The Role of Azols in the Treatment of Mucormycosys

Welcome to PICU Doc On Call, A Podcast Dedicated to Current and Aspiring Intensivists.

I'm Pradip Kamat coming to you from Children’s Healthcare of Atlanta/Emory University School of Medicine. Today we are joined by two wonderful clinical pharmacists — Whitney Moore & Stephanie Yasechko.

Whitney is a Clinical Pharmacy Specialist at Children’s Healthcare of Atlanta. She is on Twitter at @MoorephinRx.

Stephanie is a Pediatric Lung Transplant Clinical Pharmacy Specialist at Cincinnati Children’s Hospital Medical Center.

We are so excited to have you both on today. My name is Rahul Damania and I am a Pediatric Intensivist at Cleveland Clinic Children’s Hospital; Welcome to PICU Doc On Call where we focus on all things MED-ED in the PICU. Our podcast focuses on interesting PICU cases & management in the acute care pediatric setting so let’s get into our episode:

Welcome to our Episode an 18 yo immunocompromised patient with headache & sore throat

Here's the case presented by Rahul:

An 18-year-old female (40 kg) with PMH significant for fibrolamellar carcinoma of the liver, presents to the ED with headache and sore throat. She is febrile to 38.3, tachycardic, tachypneic, and has a WBC of 27K on her CBC. She is markedly hypotensive with BP on the arrival of 99/65. Cultures were drawn, the patient was given x1 doses of vancomycin and meropenem, and she was transported to the PICU for further workup and management. Due to her progressive hemodynamic instability, increased inflammatory markers, and marked immunocompromised state, the team is considering broadening her anti-microbial coverage.

To summarize key elements from this case, this patient has:

• Fibrolamellar carcinoma of the liver
• A presentation of headache, sore throat, and hemodynamic instability with concern for sepsis
• A current regimen of just antibacterials, which brings up the consideration of adding anti-fungal coverage in her clinically ill state.

Our episode today will be covering anti-fungal agents in the PICU.

We will review general mycology, understand different classes of antifungals, and highlight practical clinical pearls in the acute care setting.

As mentioned, this patient has risk factors for an immunocompromised state due to her underlying liver condition. As we dive deeper into antifungals, Whitney, can you please give us an overview of common fungal pathogens in the PICU?

Before we discuss the major drugs, it’s important that we take some time to briefly review the most common fungi we encounter clinically since it’s hard to choose the right agent when you don’t know exactly what you are treating.

Clinically, Candida is probably the most common fungal pathogen encountered, especially in warm, moist environments. It is important to determine what type of species is growing. The three major species known to cause infection are C. albicans, C. glabrata, and C. krusei, but it is important to differentiate these species when identified since they have different resistance patterns.

Cryptococcus is another type of fungus that is known to cause meningitis or fungemia, especially in immunocompromised or cirrhotic patients. Both Candida and Cryptococcus are classified as yeast on Gram stain. Treating cryptococcus will require the use of an agent that has good penetration to the CNS.

Endemic fungi known as Coccidia, Histoplasma, and Blastomyces are known to cause disseminated infections in immunocompromised hosts; however, each fungus is associated with a different geographic region in the United States. With any type of infection, it is always very important to consider your patients’ exposures and recent travel history.

And finally, there are two major molds that have the potential to be pathogenic. The first is Aspergillus which is identified via hyphae (tall filaments) on Gram stain well known to cause invasive pulmonary infections in the immunocompromised, specifically those who are neutropenic and/or received a lung transplant. Cystic fibrosis patients are also well-known hosts to aspergillus. The next mold is Mucorates, otherwise known as Mucor. Mucor has the propensity to cause an aggressive infection that necessitates surgical debridement. While rare, you can see this pathogen affect patients who are diabetic, neutropenic, taking chronic steroids or other immunosuppressants, or who have just sustained a trauma.

So now that we have some background on fungal pathogens and who they most commonly affect, let’s now dive into the medications we have available to treat them, but first, let’s circle back to our case.

While cultures remained negative for bacteria, the patient’s headache and sore throat worsened, congestion developed, and ENT was consulted to evaluate nasal cavities which appeared concerning for necrosis. The patient was then taken to the OR for investigation and debridement, and fungal cultures were taken.

After a close consult with ID, the recommendation was made to empirically treat with liposomal amphotericin B at 10 mg/kg IV once daily due to CNS concern and immunocompromised host status.

As mentioned in the case, the patient was started on amphotericin B, let’s take a step back and review some key classes of anti-fungal medications commonly used in the PICU.

As a big picture, we will be covering Poleyenes, Azoles, and Echinocandins

Whitney, do you mind highlighting our first class, the polyenes?

The first class of antifungal agents we will discuss is polyenes. Within this class, there are two agents that we encounter clinically: Amphotericin B and Nystatin. These two agents bind to ergosterol in the fungal cell membrane to disrupt fungal cell permeability and cause rapid cell death.

For the purposes of this podcast, we will focus our attention on amphotericin B, as this agent is a broad spectrum IV antifungal agent used clinically to treat most all fungal infections including cryptococcus, aspergillus, fusarium, and mucor.

However, this medication is known for its many toxicities including electrolyte derangements, headaches, fevers, and renal impairment. There is a liposomal formulation of this medication in which most hospitals now have on formulary exclusively to help mitigate some of these adverse effects, but this formulation is also known to cause them to a lesser extent, and electrolytes should be closely monitored and aggressively replaced during therapy.

Nephrotoxicity also means the use of concomitant nephrotoxic medications should be minimized as much as possible. So in our patient case, since blood cultures remained no growth to date, vancomycin, as well as meropenem, were discontinued.

Returning to our case, Histopathology and debridement ended up showing evidence for mucormycosis susceptible to posaconazole and isavuconazole. Let's talk a little bit now about the Azole class.

The azoles are our second group of antifungals; this class of antifungals works by preventing the formation of ergosterol, and there are five common azoles that every clinician should be familiar with, and taking into consideration our case, we will start by discussing posaconazole and isavuconazole.

Posaconazole is a broad spectrum azole that covers all of your Candida as well as both Aspergillus and Mucor. It is available both IV and orally, in the form of tablets and a suspension. The oral formulations are not interchangeable since the oral suspension has erratic pharmacokinetics given that it is highly lipophilic and difficult to absorb. Therefore, it is recommended to use the tablets when able, especially given their convenience of once daily dosing.

Otherwise, the drug will require therapeutic drug monitoring to ensure the patient is achieving adequate levels. The target trough concentration for adequate posaconazole prophylaxis is > 700 ng/mL and > 1,250 ng/mL for treatment drawn 5-7 days following medication initiation.

Like most all of the other drugs in this class, posaconazole is a strong CYP3A4 and p-glycoprotein inhibitor; therefore, many drug interactions exist. These types of azoles are also known to prolong QTc and cause hepatotoxicity.

It is important to highlight that children in the PICU may frequently be frequently on concurrent medications which also prolong the QT interval. Having close collaboration with your clinical pharmacy team and a daily discussion of the medications the patient may be on is essential in optimizing electrocardiographic monitoring for these patients.

Now that we have talked about posaconazole, let’s contrast this with isavuconazole (cresemba). Whitney, do you mind highlighting some similarities & differences?

Isavuconazole is the newest azole and is also available in an IV and PO formulation. Coverage is pretty similar to posaconazole; however, the additional benefits of this agent are that it does not require therapeutic drug monitoring, has QTc prolonging effects, or have as significant of drug interactions when compared to the other azoles, given that it is a moderate CYP3A4 inhibitor versus a strong one.

Major side effects to be mindful of include hypersensitivity and skin reactions, hypokalemia, hepatotoxicity, peripheral edema, and cough.

To summarize, Given that our patient here is an oncology patient with chemotherapy and anti-emetics on board, isavuconazole is the drug of choice for her due to the lack of QTc prolonging and minimal drug interactions. Therefore, we can then narrow her from the liposomal  amphotericin B to isavuconazole, where we would first load her with 372 mg IV Q8H x6 doses, and then continue her on a maintenance dose of 372 mg IV or PO when able for as long as she is receiving chemotherapy and is immunosuppressed.

Ok, so far we have covered posaconazole, isavuconazle, let’s close out this class by highlighting voriconazole, itraconazole and fluconazole?

So while our patient was growing Mucor which was susceptible to both posaconazole and isavuconazole, another agent to highlight voriconazole. While it does not cover Mucor, it is the drug of choice in the treatment of Aspergillus and has good Fusarium coverage as well.

It is also available in both IV and PO which can be converted 1:1. However, it does have the most toxicities compared to any of the other azoles which can include hallucinations, visual disturbances, and phototoxicity. Therefore, therapeutic drug monitoring is essential with a goal trough level of about 2-6 mcg/mL.

Absolutely, Stephanie, I want to also highlight Itraconazole. This is the azole most commonly used to treat Histoplasma and Blastomyces. It can also be used as a prophylactic agent for Aspergillus. It is only available orally as a solution and as a capsule, but they are not interchangeable. The capsules must be taken on an acidic stomach and with a full meal while the solution needs to be administered in a fasting state. This drug is also monitored via a serum trough concentration with a goal level > 0.5 mcg/mL.

It is important to keep in mind, however, that this agent has two black box warnings. The first is that it may cause negative inotropic properties which may lead to heart failure, and the other is that it has the potential to lead to torsades de pointes. Therefore, it should not be used in patients with a history of heart failure and/or ventricular dysfunction.

And finally, the last azole and most narrow azole we are going to discuss is fluconazole. Fluconazole is the drug of choice for Candida albicans, Cryptococcus, and Coccidia. This drug is available both IV and orally with a 1:1 conversion, and distributes everywhere in the body, including the CNS.

Our final discussion today will be on echinocandins, Stephanie, how do these agents work?

These agents work mechanistically by inhibiting 1,3-beta-D glucan synthase which is also involved in the synthesis of the fungal cell wall.

There are three agents in this class (caspofungin, micafungin, and anidulafungin). All three are available IV only, have a similar spectrum of activity which is essentially all Candida as well as Aspergillus, and are dosed once daily.

The great thing about these agents is that they have very few drug reactions and do not require therapeutic drug monitoring.

To summarize our discussion today, we spoke about major classes of antifungals, polyenes, azoles, and echinocandins. While each of them has its own specific coverage, it is important to also monitor for side effects and toxicities. Working closely with your clinical pharmacist and infectious disease physicians is a high-fidelity strategy to optimize therapeutic treatment.

Also, in the spirit of anti-microbials, I would like to add that if you have not checked out our prior episode number 23: PICU Bugs and Drugs, I would highly recommend you listening as it covers the: Rational Use of Antibiotics In The PICU!

This concludes our episode on Approach to Anti-fungals in the PICU. We hope you found value in our short, case-based podcast. We welcome you to share your feedback, subscribe & place a review on our podcast! Please visit our website picudoconcall.org which showcases our episodes as well as our Doc on Call management cards. PICU Doc on Call is co-hosted by myself Dr. Pradip Kamat and Dr. Rahul Damania. A special thank you to Dr. Whitney Moore & Stephanie Yasechko for joining us today and sharing their expertise. Stay tuned for our next episode! Thank you!

• References:
• Antifungal Therapeutic Drug Monitoring Recommendations for Adult and Pediatric Patients. The Michigan Medicine University of Michigan. January 31, 2017.
• Curran, M. There’s a Fungus Among Us: A Beginner’s Guide to Antifungals. TLDRPharmcy.com. February 14, 2018.
• Lexi-Drugs. Hudson, OH: Lexicomp. Accessed June 5, 2022.