Chapter 37  ·  Module 3
Extended-Spectrum Azoles
Voriconazole, Posaconazole, and Isavuconazole — pharmacology, spectrum, resistance, and clinical positioning
CYP51 = cytochrome P450 51  ·  TDM = therapeutic drug monitoring  ·  AUC = area under the concentration-time curve  ·  SBECD = sulfobutylether-beta-cyclodextrin  ·  QTc = corrected QT interval  ·  CNS = central nervous system  ·  GVHD = graft-versus-host disease  ·  HSCT = hematopoietic stem cell transplant
Agent Comparison at a Glance
Property Voriconazole Posaconazole Isavuconazole
Oral bioavailability ~96% fasting; food reduces AUC 24% Suspension: variable, food-dependent. DR tablet: consistent, once daily ~98%; no food effect
Pharmacokinetics Non-linear (CYP2C19 saturable); high variability Linear; DR tablet more predictable than suspension Linear; half-life ~130 hrs
IV vehicle SBECD — avoid if creatinine clearance below 50 mL/min SBECD — same restriction No SBECD — safe in renal failure
Mucorales coverage NO YES YES
QTc effect Prolongs QTc Prolongs QTc Shortens QTc
TDM target (trough) 1.0–5.5 mg/L Above 0.7 mg/L (prophylaxis); above 1.0 mg/L (treatment) Not standardized
Primary clinical role 1st-line invasive aspergillosis; CNS aspergillosis Prophylaxis in AML, MDS, GVHD; step-down for mucormycosis 1st-line invasive aspergillosis; mucormycosis treatment
Key Toxicities by Agent
Voriconazole
Three Dominant Toxicities
  • Visual disturbances: 20–30%; transient; reversible
  • Hepatotoxicity: 5–15%; monitor liver enzymes
  • Phototoxicity: prolonged use; skin malignancy risk
  • Neuropsychiatric: hallucinations at high concentrations
Posaconazole
Tolerable Profile
  • Nausea and GI effects with suspension formulation
  • QTc prolongation — monitor electrolytes
  • Hepatotoxicity: mild; less than voriconazole
  • Absorption failure: most common clinical problem
Isavuconazole
Favorable Tolerability
  • No visual disturbances (vs. voriconazole)
  • Less hepatotoxicity than voriconazole
  • No photosensitivity
  • QTc shortening: diagnostic if unexpected
Environmental Azole Resistance in Aspergillus fumigatus
TR34/L98H Mutation
Pan-Azole Resistance
  • 34-bp tandem repeat in cyp51A promoter + L98H substitution
  • Resistant to voriconazole, itraconazole, AND posaconazole
  • Found in environmental soil, compost, flower bulbs
  • Driven by agricultural demethylase inhibitor fungicides
  • Patients often have NO prior medical azole exposure
TR46/Y121F/T289A Mutation
Voriconazole-Specific Resistance
  • 46-bp tandem repeat + dual amino acid substitutions
  • Resistant to voriconazole specifically
  • Retains itraconazole susceptibility
  • Test ALL invasive Aspergillus isolates where resistance exceeds 5–10%
  • Higher mortality than susceptible infections
Clinical Rule — Mucorales Coverage Gap

Voriconazole has NO activity against the Mucorales (Rhizopus, Mucor, Lichtheimia). Breakthrough mucormycosis has been reported in patients receiving voriconazole prophylaxis. In any patient with suspected mucormycosis, switch to liposomal amphotericin B or use posaconazole or isavuconazole. Never rely on voriconazole when Mucorales infection is possible.