Sirolimus y profilaxis de infección fúngica invasora con azoles/Sirolimus and IFI prophylaxis with azoles


Queremos presentar aquí un problema de manejo de antimicrobianos en la práctica diaria. De forma no excepcional, para pacientes hematológicos tras trasplante alogénico con enfermedad injerto contra huésped intestinal/pulmonar se debe utilizar sirolimus como agente inmunosupresor. Estos pacientes están en riesgo alto de adquirir una infección fúngica invasora especialmente si estos pacientes reciben además esteroides. Por eso en estos pacientes hay indicación para utilizar antifúngicos de forma profiláctica.

El problema radica en que la utilización de azoles interacciona con el metabolismo del sirolimus a través del citocromo P45o elevando de forma significativa los niveles de siroliumus. A este respecto las cuestiones sobre las que se podría discutir son:

  1. ¿Cómo manejáis esta situación en vuestra práctica diaria?
  2. ¿Estáis tranquilos si con dosis anecdóticas de sirolimus alcanzáis niveles en rango terapéutico (estrecho margen terapéutico)?
  3. ¿Tenéis experiencia con otras opciones para profilaxis como Anfotericina B liposomal inhalada?

Gracias

Managing antifungal prophylaxis with posaconazole/itraconazole in patients with intestinal graft vs host disease who need sirolimus in addition to steroids, especially when patients are going to be discharged is troublesome. Rapamycin is one of the mainstem options for intestinal GVHD. With usual posaconazole/itraconazole dosing, rapamycin levels go over the therapeutic limit even using 1/10th of the usual doses. Main questions are:

  1. Are you experiencing these difficulties too? 
  2. Would you be confident if you get good rapamycin target levels even with “symbolic” doses? 
  3. What are your alternatives for these high risk patients, especially if they need steroids too? Any experience with inhaled liposomal amphotericin B in HSCT?
Thank you
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One Response to Sirolimus y profilaxis de infección fúngica invasora con azoles/Sirolimus and IFI prophylaxis with azoles

  1. A continuación la respuesta del Dr. Greene de Tampa (Florida)

    Here is the response from our HSCT pharmacist Donn Davis below:

    1. it is no longer an issue in the United States since itraconazole is not available. With the GI distress side effect profile of itraconazole, there is no way I would recommend using this in a patient with active GVHD of the intestinal tract.

    2. Now to posaconazole issue. So for patients who are having large amounts of diarrhea from active GVHD, it is very difficult to expect them to consistently consume the proper amounts of high fatty foods (or cola/ginger ale with ascorbic acid) in order to optimize the acidic environment for posaconazole absorption. Our standard extended spectrum azole is voriconazole for this very reason when we have patients with active GVHD of the intestinal tract (plus an intravenous route being available if needed). Now both voriconazole and posaconazole greatly inhibit the CYP 3A4 so when we start these Now if your issue is that you are starting posaconazole at the same time you are starting sirolimus, the difficulty you are having at managing these levels does not surprise me. Our standard dose for starting patients on sirolimus when they are NOT on voriconazole or posaconazole is a loading dose of 12 mg followed by 4 mg daily. If the patients are on posaconazole or voriconazole, we give a 3 mg loading dose followed by 1 mg daily. I would not recommend starting vori/posa the same day as sirolimus. You should consider bridging with an echinocandin (micafungin or caspofungin) until you have stable sirolimus levels then drop the dose by 50% once you start voriconazole or posaconazole. The 50% standard dose reduction does not guarantee that the patient will have a super high level of sirolimus after change of dose especially those patients who are tolerating posaconazole and absorbing it since this medication even has a higher CYP 3A4 inhibition compared to voriconazole. Again we use voriconazole as our preferred azole unless that patient is suspected of having or proven mucormycosis.

    John Greene MD
    Professor of Medicine
    Moffitt Cancer Center
    Tampa, FL

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