avoid voriconazole with cyp inducers

Voriconazole, an antifungal agent with potent activity against Aspergillus, is almost exclusively metabolized by the cytochrome P450 system. Clinically significant reductions in the plasma concentration of voriconazole are observed when the drug is coadministered with medications that induce the cytochrome P450 system, such as carbamazepine. In this case, administration of voriconazole and carbamazepine likely led to subtherapeutic dosing of voriconazole, which led to ineffective treatment of the invasive fungal disease.

Invasive aspergillosis is most commonly seen in immunocompromised hosts and is characterized by nonspecific symptoms such as fever, malaise, and encephalopathy. Aspergillosis can be angioinvasive, and patients may present with symptoms that reflect tissue destruction of the affected organ (eg, pulmonary infarction or hemoptysis in invasive pulmonary aspergillosis). Cerebral aspergillosis typically results from hematogenous spread of disease and may manifest as meningitis, stroke from infarction or hemorrhage, or intracranial abscess.

Voriconazole is a triazole antifungal agent indicated as first-line treatment for invasive pulmonary aspergillosis. Compared with amphotericin B, voriconazole led to increased survival rates at 12 weeks of therapy (70.8% in the voriconazole group vs 57.9% in the amphotericin B group) and more successful outcomes in a randomized controlled trial of patients with hematologic malignancy and/or stem cell transplantation. Voriconazole is also indicated for the treatment of candidemia in nonneutropenic patients and for infections caused by Fusarium and Scedosporium species. Because these infections are increasingly prevalent in critically ill populations, potential drug interactions with voriconazole are important to recognize. Voriconazole exerts antifungal activity via inhibition of fungal cytochrome P450-mediated demethylation, a critical step in fungal cell membrane synthesis.

Voriconazole is extensively metabolized by liver, specifically as a substrate for the cytochrome P450 isoenzymes. Cytochrome P450 isoenzymes have multiple genetic polymorphisms that can result in extensive or limited metabolism of a given substrate. This leads to considerable variability in plasma concentrations of the metabolized drug. There are several drugs that also either inhibit or induce cytochrome P450 enzyme activity, further contributing to variable plasma concentrations of a substrate.

Common inducers of the cytochrome P450 system are carbamazepine, rifampin, alcohol, phenytoin, and phenobarbital. Administration of these drugs is contraindicated in patients receiving voriconazole because of the drug interaction and potential for subtherapeutic (or supratherapeutic) levels. Some literature suggests clinical benefit to therapeutic drug monitoring of voriconazole because of its variable pharmacokinetics. A meta-analysis of 24 studies concluded that patients with therapeutic serum concentrations were more likely to achieve successful outcomes and that supratherapeutic dosing posed increased risk of toxicity. A multicenter retrospective study reported approximately 20% of A fumigatus cases were resistant to voriconazole. While this should be an important consideration, drug susceptibility testing was recently performed for this patient’s case and demonstrated that voriconazole was an appropriate choice for therapy. The development of drug resistance and progressive disease in the span of 4 weeks would be unlikely.

While leukemic infiltrates in lung can appear nodular and this patient has fevers, which can be a sign of relapsed leukemia, there is no other suggestion of relapsed disease in the question stem. Nodules with surrounding ground-glass pattern (halo sign) are not typically a result of leukemic infiltration in lung. Pulmonary tuberculosis is an important consideration in an immunocompromised host with pulmonary nodules; however, recent bronchoscopy provided an alternative diagnosis, and pulmonary tuberculosis would not explain elevated serum galactomannan index.123456

A 64-year-old patient with recent hematopoietic stem cell transplant for acute myeloid leukemia is found to be febrile and lethargic at home. Her daughter calls emergency medical services, and the patient is intubated in the field. The patient is on immunosuppression and prophylactic antibiotics for her stem cell transplant, carbamazepine for seizures, lisinopril for hypertension, and insulin for type 2 diabetes mellitus.

Four weeks prior to this admission, the patient had a CT scan of the chest, which showed a 1-cm nodule with surrounding ground-glass pattern. She subsequently underwent bronchoalveolar lavage, and the fungal culture grew Aspergillus fumigatus. Galactomannan index from the bronchoalveolar lavage fluid was 1.1. The patient was prescribed voriconazole, and antibiotic susceptibility testing demonstrated that the strain was susceptible to the medication.

On this admission, the patient is intubated and sedated. On examination, her temperature is 38.3 °C, heart rate is 110/min, BP is 125/80 mm Hg, and respiratory rate is 24/min. CT scan of the chest shows enlargement of the prior nodule and several new nodules with surrounding ground-glass pattern. CT scan of the head shows a nodular lesion. Serum galactomannan index is 1.9 (normal, <0.5).

Which is the most likely explanation for this clinical presentation?

Footnotes

  1. SEEK Questionnaires ↩

  2. El-Baba F, Watza D, Soubani AO. Is Aspergillus isolated from respiratory cultures clinically significant? Cleve Clin J Med. 2021;88(10):543-546. PubMed ↩

  3. Herbrecht R, Denning DW, Patterson TF, et al; Invasive Fungal Infections Group of the European Organisation for Research and Treatment of Cancer and the Global Aspergillus Study Group. Voriconazole versus amphotericin B for primary therapy of invasive aspergillosis. N Engl J Med. 2002;347(6):408-415. PubMed ↩

  4. Li TY, Liu W, Chen K, et al. The influence of combination use of CYP450 inducers on the pharmacokinetics of voriconazole: a systematic review. J Clin Pharm Ther. 2017;42(2):135-146. PubMed ↩

  5. Luong ML, Al-Dabbagh M, Groll AH, et al. Utility of voriconazole therapeutic drug monitoring: a meta-analysis. J Antimicrob Chemother. 2016;71(7):1786-1799. PubMed ↩

  6. Zonios D, Yamazaki H, Murayama N, et al. Voriconazole metabolism, toxicity, and the effect of cytochrome P450 2C19 genotype. J Infect Dis. 2014;209(12):1941-1948. PubMed ↩