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Antifungal therapy monitoring may be new standard of care
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Invasive fungal infections are a serious clinical problem and remain a leading cause of morbidity and mortality in immunocompromised patients. Aspergillosis and candidiasis are two of the most common invasive fungal infections, but despite recent advances in antifungal therapy, mortality remains as high as 70% and 30%, respectively.
Traditionally, treatment for invasive fungal infections was limited due to few available drugs on the market, antifungal resistance and drug toxicity. Since 2001, five new antifungals have been approved by the FDA that gives the provider more options to select the best treatment regimen. Patients who develop invasive fungal infections are often quite complex, have multiple medical issues, and take many potentially interacting medications. This should all be considered when selecting an antifungal agent.
Kimberly D.
Boeser
Appropriate antifungal selection is important, but so is monitoring the patient for efficacy and toxicity. Therapeutic drug monitoring (TDM) can play a key role in optimizing antifungal therapy and preventing toxicity. TDM is useful when medications meet the following criteria:
- The drug has inconsistent absorption, elimination or significant drug interactions that cause variations in the drug concentration, especially when it is difficult to predict the degree of variation.
- A correlation must be identified between drug concentration and efficacy, toxicity or both.
- A valid assay must be available, and the results must be accessible in a timely manner to guide clinical decision-making.
Several antifungals meet criteria to where TDM is beneficial. Studies have shown that monitoring antifungal levels has potential to improve efficacy and safety outcomes. The remainder of this column looks at specific antifungals regarding TDM. The echinocandins and polyenes will not be discussed since TDM is not recommended because they have a predictable dose-exposure relationship.
Voriconazole
Voriconazole (Vfend, Pfizer) is a triazole and is considered first-line therapy for Aspergillus spp. Voriconazole exhibits broad-spectrum antifungal activity. It is used for both prophylactic and treatment indications. It comes in oral and IV formulations with the oral formula demonstrating excellent bioavailability; however, absorption is reduced when administered with fatty foods. Demonstrating nonlinear pharmacokinetics, drug-level changes are not proportionate to changes in doses. This medication also has interpatient variability, which is thought to be due to differences in drug metabolism through the CYP450 system — primarily the CYP2C19 enzyme.
Kati Shihadeh
Patients can have polymorphisms of this enzyme, making them extensive or poor metabolizers. Anyone can have a polymorphism of this enzyme, but it is more common in certain subgroups of patients. Approximately 5% of the Caucasians in the United States are homozygous poor metabolizers, whereas 75% are homozygous extensive metabolizers. On the other hand, 20% of the Asian population is homozygous poor metabolizers and 35% is homozygous extensive metabolizers.
An exact goal trough for voriconazole has yet to be defined. Yet, results from several studies suggest a goal trough of at least 1 mcg/mL to 2 mcg/mL should be maintained when treating a fungal infection. Results from one study in bone marrow transplant patients suggest goal troughs for prophylaxis do not need to be as high as goal troughs for treatment. Levels greater than 5.5 mcg/mL have been associated with a higher incidence of hepatotoxicity and visual disturbances, two of the more notable adverse reactions.
The voriconazole trough should be drawn after 5 to 7 days of therapy to ensure steady-state concentrations. Levels should be drawn weekly until goal is reached, but continued monitoring is likely unnecessary unless the patient clinically declines, has a dose change or has initiation of an interacting medication.
Fluconazole
Fluconazole (Diflucan, Pfizer) levels are not recommended to be routinely monitored for the following reasons: It is well tolerated, even at higher doses; it is highly bioavailable and well absorbed and distributed to tissues; and it displays linear pharmacokinetics. Fluconazole exhibits an exposure-effect relationship to where an area under the curve (AUC) to minimum inhibitory concentration ratio target greater than 25 to 50 has been associated with optimal therapy. There is also a relationship of fluconazole dose and AUC in that the two values are nearly identical, which allows practitioners to quickly check the AUC (or dose) to MIC ratio and ensure that the value is greater than 25 to 50.15
Posaconazole
Posaconazole (Noxafil, Schering-Plough) is the newest member of the triazole family and has an expanded spectrum of coverage that includes zygomycetes. Posaconazole has a long half-life, but due to saturable absorption, it must be administered multiple times during the day. Similar to voriconazole, interpatient variability in pharmacokinetics has been noted, which could be, in part, due to absorption of the medication. It is substantially better absorbed when taken with meals or nutritional supplements, especially high fat-containing foods. Due to variable absorption and pharmacokinetics, TDM is recommended. A definite target level has yet to be determined; however, one clinical trial evaluating posaconazole exposure and clinical outcome found patients who had an average steady-state level of 1.25 mcg/mL (the group with the highest concentration) had the highest clinical response rate. It is recommended to draw a level between 7 and 14 days of initiating therapy, changing dose or initiating an interacting medication. The levels can be drawn at random without regard to timing of doses, as there is little variation in drug level once steady-state is reached.
Itraconazole
Itraconazole (Sporanox, Janssen Pharmaceuticals) is a triazole with a spectrum of coverage similar to voriconazole and is considered the drug of choice for mild to moderate endemic fungal infections. Itraconazole comes in an oral solution and capsule and both have erratic absorption. Itraconazole also has a variable dose-concentration relationship and alterations in kinetics during long durations of therapy. Itraconazole has many drug-drug interactions, which further makes serum levels unpredictable. Several studies have found that both treatment and prophylactic efficacy correlates with serum levels. There are two ways to measure itraconazole levels. High-performance liquid chromatography (HPLC) measures just itraconazole and not active metabolite, hydroxyitraconazole (bioassay detects both itraconazole and active metabolite). The recommended goal level for prophylaxis is at least 0.5 mg/L (HPLC), whereas the goal level for treatment is at least 1 mg/L (HPLC) or greater than 6 (bioassay).
The upper limit in relation to toxicity is not as well defined using HPLC, but a study using bioassay noted more adverse events when the trough was more than 17 mg/L. Once at steady-state, there is little variation in drug level, so a random level should be obtained within 7 to 14 days of initiating therapy, changing dose or starting an interacting medication.
Flucytosine
Flucytosine (Ancobon, Valeant Pharmaceuticals International) is a pyrimidine analogue and one of the earliest antifungals on the market. It is most commonly used in combination with another agent for treatment of cryptococcal meningitis. TDM for flucytosine is recommended due to variable pharmacokinetics. The IDSA guidelines for cryptococcal infections recommend a peak level be drawn 2 hours following dose administration after 3 to 5 days of therapy. A therapeutic range of 30 mcg/mL to 80 mcg/mL is recommended and levels greater than 100 mcg/mL have been associated with adverse effects. Drug levels should be obtained on initiation of therapy, with a change in renal function or with signs of toxicity, including bone marrow suppression or hepatotoxicity.
Near future
Antifungal TDM may become the standard of care. Definitive goal levels for efficacy, safety or both should be established and widely accepted among clinicians.
Furthermore, turnaround time for antifungal levels will likely need to be quicker. Most institutions send out these labs and do not receive the level back until 1 week later. This makes the clinical relevance of the level difficult to interpret. As goal levels become more established and more institutions begin to run levels in-house, TDM of antifungals may soon become the standard of care.
Until that time comes, TDM of antifungals should be highly considered for patients who are initiated on these medications.
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