness; may be irreversible
• CNS toxicity: Headache, dizziness, insomnia; rarely seizures (especially in elderly, CNS pathology, concurrent NSAIDs/theophylline)
• QT prolongation: Risk of torsades de pointes - especially moxifloxacin > levofloxacin > ciprofloxacin; avoid with other QT-prolonging drugs
• Phototoxicity: Lomefloxacin, sparfloxacin - significant; levofloxacin, ciprofloxacin - mild; avoid sun exposure
• Cartilage damage in immature animals: Basis for avoiding in children and pregnancy (black box warning); arthropathy in weight-bearing joints
• Drug interactions: Fluoroquinolones are inhibited by antacids, calcium, iron, zinc, sucralfate - reduce absorption; administer 2 hours apart. Ciprofloxacin inhibits CYP1A2 - raises levels of theophylline, caffeine, warfarin.
• GI: Nausea, diarrhea, C. difficile colitis (broad-spectrum disturbance of gut flora - one of the most common antibiotic triggers for C. diff)
• Hepatotoxicity (rare - trovafloxacin withdrawn for this reason)
• Hypoglycemia (especially with sulfonylureas - ciprofloxacin/gatifloxacin increase insulin secretion)

• Children and adolescents (< 18 years) - cartilage toxicity (relative; used in cystic fibrosis when no alternative)
• Pregnancy and breastfeeding
• Pre-existing tendon disorders, on corticosteroids (tendon rupture risk)
• QT prolongation, hypokalemia, concurrent QT-prolonging drugs
• History of myasthenia gravis (can exacerbate neuromuscular blockade)

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7. SULFONAMIDES AND TRIMETHOPRIM

Sulfonamides

• Structural analogues of para-aminobenzoic acid (PABA)
• Competitively inhibit dihydropteroate synthetase - blocks conversion of PABA into dihydropteroic acid (first step in folate synthesis)
• Bacteria synthesize their own folate (humans obtain it from diet) - selective toxicity
• Bacteriostatic

Trimethoprim

• Inhibits dihydrofolate reductase (DHFR) - blocks conversion of dihydrofolate to tetrahydrofolate (active form)
• 50,000-100,000x more potent against bacterial DHFR than human DHFR
• Bacteriostatic

TMP-SMX (Co-trimoxazole) - the combination (1:5 ratio)

• Pneumocystis jirovecii (PCP): Drug of choice for treatment AND prophylaxis in HIV (CD4 < 200) - high-dose TMP-SMX
• Toxoplasma gondii: Prophylaxis in HIV (pyrimethamine + sulfadiazine for treatment; TMP-SMX prophylaxis)
• MRSA (community-associated): TMP-SMX effective for skin/soft tissue infections
• UTIs (E. coli - though resistance >20% in many areas), Proteus mirabilis
• Respiratory: H. influenzae, Moraxella catarrhalis, S. pneumoniae (CAP - resistance limits use)
• GI: Shigella, Salmonella (resistance increasing), Cyclospora, Isospora
• Nocardia (TMP-SMX drug of choice)
• Listeria monocytogenes (alternative to ampicillin)

• UTI treatment and prophylaxis
• PCP treatment and prophylaxis (HIV/AIDS)
• MRSA skin/soft tissue infections
• Nocardiosis
• Traveler's diarrhea (prophylaxis/treatment in endemic areas)

• Hypersensitivity: Rash (including Stevens-Johnson syndrome, TEN - toxic epidermal necrolysis), fever, serum sickness; much more common in HIV patients (up to 40-80% develop rash during PCP treatment)
• Hematologic: Dose-related bone marrow suppression - megaloblastic anemia (folate depletion), thrombocytopenia, leukopenia, agranulocytosis; supplement with folinic acid (leucovorin) during high-dose treatment
• Kernicterus: Sulfonamides displace bilirubin from albumin - contraindicated in neonates and last trimester of pregnancy (risk of neonatal jaundice/kernicterus)
• Renal: Crystalluria/urolithiasis (older sulfonamides, less with newer ones) - maintain adequate hydration; interstitial nephritis, hyperkalemia (TMP inhibits potassium secretion in collecting duct - acts like potassium-sparing diuretic)
• Hepatotoxicity: Cholestatic jaundice (rare)
• Drug interactions: TMP-SMX raises serum creatinine without true GFR reduction (TMP inhibits tubular secretion of creatinine); potentiates warfarin (inhibits CYP2C9); potentiates methotrexate (folate antagonism)

• Pregnancy (especially late trimester - kernicterus risk), nursing mothers
• Neonates < 2 months old (kernicterus)
• Severe renal/hepatic failure
• G6PD deficiency (hemolysis with dapsone/sulfones particularly)
• Megaloblastic anemia due to folate deficiency

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8. CHLORAMPHENICOL

• Bacterial meningitis (H. influenzae, meningococcal, pneumococcal) in penicillin-allergic patients
• Typhoid fever (Salmonella typhi) - ciprofloxacin preferred now
• Rickettsia in pregnancy (doxycycline contraindicated)
• Brain abscess (excellent CNS penetration)
• Now largely replaced due to toxicity; reserve for life-threatening infections when alternatives fail

• Bone marrow toxicity - two types:
  • Dose-related (reversible): Inhibits mitochondrial protein synthesis in bone marrow - anemia, leukopenia, thrombocytopenia at >25 mcg/mL; reversible on discontinuation
  • Idiosyncratic aplastic anemia (irreversible): Rare (1:25,000-40,000), fatal - no dose relationship; not predictable; requires no rechallenge
• "Gray Baby Syndrome": Neonates and premature infants lack adequate hepatic glucuronyl transferase (conjugation) and renal excretion - accumulation causes: abdominal distension, vomiting, progressive pallid cyanosis, circulatory collapse, death. Avoid in neonates; if must use, monitor levels (keep <25 mcg/mL)
• GI: Nausea, vomiting, diarrhea; oral and vaginal candidiasis (suppresses normal flora)
• Drug interactions: Potent inhibitor of CYP2C9 and CYP3A4 - raises levels of phenytoin, warfarin, sulfonylureas, cyclosporine

• Neonates and premature infants (Gray Baby Syndrome)
• Pre-existing bone marrow depression
• Pregnancy (avoid; Gray Baby Syndrome in neonate)
• Prior history of chloramphenicol-associated blood dyscrasias
• Concurrent myelosuppressive therapy (chemotherapy, zidovudine)

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9. LINCOSAMIDES

• Streptococcus pyogenes, S. agalactiae, S. pneumoniae
• MSSA, MRSA (community - check D-zone test for inducible resistance)
• Peptostreptococcus, Clostridium (except C. difficile), Bacteroides fragilis (excellent), Fusobacterium
• Toxoplasma gondii (with pyrimethamine - alternative regimen)
• Babesia (with quinine)
• Note: INACTIVE against gram-negative aerobes, Enterococcus

• Anaerobic infections: Aspiration pneumonia, lung abscess, intra-abdominal, pelvic infections (excellent anaerobic coverage)
• Diabetic foot infections (polymicrobial - gram-positive + anaerobes)
• MRSA skin/soft tissue infections (community-acquired) - in areas with susceptible strains
• Necrotizing fasciitis (with beta-lactam - clindamycin suppresses toxin production by inhibiting protein synthesis)
• Osteomyelitis, septic arthritis (excellent bone penetration)
• Toxin suppression in invasive GAS (Group A Strep) - clindamycin added to penicillin (Eagle effect prevention + toxin suppression)
• Acne vulgaris (topical clindamycin)
• Vaginal infections: Bacterial vaginosis (topical or oral)
• PID (pelvic inflammatory disease) - with gentamicin

• C. difficile colitis: HIGH RISK - clindamycin is one of the top antibiotics causing C. diff (along with cephalosporins, fluoroquinolones, ampicillin); disrupts normal gut flora, allows C. diff overgrowth. Severe cases: pseudomembranous colitis
• GI: Diarrhea (10-30%), nausea, abdominal cramps
• Hepatotoxicity: Elevated LFTs (mild, transient)
• Hypersensitivity: Rash, Stevens-Johnson syndrome (rare)
• Metallic taste (IV administration)

• History of clindamycin-associated C. difficile colitis or pseudomembranous colitis
• Active C. difficile infection
• Check inducible macrolide resistance (D-zone test/D-test) before using for MRSA

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10. OXAZOLIDINONES

• Bind to 23S rRNA of 50S ribosomal subunit at the peptidyl transferase center
• Unique mechanism: Block formation of the initiation complex (70S ribosome assembly) by binding 50S and preventing it from joining 30S - inhibit the very first step of translation
• No cross-resistance with other ribosomal antibiotics (different binding site/mechanism)
• Bacteriostatic against most organisms (including MRSA, VRE)

• MRSA (methicillin-resistant Staphylococcus aureus) - alternative to vancomycin
• VRE (vancomycin-resistant Enterococcus) - drug of choice with daptomycin
• MSSA, MRSE (coagulase-negative staph)
• Streptococci (including penicillin-resistant S. pneumoniae)
• MDR-TB (Mycobacterium tuberculosis) - as part of MDR-TB regimens
• Nocardia (alternative)

• VRE infections (gold standard) - bacteremia, endocarditis, UTI
• MRSA: Skin/soft tissue, pneumonia (IV or oral), osteomyelitis (oral therapy - 100% bioavailability)
• 100% oral bioavailability - unique among antibiotics active vs MRSA; allows IV-to-oral switch

• Myelosuppression (bone marrow suppression): Thrombocytopenia most common (5-10%), also anemia and neutropenia; usually reversible; occurs with prolonged use (>2 weeks); monitor CBC weekly
• Serotonin syndrome: Linezolid is a weak, reversible MAO inhibitor - inhibits MAO-A - interacts with serotonergic drugs (SSRIs, SNRIs, TCAs, meperidine, tramadol) causing potentially fatal serotonin syndrome (hyperthermia, agitation, myoclonus, autonomic instability)
• Peripheral and optic neuropathy: With prolonged use (>28 days) - irreversible optic neuropathy reported; patients should have regular ophthalmology monitoring
• Lactic acidosis: Inhibition of mitochondrial protein synthesis (similar to chloramphenicol) - rare but serious
• GI: Nausea, diarrhea, headache

• Concurrent serotonergic drugs (SSRIs, SNRIs, MAOIs, tramadol, meperidine) - serotonin syndrome risk
• Uncontrolled hypertension (MAO inhibition - avoid tyramine-rich foods during treatment)
• Prolonged use in pediatrics or patients requiring >2-4 weeks therapy (neuropathy, myelosuppression risk) - tedizolid preferred for shorter courses

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11. GLYCYLCYCLINES

• Gram-positives: MRSA, VRE, penicillin-resistant S. pneumoniae
• Gram-negatives: ESBL-producing Enterobacterales, carbapenem-resistant Acinetobacter baumannii, Bacteroides
• Anaerobes, atypicals
• NOT active against: Pseudomonas aeruginosa, Proteus, Providencia (intrinsic resistance via efflux pumps)

• Nausea and vomiting: Major limitation - highest GI ADR rate among antibiotics (~40%)
• Black box warning: Increased all-cause mortality in clinical trials (mechanism unclear); should only be used when alternative antibiotics not suitable
• Photosensitivity, hepatotoxicity, pancreatitis (rare)
• Permanent tooth discoloration in children (tetracycline class effect)

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12. POLYMYXINS

• Pseudomonas aeruginosa (MDR strains)
• Acinetobacter baumannii (carbapenem-resistant)
• Klebsiella pneumoniae (carbapenem-resistant - KPC, NDR)
• Enterobacterales (MDR)
• "Last-resort" antibiotics for pan-drug-resistant gram-negative infections

• Nephrotoxicity: Major dose-limiting toxicity - acute tubular necrosis - up to 30-50% incidence with systemic use. Requires careful renal monitoring and dose adjustment.
• Neurotoxicity: Dizziness, paresthesias, peripheral neuropathy, ataxia, slurred speech, respiratory arrest (rare)
• Neuromuscular blockade (use caution in myasthenia gravis)
• Injection site pain (IM)
• Colistin: Can be inhaled (nebulized) for chronic Pseudomonas in cystic fibrosis - local toxicity minimal

• Renal failure (without dose adjustment)
• Concurrent nephrotoxic drugs
• Myasthenia gravis
• Pregnancy (potential fetal nephrotoxicity/neurotoxicity)

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13. DAPTOMYCIN

• MRSA (bacteremia, right-sided endocarditis - drug of choice for vancomycin-resistant MRSA bacteremia)
• VRE
• MSSA (bacteremia)
• Streptococci, Enterococci
• Daptomycin is INACTIVATED by pulmonary surfactant - do NOT use for pneumonia

• MRSA and S. aureus bacteremia and right-sided endocarditis - FDA approved (gold standard)
• VRE infections
• Complicated skin/soft tissue infections (cSSTI)
• NOT for pneumonia (inactivated by surfactant)

• Myopathy/CPK elevation: Most important - elevated creatine phosphokinase (CPK) levels, muscle pain, weakness; rare rhabdomyolysis; monitor CPK weekly; discontinue if CPK >5x ULN
• Peripheral neuropathy (rare, with prolonged use)
• Eosinophilic pneumonia (rare but serious)
• Drug interaction: Statins increase myopathy risk (both inhibit HMG-CoA reductase/mitochondrial function) - consider holding statins during daptomycin therapy

• Pneumonia (drug inactivated by surfactant)
• Concurrent statin use (myopathy risk - consider holding statin)
• Monitor CPK - hold if >1000 IU/L or symptomatic myopathy

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14. RIFAMYCINS

• Bind to beta subunit of bacterial DNA-dependent RNA polymerase (encoded by rpoB gene)
• Block initiation of RNA synthesis (transcription) - bactericidal
• Resistance develops rapidly (single step mutation in rpoB) - NEVER use as monotherapy for systemic infections

• Mycobacterium tuberculosis (backbone of all TB regimens - RIPE: Rifampin + Isoniazid + Pyrazinamide + Ethambutol)
• Mycobacterium leprae (multi-drug leprosy therapy)
• MAC (Mycobacterium avium complex) - rifabutin preferred (less CYP interaction than rifampin)
• Neisseria meningitidis (chemoprophylaxis for close contacts)
• H. influenzae type b (prophylaxis)
• MRSA biofilm infections: Rifampin + vancomycin/daptomycin for prosthetic device infections
• Staphylococci (rifampin + another agent for biofilm infections, prosthetic joint/valve infections)

• TB: Rifampin is backbone of treatment (4-drug initial phase RIPE x 2 months, then RI x 4 months)
• Meningococcal prophylaxis: 600 mg PO BID x 2 days (adults)
• Leprosy: Multi-drug therapy (MDT)
• Rifaximin: Non-absorbable (GI local action) - traveler's diarrhea, hepatic encephalopathy (reduces ammonia-producing bacteria), C. difficile prevention

• Harmless orange/red discoloration of urine, feces, tears, sweat, saliva, contact lenses - warn patients! Not dangerous but alarming.
• Hepatotoxicity: Elevated LFTs, drug-induced hepatitis (especially when combined with isoniazid - synergistic hepatotoxicity); monitor LFTs
• GI: Nausea, vomiting, anorexia, abdominal pain
• Flu-like syndrome: With intermittent dosing (not daily) - fever, chills, headache, myalgias
• Thrombocytopenia, hemolytic anemia (rare, with intermittent dosing)
• Drug interactions (MOST IMPORTANT): Rifampin is the most potent inducer of CYP450 enzymes (CYP3A4, CYP2C9, CYP2C19) and P-glycoprotein in clinical use. Dramatically reduces levels of:
  • Oral contraceptives (pregnancy risk - use alternative contraception)
  • HIV antiretrovirals (especially PIs and NNRTIs - use rifabutin instead)
  • Warfarin (increased dose needed)
  • Methadone (withdrawal)
  • Statins, azole antifungals, benzodiazepines, calcium channel blockers, immunosuppressants (cyclosporine, tacrolimus), many others

• Severe hepatic disease (relative - monitor LFTs)
• Concurrent protease inhibitors (use rifabutin instead - weaker CYP inducer)
• Monotherapy in active infection (rapid resistance)
• Concurrent drug interactions: Review all patient medications

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15. METRONIDAZOLE (NITROIMIDAZOLES)

• Prodrug - activated exclusively in anaerobic/microaerophilic organisms with low redox potential
• Reduced by ferredoxin/flavodoxin electron transport system in anaerobes/protozoa to reactive nitro radical intermediates
• These intermediates cause double-strand DNA breaks - bactericidal
• Not activated in aerobic cells - basis for selective toxicity against anaerobes and parasites

• Anaerobic bacteria: Bacteroides fragilis (drug of choice), Fusobacterium, Clostridium species (including C. difficile - now preferred oral agent over vancomycin in non-severe colitis), Peptostreptococcus
• Protozoa (antiparasitic): Entamoeba histolytica (intestinal amebiasis, amebic liver abscess - drug of choice), Giardia lamblia, Trichomonas vaginalis, Blastocystis hominis
• H. pylori (component of triple therapy - but resistance emerging)

• Anaerobic/mixed infections: Intra-abdominal, pelvic, aspiration pneumonia, brain abscess
• C. difficile colitis (oral - non-severe cases; vancomycin preferred for severe)
• Bacterial vaginosis (metronidazole gel or oral)
• Trichomoniasis (2 g single dose; treat partner simultaneously)
• Amebiasis (intestinal and systemic - liver abscess)
• Giardiasis
• H. pylori eradication (component of triple/quadruple regimens)

• Metallic taste: Very common, unpleasant - patients should be warned
• GI: Nausea, vomiting, anorexia, abdominal cramps
• Disulfiram-like reaction with alcohol: Block aldehyde dehydrogenase (similar to disulfiram) - accumulate acetaldehyde - flushing, tachycardia, vomiting; avoid alcohol during and 48-72 hours after completing course
• Neurotoxicity: With high doses or prolonged use - peripheral neuropathy (burning, tingling), ataxia, dizziness, seizures; discontinue if neuro symptoms develop
• Darkening of urine (metabolites)
• Drug interactions: Potentiates warfarin (inhibits CYP2C9); prolongs action of vecuronium

• First trimester of pregnancy (theoretical teratogenicity - though no proven harm in humans; use after 1st trimester if necessary)
• Concurrent alcohol use (disulfiram reaction)
• Avoid in neurological disease (seizure risk at high doses)
• Not active against aerobic organisms - cannot substitute for aerobic coverage

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16. GLYCOPEPTIDE LIPOPEPTIDES / LIPOGLYCOPEPTIDES

• Acute bacterial skin/soft tissue infections (ABSSSI) - single-dose (oritavancin, dalbavancin) or once-weekly dosing
• Allows early hospital discharge with definitive therapy

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17. FOSFOMYCIN

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18. NITROFURANTOIN

• Pulmonary toxicity: Acute pneumonitis (rare, reversible hypersensitivity) or chronic pulmonary fibrosis (rare, with prolonged use >6 months)
• Hepatotoxicity: Chronic active hepatitis (rare, with long-term use)
• Peripheral neuropathy with prolonged use or renal failure
• GI: Nausea (macrocrystal formulation better tolerated)
• Hemolytic anemia in G6PD-deficient patients

• GFR <30 mL/min (inadequate urinary concentrations AND metabolite accumulation causing toxicity) - also Creatinine >1.5 mg/dL in older guidelines
• Pregnancy at term (39-42 weeks) - neonatal hemolytic anemia risk
• G6PD deficiency (hemolysis)

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19. ANTI-MRSA AGENTS SUMMARY

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QUICK REFERENCE: Ribosomal Targets

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ANTIBIOTIC SAFETY IN PREGNANCY (Quick Summary)

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KEY MNEMONICS

• "ESKAPE" pathogens (require special antibiotics): Enterococcus faecium, Staph aureus (MRSA), Klebsiella, Acinetobacter, Pseudomonas, Enterobacter
• "30S antibiotics" = "TACE": Tetracyclines, Aminoglycosides, Chloramphenicol (though it's 50S), wait - 30S: Tetracyclines + Aminoglycosides; 50S: MaCLO = Macrolides, Clindamycin, Linezolid, Oxazolidinones, Chloramphenicol
• Red Man Syndrome = Vancomycin, rate-related (slow infusion prevents it)
• Disulfiram reaction = Metronidazole + alcohol; MTT-containing cephalosporins + alcohol
• QT prolongation = Macrolides + Fluoroquinolones ("Mac & Floxin")
• Avoid in pregnancy = "FACT" = Fluoroquinolones, Aminoglycosides (C or D), Chloramphenicol (near term), Tetracyclines

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