Anti-Tubercular Drugs (KDT Style - Detailed)

Overview

Classification

First-Line (Preferred) Drugs

Second-Line Drugs

Standard Treatment Regimen

FIRST-LINE DRUGS (Detailed)

1. ISONIAZID (INH)

• INH is a prodrug activated by the mycobacterial catalase-peroxidase enzyme KatG
• The activated form covalently binds to acyl carrier protein reductase (InhA) and β-ketoacyl-ACP synthase (KasA)
• This inhibits mycolic acid synthesis, destroying the integrity of the mycobacterial cell wall
• Active against both intracellular (inside macrophages) and extracellular organisms
• MIC: inhibits most M. tuberculosis at ≤0.2 mcg/mL

• Well absorbed orally; peak plasma level 3-5 mcg/mL at 1-2 hours; absorption reduced by 50% with fatty meals
• Penetrates all body fluids including CSF (CSF level = 20-100% of serum level), caseous material, and macrophages
• Metabolized by N-acetyltransferase (NAT2) in the liver - genetically polymorphic
  • Fast acetylators: half-life <1 hour (common in East Asians, Eskimos)
  • Slow acetylators: half-life ~3 hours (common in Egyptians, Scandinavians)
• Slow acetylators accumulate more drug and parent compound but generally similar efficacy with daily dosing; risk of toxicity is higher
• Inhibits CYP450 enzymes - raises levels of phenytoin, carbamazepine, benzodiazepines

• Mutation/deletion of KatG gene → inability to activate prodrug (high-level resistance)
• Overexpression of inhA → low-level resistance (also cross-resistance with ethionamide)
• Mutations in KasA or ahpC

• Peripheral neuropathy (most common): due to pyridoxine (B6) deficiency caused by INH competing with pyridoxal phosphate. Prevented by co-administering pyridoxine 10-25 mg/day. Seen more in slow acetylators, malnourished, diabetics, alcoholics, pregnant women
• Hepatotoxicity: elevated transaminases in 10-20% of patients; clinical hepatitis in 1%; more common in >35 years and with alcohol use. Fatal hepatitis rare
• CNS effects: memory impairment, psychosis, seizures (especially in overdose)
• Lupus-like syndrome (antinuclear antibodies)
• Drug interactions: inhibits metabolism of phenytoin (toxicity), carbamazepine, warfarin

2. RIFAMPICIN (Rifampin)

• Binds to the beta subunit of DNA-dependent RNA polymerase (rpoB gene product)
• Blocks RNA transcription → inhibits mRNA synthesis
• Bactericidal; active against M. tuberculosis, MAC, M. leprae, as well as many gram-positive and gram-negative bacteria
• Active against both intracellular and extracellular organisms, including dormant/persister bacilli

• Good oral absorption; taken on an empty stomach (food reduces absorption)
• Widely distributed; penetrates CSF, cells, and caseous material
• Half-life 1.5-5 hours; undergoes enterohepatic recirculation
• Metabolized to desacetylrifampin (still active); excreted primarily in bile/feces
• Colours body secretions red-orange (urine, tears, saliva, sweat, sputum) - warn patients; can stain soft contact lenses

• Mutations in rpoB gene (beta subunit of RNA polymerase) - >96% of resistant strains
• Resistance develops rapidly with monotherapy (never give alone for active TB)
• Cross-resistance between rifampicin and rifabutin is virtually complete

• Hepatotoxicity: liver enzyme elevation; dose-related
• GI upset: nausea, vomiting, abdominal pain
• "Flu-like" syndrome: fever, chills, myalgias - especially with intermittent therapy (hypersensitivity)
• Thrombocytopenia, hemolytic anemia (rare)
• Drug interactions (most important): Rifampicin is a potent inducer of CYP3A4 and other CYP enzymes and P-glycoprotein. It reduces levels of: oral contraceptives (use alternative contraception!), warfarin, antiretrovirals (PIs, NNRTIs), methadone, corticosteroids, azole antifungals, digoxin, phenytoin, sulfonylureas

3. PYRAZINAMIDE (PZA)

• Pyrazinamide is a prodrug hydrolyzed by pyrazinamidase (encoded by pncA gene) to the active form pyrazinoic acid
• Exact mechanism not fully established; likely acidifies intracellular environment of mycobacteria
• Only active in acidic pH (inside macrophage phagolysosomes and necrotic/caseous lesions - pH 5-5.5)
• Active against intracellular organisms and slowly metabolizing "persister" bacilli
• Bactericidal at acidic pH; bacteriostatic at neutral pH
• This unique activity in acidic environments allows the treatment duration to be shortened from 9 months to 6 months

• Good oral absorption; widely distributed; penetrates CSF
• Metabolized by liver; excreted by kidneys
• Half-life ~9 hours

• Loss of pyrazinamidase activity (mutations in pncA)
• Resistance is NOT cross-resistant with other first-line drugs (important advantage)

• Hyperuricemia (most common): inhibits renal tubular secretion of uric acid; asymptomatic in most; rarely precipitates gout
• Hepatotoxicity: most significant toxicity; dose-related elevation of liver enzymes; serious hepatitis possible
• Arthralgia/joint pains (common, related to hyperuricemia)
• Nausea, rash
• Used only for the first 2 months in the standard 6-month regimen (most benefit early in treatment)

4. ETHAMBUTOL (EMB)

• Inhibits arabinosyl transferase (encoded by embCAB operon)
• Arabinosyl transferase is essential for synthesis of arabinogalactan, a major component of the mycobacterial cell wall
• Bacteriostatic (not bactericidal); specific for mycobacteria
• Prevents incorporation of arabinose into the cell wall

• Good oral absorption; penetrates most tissues well
• CNS penetration is variable (adequate in meningeal inflammation, questionably adequate in tuberculous meningitis)
• Excreted mainly in urine (parent drug + metabolites); dose reduction needed in renal failure

• Mutations in embB gene (arabinosyl transferase)

• Optic neuritis (most important and distinctive toxicity): dose-dependent
  • Reduced visual acuity, loss of red-green color discrimination, central scotoma
  • More common at higher doses (25 mg/kg) and in renal impairment
  • Baseline visual acuity and color vision testing is mandatory; repeat monthly
  • Usually reversible if drug stopped early
• Hyperuricemia (decreased uric acid excretion)
• Peripheral neuropathy (rare)

5. STREPTOMYCIN

• Aminoglycoside that binds to 30S ribosomal subunit → inhibits protein synthesis
• Bactericidal; active against extracellular organisms
• Poor intracellular penetration (inactive against intracellular bacilli)

• Given intramuscularly (IM) or IV; not absorbed orally
• Does NOT penetrate CSF (poor in normal meningitis; better in inflamed meninges)
• Excreted unchanged by kidneys; accumulates in renal failure

• Mutations in 16S rRNA (rrs gene) or ribosomal protein S12 (rpsL)

• Ototoxicity: both vestibular (balance disturbance, nystagmus, vertigo) and auditory (irreversible hearing loss)
• Nephrotoxicity: dose-dependent; monitor renal function
• Neuromuscular blockade

SECOND-LINE DRUGS

Bedaquiline

• First novel anti-TB drug approved in 40 years (FDA 2012) - a diarylquinoline
• Mechanism: inhibits mycobacterial ATP synthase (novel target) → depletes energy
• Active against both replicating and non-replicating bacilli
• Used in MDR-TB and XDR-TB regimens; part of the BPaL regimen (Bedaquiline + Pretomanid + Linezolid)
• Adverse effects: QT prolongation (serious - ECG monitoring required), hepatotoxicity, nausea
• Dose: 400 mg/day for 2 weeks, then 200 mg 3x/week for 22 weeks

Fluoroquinolones (Levofloxacin, Moxifloxacin)

• Inhibit DNA gyrase (topoisomerase II) and topoisomerase IV
• Used in MDR-TB regimens
• Moxifloxacin is part of the newer 4-month regimen (RPMZ = Rifapentine + Moxifloxacin + Pyrazinamide + INH)
• Adverse effects: QT prolongation (moxifloxacin), tendinopathy, GI upset

Cycloserine

• Structural analogue of D-alanine
• Inhibits D-alanine racemase and D-Ala-D-Ala ligase → blocks cell wall peptidoglycan synthesis
• Used in MDR-TB
• Adverse effects: CNS toxicity (seizures, depression, psychosis) - pyridoxine supplementation required
• Dose: 500-1000 mg/day in divided doses

Ethionamide

• Prodrug structurally similar to INH; also inhibits InhA (mycolic acid synthesis)
• Cross-resistance with INH (inhA mutations)
• Used in MDR-TB
• Adverse effects: GI intolerance (major problem), hepatotoxicity, hypothyroidism (with prolonged use), teratogenic

Para-Aminosalicylic Acid (PAS)

• Inhibits folate synthesis in mycobacteria (similar to sulfonamides)
• Also interferes with iron metabolism and mycobactin synthesis
• Second-line; used in MDR-TB
• Adverse effects: severe GI intolerance, hepatotoxicity, hypothyroidism

Rifabutin

• Rifamycin derivative; similar mechanism to rifampicin (rpoB inhibition)
• Cross-resistance with rifampicin nearly complete
• Preferred over rifampicin in HIV patients on antiretroviral therapy (less potent CYP inducer)
• Adverse effects: hepatotoxicity, leukopenia, thrombocytopenia, optic neuritis; uveitis (dose-related)

Linezolid

• Oxazolidinone; inhibits 50S ribosomal subunit (23S rRNA binding site)
• Active against MDR-TB and XDR-TB; part of BPaL regimen
• Adverse effects: bone marrow suppression (anemia, thrombocytopenia), peripheral neuropathy, optic neuropathy (with prolonged use), serotonin syndrome (with serotonergic agents)
• Pyridoxine supplementation recommended

Capreomycin / Amikacin

• Capreomycin: cyclic polypeptide antibiotic; inhibits protein synthesis (30S ribosome)
• Amikacin: aminoglycoside; inhibits 30S ribosome
• Both given parenterally (IM/IV)
• Adverse effects: ototoxicity, nephrotoxicity

Pretomanid

• Nitroimidazole prodrug; activated in anaerobic conditions
• Inhibits cell wall synthesis and generates cytotoxic nitric oxide
• Used in combination (BPaL regimen) for MDR/XDR-TB
• FDA approved 2019

MDR-TB and XDR-TB Treatment

Adverse Effects - High-Yield Summary

Key Pharmacological Facts (KDT High-Yield Points)

1. INH is the most active drug for drug-susceptible TB; the only one with confirmed bactericidal activity across all mycobacterial populations
2. Rifampicin is the most important "sterilizing" drug - eradicates persister bacilli
3. Pyrazinamide - allows shortening from 9 to 6 months due to activity in acidic environments
4. Ethambutol - primarily bacteriostatic; used to protect against undetected resistance
5. Fast vs. slow acetylators of INH: peripheral neuropathy more in slow acetylators; hepatotoxicity more in fast acetylators
6. INH + rifampicin + B6 is the regime for latent TB infection (LTBI) prophylaxis (preventive therapy)
7. Directly Observed Therapy (DOT) is the standard strategy to improve adherence
8. Rifampicin increases metabolism of oral contraceptive pills - use alternative contraception
9. All first-line drugs are active orally except streptomycin (parenteral only)
10. Bedaquiline has the novel mechanism of ATP synthase inhibition - first new TB drug in 40 years

Antifungal Drugs (KDT Style - Detailed)

Why Fungal Infections Are Difficult to Treat

Classification of Antifungal Drugs

By Site of Action:

Sites of action diagram:

GROUP 1: POLYENE MACROLIDES

AMPHOTERICIN B

• Binds specifically to ergosterol in the fungal cell membrane
• Forms transmembrane pores (ion channels) in the membrane
• Pores cause leakage of K⁺, Mg²⁺, and other intracellular contents
• Results in depolarization and osmotic lysis → fungicidal
• Human cell membranes contain cholesterol (not ergosterol), so there is selective toxicity - but amphotericin B still has some affinity for cholesterol, explaining its toxicity

• Candida spp., Cryptococcus neoformans, Aspergillus spp.
• Endemic fungi: Histoplasma capsulatum, Blastomyces dermatitidis, Coccidioides immitis
• Mucor spp. (Mucormycosis)
• Resistance is rare

• Nearly insoluble in water; formulated as colloidal suspension with sodium deoxycholate for IV use
• NOT absorbed orally (used only topically/orally for GI candidiasis)
• Widely distributed; penetrates most tissues including pleural, peritoneal, synovial fluids
• Poor CSF penetration with IV administration → requires intrathecal injection for fungal meningitis
• Half-life biphasic: initial ~24 hours, terminal ~15 days
• Excreted very slowly; detected in urine for up to 7 weeks after stopping

• Fever, chills, rigors, muscle spasms, vomiting, headache, hypotension - nearly universal
• Management: Slow infusion rate; premedicate with antipyretics, antihistamines, meperidine (for rigors), or corticosteroids
• Give a 1 mg test dose IV first to gauge severity

• Nephrotoxicity (most serious and clinically significant): occurs in almost all patients
  • Azotemia (BUN/creatinine rise) - partly reversible (vasoconstriction/prerenal) and partly irreversible (tubular injury)
  • Renal tubular acidosis - K⁺ and Mg²⁺ wasting (hypokalemia, hypomagnesemia)
  • Risk reduced by sodium loading (normal saline infusion before each dose)
  • Irreversible damage usually with >4 g cumulative dose
• Normocytic normochromic anemia: reduced erythropoietin production from damaged renal tubular cells
• Liver function abnormalities (occasional)
• Intrathecal administration: seizures, chemical arachnoiditis, serious neurological sequelae

• Drug of choice for severe, life-threatening systemic fungal infections
• Cryptococcal meningitis (with flucytosine)
• Invasive aspergillosis (now often superseded by voriconazole)
• Invasive candidiasis
• Mucormycosis (only effective option)
• Empirical therapy in febrile neutropenic patients

NYSTATIN

• Polyene macrolide, same mechanism as amphotericin B (binds ergosterol, forms pores)
• TOO TOXIC for parenteral use - used only topically
• Not absorbed from skin, mucous membranes, or GI tract → minimal systemic toxicity
• Available as creams, ointments, lozenges, vaginal suppositories
• Uses: Oropharyngeal candidiasis (thrush), vaginal candidiasis, intertriginous candidal infections, oral GI candidiasis (swish-and-swallow)
• Adverse effects: Unpleasant bitter taste (oral preparations)

GROUP 2: AZOLES

• Inhibit fungal cytochrome P450 enzyme CYP51 (also called lanosterol 14-α-demethylase)
• This enzyme is essential for converting lanosterol → ergosterol in the ergosterol biosynthesis pathway
• Result: depletion of ergosterol + accumulation of toxic methylated sterols → impaired cell membrane function → fungistatic (mostly)
• Triazoles have greater selectivity for fungal CYP than imidazoles → less human toxicity and fewer drug interactions

• Overexpression of efflux pumps (MDR1, CDR1/CDR2)
• Mutations in ERG11 gene (CYP51) reducing azole binding affinity
• Upregulation of ERG11

Pharmacokinetic Comparison Table

IMIDAZOLES

Ketoconazole

• First systemic azole; now largely replaced by triazoles
• Limited spectrum; poor CNS penetration; significant drug interactions and toxicity
• Adverse effects:
  • Inhibits adrenal and gonadal steroid synthesis (CYP11A1, CYP17A1): gynecomastia, menstrual irregularities, impotence, adrenal insufficiency - unique among azoles
  • Hepatotoxicity (most significant)
  • GI intolerance
• Still used topically: seborrheic dermatitis, pityriasis versicolor (shampoo, cream)

Clotrimazole, Miconazole

• Used topically only - too toxic for systemic use
• Available OTC; used for vulvovaginal candidiasis, tinea infections, oral thrush (clotrimazole loches)
• Negligible systemic absorption; adverse effects rare

TRIAZOLES (The "Big Four")

1. Fluconazole

• Most widely used antifungal; excellent oral bioavailability and safety
• Unique features:
  • Water-soluble → excellent distribution including CSF (CSF:serum >0.7 - best of all azoles)
  • Renally excreted (only azole primarily excreted by kidneys); dose adjustment in renal failure required
  • Available both oral and IV (same bioavailability - oral preferred when possible)
• Spectrum: Candida (most species), Cryptococcus neoformans
  • Resistance: C. krusei (inherently resistant), C. glabrata (often resistant/dose-dependent)
  • NOT active against Aspergillus
• Clinical Uses:
  • Drug of choice for oropharyngeal and esophageal candidiasis
  • Cryptococcal meningitis (maintenance/consolidation after AmB induction)
  • Vaginal candidiasis (single 150 mg oral dose)
  • Prophylaxis in immunocompromised patients (neutropenia, HIV)
  • Coccidioidomycosis
• Adverse effects: generally well tolerated; GI upset, headache; hepatotoxicity (rare but reported); teratogenic (avoid in pregnancy)
• Drug interactions: CYP2C9 and CYP3A4 inhibitor → raises levels of warfarin, phenytoin, sulfonylureas, cyclosporine

2. Itraconazole

• Broadest spectrum among older azoles - covers Aspergillus (unlike fluconazole)
• Spectrum: Candida, Aspergillus, Cryptococcus, endemic mycoses (Histoplasma, Blastomyces, Sporothrix, Coccidioides)
• Pharmacokinetics: poor/variable absorption (requires acidic pH; absorption reduced by antacids, PPIs); highly lipophilic; poor CSF penetration
  • Take capsules with food; oral solution (cyclodextrin vehicle) taken fasting - better absorbed
• Clinical Uses: Histoplasmosis, blastomycosis, aspergillosis (mild), dermatophytosis, onychomycosis, sporotrichosis
• Adverse effects: GI upset, hepatotoxicity; negative inotropic effect - contraindicated in heart failure; peripheral edema
• Drug interactions: CYP3A4 inhibitor; raises levels of digoxin, cyclosporine, warfarin, statins

3. Voriconazole

• Drug of choice for invasive aspergillosis (superior to amphotericin B in clinical trials)
• Extended spectrum: all Candida including fluconazole-resistant strains, Aspergillus, Fusarium, Scedosporium
• Good oral bioavailability; good CNS penetration; available oral and IV
• Adverse effects (unique):
  • Hepatotoxicity (common, dose-related)
  • Reversible visual disturbances: photopsia (flashes, color changes, blurred vision) - occurs in ~30% of patients, especially within first week; generally transient
  • Photosensitivity (long-term): increases risk of skin cancers
  • Peripheral neuropathy (with long-term use)
  • Hallucinations and encephalopathy (rare)
• Drug interactions: potent inhibitor of CYP2C19, CYP2C9, CYP3A4; complex interactions; rifampicin markedly reduces voriconazole levels (contraindicated together)

4. Posaconazole

• Broadest spectrum triazole - includes Mucor (mucormycosis) and Rhizopus
• Used for prophylaxis of invasive fungal infections in high-risk patients (AML, HSCT)
• Treatment of refractory aspergillosis and mucormycosis
• Oral (tablet or suspension) and IV
• Adverse effects: QT prolongation, hepatotoxicity, GI intolerance

5. Isavuconazole

• Similar spectrum to posaconazole; licensed for invasive aspergillosis and mucormycosis
• Half-life ~130 hours (very long; less frequent dosing)
• Generally better tolerated than voriconazole (less photosensitivity, fewer visual disturbances)
• Causes QT shortening (unique - other azoles cause QT prolongation)

GROUP 3: ALLYLAMINES

TERBINAFINE

• Inhibits squalene epoxidase (an enzyme in the ergosterol biosynthesis pathway, upstream of azoles)
• Blocks conversion of squalene → squalene epoxide
• Results in: (1) depletion of ergosterol + (2) accumulation of squalene (which is toxic to fungi)
• Fungicidal (unlike azoles, which are mostly fungistatic)

• Well absorbed orally; 250 mg/day
• Highly keratophilic and lipophilic - concentrates in skin, nails, and hair follicles
• Long half-life allows drug to persist in nails for months after stopping

• Onychomycosis (nail fungal infection) - drug of choice; 250 mg/day for 6 weeks (fingernails) or 12 weeks (toenails); cure rate up to 90%
• More effective than griseofulvin or itraconazole for onychomycosis
• Tinea pedis, tinea cruris, tinea corporis (oral and topical)

GROUP 4: ECHINOCANDINS

Caspofungin, Micafungin, Anidulafungin

• Inhibit β-1,3-D-glucan synthase - the enzyme that synthesizes β-1,3-glucan, a key structural polysaccharide in the fungal cell wall
• Depletion of glucan compromises cell wall integrity → osmotic instability → fungicidal against Candida, fungistatic against Aspergillus
• Highly selective: β-1,3-glucan is absent from human cells → minimal human toxicity
• No action against Cryptococcus neoformans, zygomycetes (Mucor), or dermatophytes (they lack the target or have different cell wall composition)

• Available IV only (large cyclic peptides; not orally absorbed)
• Widely distributed; poor CNS penetration
• Metabolized in liver; excreted in urine and feces
• Caspofungin: 70 mg loading dose, then 50 mg/day
• Micafungin: 100-150 mg/day
• Anidulafungin: 200 mg loading dose, then 100 mg/day

• Invasive candidiasis (first-line, including candidemia)
• Esophageal candidiasis
• Invasive aspergillosis (alternative to voriconazole)
• Empirical antifungal therapy in febrile neutropenia (caspofungin)
• Treatment of candidiasis in ICU patients

• Caspofungin: infusion-related reactions (histamine-mediated flushing, rash), hepatotoxicity (mild elevation of LFTs)
• Micafungin: hepatotoxicity (increased risk in patients with hepatic impairment)
• Anidulafungin: diarrhea, hypokalemia; rare infusion reactions
• Echinocandins are safe in pregnancy compared to azoles

GROUP 5: PYRIMIDINE ANALOG

FLUCYTOSINE (5-Fluorocytosine, 5-FC)

• Prodrug; taken up by fungi via cytosine permease
• Converted intracellularly: flucytosine → 5-fluorouracil (5-FU) by cytosine deaminase
• 5-FU is incorporated into fungal RNA → disrupts RNA function → interferes with protein synthesis
• Also phosphorylated to 5-fluorodeoxyuridine monophosphate → inhibits thymidylate synthase → blocks DNA synthesis
• Selective: human cells lack cytosine deaminase → minimal conversion of 5-FC to 5-FU in human cells

• Well absorbed orally (>90%); peak levels 1-2 hours
• Excellent CSF penetration (CSF = 70-80% of serum)
• Excreted unchanged by kidneys (GFR); dose adjustment required in renal failure
• Half-life 3-4 hours (normal renal function)
• Removed by hemodialysis

• Combined with amphotericin B for cryptococcal meningitis (synergistic combination; standard of care)
• Never used as monotherapy (resistance develops rapidly)

• Bone marrow suppression: leukopenia, thrombocytopenia, anemia (due to conversion to 5-FU)
• Hepatotoxicity: elevated liver enzymes
• GI: nausea, vomiting, diarrhea
• Monitor serum levels: therapeutic range 25-100 mcg/mL; toxic at >100 mcg/mL

GROUP 6: GRISEOFULVIN

• Fungistatic against dermatophytes only (Trichophyton, Microsporum, Epidermophyton)
• Mechanism: binds to microtubules (tubulin polymerization) → disrupts mitotic spindle → arrests fungal cell division at metaphase
• Also: deposited in newly forming keratin of skin, hair, and nails → binds keratin → protects new keratin from fungal infection

• Orally administered (microcrystalline form, 1 g/day); absorption improved with fatty meals
• Concentrated in keratin-containing structures (skin, hair, nails)
• Metabolized by liver; induces CYP enzymes

• Drug only prevents infection of new keratin - old infected keratin must be shed
• Skin and hair: 2-6 weeks
• Nails: months (often 6-12 months for toenails); high relapse rate

• Allergic reactions: serum-sickness-like syndrome, urticaria
• Serious skin reactions (rarely)
• Lupus-like syndrome
• Hepatotoxicity
• Drug interactions: CYP inducer → reduces warfarin levels (anticoagulant effect decreases), reduces OCP efficacy; antagonized by phenobarbital

High-Yield Comparison Summary Table

Key High-Yield Points (KDT Exam Facts)

1. Ergosterol is the main target of antifungal drugs (polyenes and azoles both target it at different steps)
2. Amphotericin B - broadest spectrum, drug of choice for life-threatening fungal infections; the "gold standard" but major nephrotoxicity
3. Fluconazole - best CSF penetration among azoles; renally excreted; drug of choice for Candida and Cryptococcus
4. Voriconazole - drug of choice for invasive aspergillosis; causes visual disturbances (unique)
5. Terbinafine - inhibits squalene epoxidase (not CYP51); fungicidal; drug of choice for onychomycosis
6. Echinocandins - target fungal cell wall (not membrane); IV only; best tolerated; drug of choice for invasive candidiasis especially in ICU
7. Flucytosine - NEVER used alone (rapid resistance); always combined with amphotericin B for cryptococcal meningitis
8. Griseofulvin - only for dermatophytes (not yeasts); binds keratin; arrests mitosis; largely replaced now
9. Nystatin - too toxic for systemic use; topical only
10. Ketoconazole - only azole that inhibits steroid synthesis (used to treat Cushing's syndrome off-label); causes gynecomastia, adrenal suppression
11. Amphotericin B + flucytosine = synergistic for cryptococcal meningitis
12. Posaconazole is the only azole with reliable activity against Mucor (mucormycosis)
13. Echinocandins have no activity against Cryptococcus (lacks β-1,3-glucan synthase target)
14. All azoles are inhibitors of CYP enzymes → multiple drug interactions (ketoconazole > itraconazole > fluconazole)
15. Rifampicin is a CYP inducer - contraindicated with voriconazole (dramatically reduces voriconazole levels)