An 11-year-old boy with HIV and esophageal candidiasis is being treated with caspofungin. What is the mechanism of action of this drug?

Inhibition of 1,3-Beta-glucan synthase

Pore formation in cell membranes

Inhibition of ergosterol synthesis

Inhibition of squalene epoxidase

Inhibition of pyrimidine synthesis

A 72-year-old woman with type 2 diabetes mellitus comes to the physician because she is concerned about the appearance of her toenails. Examination shows yellowish discoloration of all toenails on both feet. The edges of the toenails are lifted, and there is subungual debris. Potassium hydroxide preparation of scrapings from the nails shows multiple branching septate hyphae. Treatment with oral terbinafine is begun. Which of the following is the primary mechanism of action of this drug?

Inhibition of squalene epoxidase

Formation of pores in cell membrane

Inhibition of β-glucan synthesis

Interference with mitosis during metaphase

Prevention of lanosterol to ergosterol conversion

A 41-year-old man comes to the physician because of a 3-week history of fatigue, cough, and a 4.5-kg (10-lb) weight loss. He does not smoke or drink alcohol. He appears emaciated. A chest x-ray shows a calcified nodule in the left lower lobe and left hilar lymphadenopathy. The physician initiates therapy for the condition and informs him that he will have to return for monthly ophthalmologic examination for the next 2 months. These examinations are most likely to evaluate the patient for an adverse effect of a drug with which of the following mechanisms of action?

Impaired synthesis of cell wall polysaccharides

Impaired synthesis of mycolic acids

Impaired protein synthesis due to binding to 50S ribosomes

Impaired production of hemozoin from heme

Impaired protein synthesis due to binding to 30S ribosomes

A 72-year-old woman comes to the physician because she is seeing things that she knows are not there. Sometimes she sees a dog in her kitchen and at other times she sees a stranger in her garden, both of which no one else can see. She also reports a lack of motivation to do daily tasks for the past week. Three years ago, she was diagnosed with Parkinson disease and was started on levodopa and carbidopa. Her younger brother has schizophrenia. The patient also takes levothyroxine for hypothyroidism. She used to drink a bottle of wine every day, but she stopped drinking alcohol 2 months ago. Neurologic examination shows a mild resting tremor of the hands and bradykinesia. Her thought process is organized and logical. Which of the following is the most likely underlying cause of this patient's symptoms?

Poorly controlled hypothyroidism

Antifungal therapeutic drug monitoring for USMLE Step 3: High-Yield Pharmacology Lessons

Antifungal TDM - Why Bother Gauging?

Optimize Efficacy & Minimize Toxicity: Key for agents with a narrow therapeutic index (e.g., voriconazole, itraconazole).
High Inter-individual Variability:
- Factors like absorption, drug-drug interactions, and genetic polymorphisms (CYP enzymes) cause unpredictable serum levels.
- Ensures target drug exposure, especially in critical illness or for prophylaxis.
Key Drugs Requiring TDM:
- Voriconazole: Target trough 1-5.5 mg/L. Levels <1 mg/L risk treatment failure; >5.5 mg/L risk neurotoxicity.
- Posaconazole: Target trough >0.7 mg/L (prophylaxis); >1.25 mg/L (treatment).
- Itraconazole: Target trough >0.5 mg/L.

⭐ Voriconazole metabolism is heavily influenced by CYP2C19 genetic polymorphisms. Poor metabolizers face ↑ toxicity risk, while ultra-rapid metabolizers may have sub-therapeutic levels and treatment failure.

TDM Targets - The Usual Suspects

Routine therapeutic drug monitoring (TDM) is critical for select azoles with unpredictable pharmacokinetics and for flucytosine to mitigate toxicity. It is not typically required for fluconazole or echinocandins.

Voriconazole
- Therapeutic Trough: 1.0 - 5.5 mg/L
- Toxicity Risk: >5.5 mg/L (neurotoxicity, visual disturbances, hepatotoxicity)
- Subtherapeutic Risk: <1.0 mg/L (treatment failure)
- Kinetics are non-linear and highly variable due to CYP2C19 polymorphisms.
Posaconazole
- Prophylaxis Trough: >0.7 mg/L
- Treatment Trough: >1.0 mg/L
- Absorption is formulation-dependent (tablet/IV preferred over suspension).
Itraconazole
- Trough (Parent + Hydroxy-metabolite): >1.0 mg/L
- For invasive aspergillosis, aim for >2.0 mg/L.
Flucytosine (5-FC)
- Peak Level (2h post-dose): 50 - 100 mg/L
- ⚠️ Toxicity Risk: >100 mg/L (profound myelosuppression)

⭐ Voriconazole metabolism is heavily influenced by CYP2C19 genetic polymorphisms. Poor metabolizers are at high risk for toxicity, while ultra-rapid metabolizers may experience treatment failure on standard doses.

TDM in Action - Troughs & Targets

Goal: Maximize efficacy, minimize toxicity. Trough levels are drawn just before the next dose.
Timing: Check levels after 4-7 days of therapy (at steady-state).

Drug	Target Trough (mg/L)	Clinical Pearls
Voriconazole	1.0 - 5.5	Prophylaxis & Treatment. >5.5 ↑ risk of neurotoxicity.
Posaconazole	>0.7 (prophylaxis) >1.0 (treatment)	Absorption is variable; requires high-fat meal.
Itraconazole	>1.0	Active metabolite (hydroxy-itraconazole). TDM essential.
Flucytosine	Peak: <100	⚠️ Peak level, not trough, to avoid bone marrow toxicity.

High‑Yield Points - ⚡ Biggest Takeaways

Therapeutic Drug Monitoring (TDM) is crucial for azoles like voriconazole, itraconazole, and posaconazole due to their variable pharmacokinetics and potential for toxicity.

Voriconazole levels are monitored to prevent neurotoxicity and hepatotoxicity while ensuring efficacy.

Itraconazole and posaconazole TDM helps overcome erratic oral absorption.

Flucytosine (5-FC) requires monitoring to avoid dose-related bone marrow suppression.

TDM is not routinely recommended for echinocandins or amphotericin B formulations.

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