|Values are valid only on day of printing.|
Survival and management of many serious conditions such as organ failure or hematological malignancy have improved greatly in recent years. This success, however, has resulted in a growing number of individuals whose immune systems are compromised, either intentionally through use of immunosuppressive drugs, or as a consequence of their disease.1 The burgeoning population of immunocompromised patients has in turn led to increased use of antimicrobial agents to prevent or treat infections associated with weakened immunity.
Fungal infections in particular are of growing concern in immunocompromised or critically ill populations. Both the number and the scope of invasive fungal infections (IFI) are increasing, with a larger proportion arising from previously uncommon pathogens. Formerly, the majority of IFI were caused by Candida albicans; however, in recent years, hospitals around the world are reporting greater incidence of IFI due to non-albicans Candida, species of Aspergillus, and fungi in the order Mucorales.2 Therapeutic options for IFI are comparatively limited, relative to the wide array of drugs available to treat bacterial infections, and few older agents are effective against emerging fungal pathogens. Compounding these issues is the fact that, as with antibacterial agents, microbial resistance to some antifungal drugs has emerged.
Pharmacological options for treating IFI have expanded during the last 2 decades.3 Newer agents tend to have broader spectra of activity, and in many cases display fewer or milder side effects than older antifungals. However, this is not universally true. For example, several antifungal drugs inhibit cytochrome P450 (CYP) metabolic enzymes, thus leading to decreased metabolism and possible toxicity of other therapeutic agents (Figure 1).4 Given that the immunocompromised and critically ill patients who are at highest risk for IFI frequently require multiple medications, such drug interactions must be managed carefully to ensure therapeutic efficacy and prevent toxicity.
Figure 1. Theoretical effects of a CYP inhibitor on CYP metabolic activity and comedication concentration: as the concentration of antifungal drugs or other CYP inhibitors increases, apparent CYP activity decreases, reducing metabolism of comedications and increasing the risk of toxicity.
To this end, the practice of therapeutic drug monitoring (TDM, also called therapeutic drug management) can assist clinicians, pharmacists, and other caregivers in optimizing patient outcomes. TDM involves the quantitation of circulating drug concentrations to assess an individual patient’s exposure to therapeutic agents. It is most useful with compounds that exhibit narrow therapeutic “windows” between efficacy and toxicity, variable pharmacokinetics (eg, absorption or metabolism), or drug interactions. Several antifungal drugs are therefore excellent candidates for TDM.
To maximize the utility of TDM, it is essential that attention is paid to obtaining the proper sample at the correct time in therapy. Although details for individual antifungal agents will be provided below, some generalizations can be made.
Typically, TDM samples should be collected after the patient has achieved steady state, which occurs after approximately 5 half-lives (assuming doses are given at or near 1 half-life); use of a loading dose can speed this process. Dose changes require re-establishing steady state, that is, allowing for 5 half-lives at the new dose before measuring concentrations. Most antifungal drugs should be monitored at trough levels, that is, immediately before the next scheduled dose. This eliminates much of the pharmacokinetic variability that can be seen with postdose samples.
Pharmacokinetic parameters provided in standard references are most often average values derived in healthy individuals, with few or no coadministered medications. Hospitalized patients may show drastically different pharmacokinetics from these average parameters; absorption, distribution, metabolism, and elimination can all be affected by serious illness. For some individuals, a single time point measurement of drug concentrations may not provide adequate information. Optimal management may require evaluating a specific patient’s individual pharmacokinetic profile (ie, multiple time points following a dose) to ensure adequate absorption and timely clearance of the therapeutic agent.
Finally, preanalytical variables can play a large role in accurately quantitating therapeutic compounds. Many drugs adsorb to polymer-based substances, including the tubing and ports of intravenous lines or catheters, and the gel present in plasma (PST) and serum separator tubes (SST). If possible, TDM specimens should not be drawn from the same line used to infuse the drug of interest; an alternate collection site should be selected. If the same line must be used, it is important to adequately flush the line and discard the initial “waste” blood prior to collecting into the sample tube. The discard volume depends upon the dead space of the tubing (length and diameter) and the likely concentration of the drug in the line. If the concentration of the drug is low, a flush volume of 2 times the dead space may suffice; if the concentration is high, a much larger flush volume (eg, 6 times the tubing dead space) is necessary to adequately remove any contaminating drug from the specimen. The type of collection tube used should conform to the recommendations of the analytical laboratory. If that information is unavailable, the safest course is to assume that a separator tube is unacceptable for drug testing. Use of a separator tube with a drug that adsorbs to the polymer gel can vastly reduce the apparent concentration of the drug in the sample, preventing accurate interpretation of TDM results.
Many antifungal drugs do not require TDM, as they have relatively wide therapeutic windows, minimal risk of drug interactions, and low variability between most patients. Examples of such agents include amphotericin B and the echinocandins (eg, caspofungin, micafungin). However, there are several antifungals that can be better managed with the assistance of TDM (Table), due either to concentration-dependent toxicity, or to variations in absorption, metabolism, or other pharmacokinetic parameters.2 The remainder of this article will discuss details of the antifungal drugs most commonly seen in TDM laboratories, namely 5-flucytosine and the triazole agents: fluconazole, itraconazole, voriconazole, and posaconazole (Figure 2).
Figure 2. Structures of antifungal drugs for which TDM may be useful
One of the first antifungal drugs synthesized, 5-flucytosine acts by inhibiting DNA and protein synthesis in fungi and is approved for combination therapy of candidiasis and cryptococcosis.5 5-flucytosine monotherapy is uncommon, due to its relative weakness as an antifungal agent and the risk of resistant organisms emerging. Multidrug therapy including flucytosine, typically in combination with amphotericin B, provides wider pathogen coverage and complementary mechanisms of action for greater effect.
The majority of pharmacokinetic parameters for 5-flucytosine are actually quite favorable: the drug is well absorbed, and undergoes minimal hepatic metabolism, thus there is little risk of drug interactions.1 However, it is eliminated almost entirely through renal excretion; this fact, combined with the short half-life necessitating frequent dosing, means that flucytosine can rapidly accumulate to potentially toxic levels in patients with renal disease. Toxicity is seen with peak serum concentrations >100 mcg/mL, and commonly presents as myelosuppression or hepatotoxicity.2
Serum concentration monitoring may help prevent 5-flucytosine-induced toxicity. Peak levels (1 to 2 hours after oral dosing) are most commonly used for TDM because, due to the drug’s short half-life, trough concentrations may be undetectable. For most patients, initial 5-flucytosine peak concentration should be measured after 3 to 5 doses have been administered, then monitored twice weekly throughout therapy.1 In patients with known renal dysfunction, trough sampling may aid in assessing clearance prior to administering subsequent doses.
Potential Antifungal Drug Interactions
Box. Select drugs potentially affected by antifungal drug use
Like all triazole antifungals, the major antifungal mechanism of fluconazole is thought to be inhibiting synthesis of ergosterol, a major component of fungal cell membranes.1 Fluconazole is effective for prophylaxis and treatment of candidiasis and cryptococcosis, as well as some less-common infections such as blastomycosis and coccidioidomycosis (valley fever).
Oral fluconazole is well absorbed, with no influence of food on its bioavailability. In adults, the majority of a dose is eliminated as parent drug in urine with only minimal hepatic metabolism; despite this, fluconazole is a potent inhibitor of CYP2C9 and a moderate inhibitor of CYP3A4.6 This provides significant opportunity for drug interactions with compounds metabolized by these enzymes, including agents used for immunosuppression (eg, cyclosporine, tacrolimus, and sirolimus) and infectious disease therapy (eg, macrolide antibiotics). If fluconazole is administered with CYP2C9 or CYP3A4 substrates, TDM of the concomitant medications may be warranted (Box).
Given the drug’s high bioavailability and minimal hepatic metabolism, most patients do not require routine monitoring of fluconazole concentrations.7 However, patients with renal dysfunction, impaired absorption, or less-susceptible pathogens may benefit from TDM measurements to ensure proper exposure to the drug. Trough sampling (ie, immediately before next scheduled dose) is recommended. The therapeutic window for fluconazole is relatively wide; trough levels between 4 mcg/mL and 20 mcg/mL are common, although dosing should be tailored to the patient’s clinical presentation.
Itraconazole can be used to treat many of the same pathogens as fluconazole, with additional efficacy against aspergillosis, histoplasmosis, and more severe presentations of sporotrichosis. It is available as either an oral solution or as capsules. In general, the bioavailability of the solution is superior to the capsule, although administering capsules with an acidic drink such as a cola can boost absorption.2 The variability of absorption, both inter- and intrapatient, is a primary rationale for performing TDM.5
Like fluconazole, itraconazole and its metabolites inhibit CYP enzymatic activity; the most potent inhibition is seen with CYP3A4. Given that this enzyme system metabolizes nearly half of all drugs on the market as well as many endogenous compounds such as steroid hormones, its inhibition by itraconazole is a notable concern in the choice of antifungal therapy.6 Effects on potentially interacting drugs must be evaluated when itraconazole treatment is added, changed, or discontinued.
Itraconazole is metabolized by CYP3A4 to hydroxyitraconazole, which has comparable activity to the parent drug. Certain laboratory analyses (bioassays) cannot distinguish parent itraconazole from its active metabolites, thus metabolite activity is included in the apparent “itraconazole” concentration. High-performance liquid chromatography (HPLC) assays such as the method used at Mayo Clinic can differentiate itraconazole from hydroxyitraconazole, and quantitate them independently of one another.7 Regardless of the method used for analysis, trough sampling is preferred.
It is recommended that patients receive itraconazole for 2 weeks prior to TDM, to ensure that steady state has been reached.1 Target therapeutic values are assay-dependent, thus reference ranges for bioassays and HPLC assays are not interchangeable. Trough itraconazole concentrations (by HPLC) should be >0.5 mcg/mL for localized infections, or >1.0 mcg/mL for systemic or more severe infections. Toxicity appears to be concentration-related, but an upper limit to the therapeutic range has not been well established. No therapeutic targets are established for hydroxyitraconazole, but its concentrations are typically similar to itraconazole levels in patients who have achieved steady state.
|CYPs inhibited||Rationale for TDM|
|5-Flucytosine||>25 *||>100 *||n/a||Clearance in renal disease|
|Fluconazole||4 to 20||not established||2C9, 3A4||Select patients only|
|not established||3A4||Variable absorption|
|Voriconazole||1.0 to 5.5||>6.0||2C9, 3A4||Nonlinear kinetics|
|Posaconazole||>0.7||not established||3A4||Variable absorption|
*Concentrations refer to peak samples
Blue indicates strong inhibition
Table. Characteristics of select antifungal drugs
More recently, newer triazole antifungals have achieved broader specificity with less severe inhibition of CYP-mediated metabolism. Voriconazole was the first of these to be approved, and is effective for treating candidiasis and aspergillosis, as well as infections with filamentous fungi including species of Fusarium and Scedosporium.1
The drug’s oral bioavailability is high, but absorption is significantly reduced by taking a dose with high-fat food. It is primarily metabolized by CYP2C19, and some studies suggest that polymorphisms in the gene encoding this protein can affect voriconazole pharmacokinetics.5 Voriconazole inhibits CYP2C9 and CYP3A4, but less potently than either fluconazole or itraconazole. Unlike the other triazoles, voriconazole exhibits nonlinear kinetics.2 This means that the apparent elimination half-life is concentration dependent (increasing as voriconazole concentration rises), and that dosing changes result in disproportional effects on patient exposure to the drug.
Concerns regarding the variability of voriconazole absorption, elimination, and nonlinear kinetics provide rationale for performing TDM. Target trough voriconazole concentrations should be >1 mcg/mL to 2 mcg/mL to treat most susceptible organisms. The upper end of the therapeutic range is established by dose-limiting toxicities (including encephalopathy, hepatotoxicity, and visual disturbances), which are more common in patients whose trough concentrations are >6 mcg/mL.4
The newest triazole antifungal, posaconazole, has a broad spectrum of efficacy. It is used for prophylaxis and treatment of candidiasis, aspergillosis, and mucormycosis (also known as zygomycosis), particularly in those with recurrent IFI, severely immunocompromised patients, or other high-risk individuals.1 Although it is metabolized primarily by glucuronidation, posaconazole has been shown to inhibit CYP3A4 with similar potency to voriconazole. Studies with sirolimus and posaconazole suggest that the antifungal drastically diminishes sirolimus clearance, necessitating dose reductions.4
Despite saturable absorption, which necessitates dosing several times a day, posaconazole shows good bioavailability in healthy individuals, particularly when administered with a high-fat meal.5 However, conditions for optimal absorption can be quite difficult to accomplish in severely ill patients. Thus, ensuring adequate absorption is a strong indication for performing TDM. Trough therapeutic targets remain an area of study: initial guidance suggested concentrations >0.7 mcg/mL were sufficient for therapy, but later studies propose higher trough levels (between 1 and 1.5 mcg/mL) for optimal efficacy. Posaconazole toxicity does not appear to be concentration dependent.1
Invasive fungal infections are increasing in both number and scope with previously uncommon pathogens increasingly becoming the cause. Immunocompromised and critically ill patients are the population frequently infected. Several antifungal drugs now available for use can be better managed through the use of TDM to achieve the delicate balance between efficacy and toxicity and assist clinicians, pharmacists, and other caregivers in optimizing patient outcomes.
Authored by Christine Snozek, PhD, DABCC, FACB