Mucormycosisblack fungus treatment – Amphotericin B injection, Isavuconazole, Posaconazole

1. Mucormycosis/black fungus treatment – Amphotericin B injection, Isavuconazole, Posaconazole Mucormycosis or black fungus is a disease that spreads aggressively and requires treatment aggressively. Mucormycosis comes under the fulminant type of fungal sinusitis, which comes under invasive fungal sinusitis. It is a super fast express version of invasive that spreads through the blood vessels. Mucormycosis's initial symptoms and Invasive fungal sinusitis symptoms are the same, but the pace at which symptoms develop in black fungus is fast that it is easy to differentiate them. Treatment on suspicion When a patient comes in with at least one symptom of mucormycosis, an ENT doctor performs a nasal endoscopy. If he finds a black material inside the nose, he will immediately scrape it and send it for culture and biopsy. Without waiting for test results to confirm, he will start with the test dose of Amphotericin B or Isavuconazole and proceed further, assuming that the patient has

2. mucormycosis. The antifungal medication will curb the fungus growth. Waiting for the test results can alter the patient's fate due to the rapid growth of fungus. For normal invasive fungal sinusitis, Dr. K. R. Meghanadh suggests antifungal medication even if takes years to heal. He would not opt for debridements even in extreme cases of invasive fungal sinusitis. But, the progress of the fulminant disease is so fast that he goes on a full-on aggressive mode with the treatment that will consist of extensive debridements. Mucormycosis/black fungus treatment Black fungus treatment involves two steps. 1.Debridement surgery 2.Treatment with antifungals The antifungal treatment and debridements should go hand in hand to save the patient. Skipping either debridements or antifungal treatment is not an option. Debridements What is debridement? The fungus attacks tissue and starts eating the tissue, and replaces the tissue. As much as possible fungus-infected tissues and tissues that are replaced with fungus must be removed by surgery. The surgical procedure to remove infected tissues is called debridement.

3. What tissues need to be removed for the treatment of mucormycosis Suppose the fungus attacks the tissue, but the tissue is viable( the tissue is attacked by the fungus but still working and not yet eaten up by fungus and still has a blood supply and nerves working), then this type of tissue needs treatment with antifungals through intravenous root or tablets. A surgeon will not remove the viable infected tissues. However, suppose the infected tissue is not vital. A doctor might choose to remove a non-vital tissue if it is partially or even doubtfully infected. This removal could decrease the unnecessary fungal load. Debridements might include removal of eyes and jaw bone too. Why do we need debridements? Why are debridements important in treating black fungus? The antifungals used for the treatment of mucormycosis are potent. They can have severe side effects on the human body compared to other drugs. The quantity of antifungal medication given to the patient is directly proportional to the amount of fungus in the body. So, the amount of fungus left out in the body during debridement will determine the dosage of antifungals. So, debridements need to be done carefully for the best results.

4. How many surgeries or debridements will be required for black fungus treatment? Any ENT surgeon or doctor can not give you an exact number of surgeries required for a particular patient. It depends on the patient’s immunity, doctor’s skill, experience, and patient’s luck. As per Dr. K. R. Meghanadh, a minimum of 3 surgeries will be required for a patient, and the number can go up from there with no limit. The highest number of debridement surgeries Dr. K. R. Meghanadh has done on a patient is 20. In the future, this number could go higher. After an adequately done surgery, the remaining fungus will replace the leftover infected tissues and spread to new tissues after 2 to 3 days while giving antifungal medication and also till the critical effective dose of antifungal medication is attained. So, the treatment involves multiple debridements done every day or on alternate days to remove the growing infection. If the infection gets under excellent control, the debridement can be done once in 3 to 4 days. Antifungal treatment for black fungus Depending on a patient’s immunity, mucormycosis can double up in a few hours. Potent antifungals can only control this rapid growth. As mentioned in the above section, the partially infected working vital tissues left out in the debridement procedure also must be treated with antifungals.

5. We do have many antifungals available. However, all do not have action on the mucormycosis infection. The antifungals that can be used for the treatment of black fungus are 1.Amphotericin B 2.Isavuconazole 3.Posaconazole All the 3 have different mechanisms of action. Amphotericin B Injection Treatment using Amphotericin B is the gold-standard treatment for mucormycosis and is available only in injection form. To treat the patient judiciously and choose the right medicine, a doctor needs to know the fundamentals of different Amphotericin B compounds and their mechanism of action. How is Amphotericin made? Amphotericin is a naturally occurring substance formed by a bacteria called Streptomyces nodosus. Amphotericin has the property of killing a majority of the fungi. There are many variants of Amphotericin. The raw product obtained from Streptomyces nodosus is a mix of all the variants.

6. This raw Amphotericin mixture is harmful to the human body. Types of Amphotericin There are many variants of Amphotericin called Amphotericin A, Amphotericin B, Amphotericin C, Amphotericin X, etc. Amphotericin B is very active against fungi and can help humans fight a fungal infection. However, Amphotericin C and Amphotericin X are the ones that are toxic to the human body. Amphotericin A is ineffective. How is Amphotericin B derived? Streptomyces nodosus bacteria produce natural Amphotericin that contains Amphotericin B and other variants of Amphotericin. Amphotericin C & Amphotericin X are toxic to the human body and hence need to be filtered out along with the ineffective Amphotericin A. Lyophilization is the process used to filter out other variants of Amphotericin B out of raw Amphotericin. The quality of the final product, i.e., Amphotericin B, entirely depends on the lyophilization process. The side effects of the medicine are directly proportional to the purity of the Amphotericin B given.

7. The purity varies from company to company and batch to batch. Per the law, filtered Amphotericin B needs to be 99% pure, but few brands sometimes achieve 99.9% purity. The batch with 99.9% purity, if used to make Amphotericin B Deoxycholate, gives the best results for most patients. Types of Amphotericin B compounds and their mechanism of action Multiple compounds are made with filtered Amphotericin B obtained from actinomycete Streptomyces nodosus’ produce. We have mainly three types of Amphotericin B compounds 1.Amphotericin B Deoxycholate (AMBDOC) or Conventional Amphotericin B 2.Amphotericin liposomal 3.Amphotericin B lipid complex Amphotericin B Deoxycholate or AMBDOC or Conventional Amphotericin B If Amphotericin B is combined with a salt called deoxycholate and hence the formula is called Amphotericin B Deoxycholate. In short, it is called AMBDOC or conventional Amphotericin B. AMBDOC is the most effective and works best in the purest form possible. A test dose must always be given to the patient and then offered at a dose of 1 to 2 milligram per kilogram of body weight, up to a cumulative dose of 1.5 to 3 grams per kilogram, depending on how much fungus is left out in the tissues after series of debridements. There could be side

8. effects like a reduction in hemoglobin, calcium, and potassium. Patients can often have fever, chills, vomiting sensation, and loose motions that need to be corrected by additional medication. There have been instances when the test doses for various patients for a particular batch have caused severe side effects leading to the disposal of other doses purchased that belong to the same batch. Similarly, there were instances of getting hands-on batches with minimal side effects and the best results. Amphotericin liposomal Another way of making the formula safe is tagging with liposomes, i.e., lipoproteins. These proteins do not have any pharmacological effect on the body, making Amphotericin B inactive on the body cells. So, Amphotericin B tagged with liposomal protein will not act on the human body eliminating the chance of side effects. Whereas the black fungus can take liposomal Amphotericin B and divide it into liposomes protein and Amphotericin B. Amphotericin B ends up killing the fungus. The Amphotericin B toxicity happens secondarily in the body after its action on the fungus. Human cells cannot take liposomal Amphotericin. It escapes from the drug action. But, after killing the fungus, the Amphotericin B separated from cells will enter the body and will give a reaction.

9. Amphotericin B lipid complex(Amphotericin BLC) & Amphotericin emulsion Similarly, we have another compound along with fats. Lipids are fats. They have a different kind of action when compared to the other two types and are safer. 5 to 6 Amphotericin B molecules are combined with a fat molecule to form an emulsion. So, the emulsion is a bigger molecule. A simple Amphotericin B molecule gets diffused from the blood vessel into the tissue easily, whereas the larger emulsion molecules cannot diffuse from the normal blood vessels to tissues. So, the medicine will stay in the blood and not go into tissues, so side effects are less. Whenever there is an infection in tissue there will be a certain amount of inflammation at the end of the blood vessels connected to the tissue, i.e., the blood vessels expand, and the pores to the tissues will also expand. So, the blood vessels make the medicine permeable through the blood vessels and reach the tissue. So, the drug reaches the infected parts of the body only. As this medicine goes to the infected areas, the side effects are less. The con with the Amphotericin B lipid complex is it doesn’t reach tissues with minor inflammation. Conclusion about Amphotericin B compounds Any variant other than AMBDOC must be given in higher doses to a patient. For example, in a scenario where 50mg AMBDOC is required, we will need 500mg of liposomal Amphotericin B. How is Amphotericin B used? So far oral form of Amphotericin B is not developed. We give these intravenously only.

10. After giving one to two doses, the vein through which the medicine is sent will inflame in a lot of pain. The inflammation of these veins due to the drug is called local reactions. So, we have to change the vein every 2 to 3 doses. After using the vein for 2 to 3 doses, it might be blocked and cannot be used for the next 10 to 15 days. So, we tend to go for a central venous line, i.e., put a central line in the major vein in the neck, arm, or leg. A central venous line can be used for 10 to 12 days comfortably without causing pain to the patient. The possibility of local reactions is relatively less when we use the central venous line. Amphoteric B can have side effects on kidneys and bring down calcium and magnesium levels. So, we need to supplement calcium and magnesium at the same time we must not increase the total fluid given to the body. This requires experienced physician and supporting staff as well. Amphotericin B Deoxycholate injection with good purity best treats mucormycosis in a general scenario. Isavuconazole Isavuconazole has action closer to Amphotericin B. But, it is not as effective as Amphotericin B anyhow much safer. Posaconazole for mucormycosis Posaconazole’s action is much lighter than Amphotericin B. Posaconazole is good for the maintenance of the therapy only.

11. Posconazole cannot replace Amphotericin B like Isavukonazole. After removing 99.9% of the fungus, the 0.1% only can be tackled with Posaconazole. Else, Isavuconazole can be used depending on the patient’s budget. Posaconazole and Isavuconazole are available in the form of injections, capsules, or syrups. The side effects are almost nill, but the lever functions must be monitored. NOTE: All the medications, capsules, and syrup medications must be used under a registered medical practitioner's guidance. Amphotericin B or Isavuconazole, which will be initially given in the IV form, must be given in an ICU only and must be started with a test dosage. This article cannot be used as a prescription by a patient. Mucormycosis is not a disease that can be treated at home. This article is insufficient for a doctor to take as a guide. There is a lot more learning that a doctor needs to do before prescribing a patient. Who can get treatment for black fungus? Late-stage mucormycosis patients might not be treated, as the chances of recovery are low. Primarily if mucormycosis has spread to the brain., The chances of recovery are almost zero, making death inevitable. If the infection has spread to multiple parts of the face, then the survival chances drop down very low.

12. When a patient reaches out to the doctor late, the doctor will not treat the patient as it can give unnecessary hope to the patient and family members. Mucormycosis treatment can be very aggressive and expensive, and the low chances of survival will not make sense to treat the patient. The standards followed for deciding to treat a patient might differ from doctor to doctor. Mucormycosis treatment cost Mucormycosis treatment costs can vary, and no doctor or hospital can give you a precise estimate before the patient is fully treated. It depends on two factors mainly. 1.Recovery rate or immunity of the patient 2.Doctor’s expertise If the doctor is experienced in treating black fungus, the treatment and recovery can be over quickly, bringing down the cost. The chances of recurrence will also be low then. 3.Complications If the fungus has spread to the eye or jawbone, the removal will cost extra bucks. Mucormycosis treatment is very costly due to many reasons. 1.Multiple surgeries Debridement surgeries for mucormycosis are in particular quoted higher than similar surgeries as the reusable equipment will need multiple sterilizations during and after the surgery. These multiple sterilizations will bring down the life of the equipment. In fact, during the Post-COVID-19 Mucormycosis outbreak in India, there was a shortage of reusable equipment used in black fungus surgeries. 2.Medication

13. 3.Long stay at the hospital, i.e., for 15 to 40 days 4.ICU Bed charges Antifungal medicines like Amphotericin B in IV form must be given in an ICU, as the patient can react and might need immediate care. The patient might occupy an ICU bed for 8 hours daily just for the medication. patient’s Mucormycosis treatment cost in India As mentioned earlier, the mucormycosis cost varies from patient to patient depending on various factors. Mucormycosis treatment costs in India should generally range from INR 10,00,000 to 18,00,000. This cost can also increase if the recurrence of mucormycosis occurs. Black fungus treatment at home Black fungus or mucormycosis treatment cannot be done at home. It doesn't have any home remedies. This is not normal fungus sinusitis that can be treated with medications. It needs surgeries, not one but multiple. A patient needs to stay for 15 to 40 days in a hospital. It involves powerful antifungals and surgeries. Even the antifungals need to be given in an ICU, and many parameters must be checked.

14. Black fungus treatment requires an experienced ENT doctor and a well-experienced supporting staff. We need to rush to an ENT doctor when we find the symptoms. The black fungus survival rate If not treated black fungus survival rate is zero, and death is inevitable. If treated in late stages, i.e., the fungus has spread to the brain, two eyes, or multiple facial organs, then the survival rate is almost 1%. Most doctors will deny treatment at this stage, as the possibility of recovery is only written in books, and most of them haven't been seen in recent times as this is a very rare disease. If treated on suspicion in the early stages, i.e., when the patient has shown only the first symptom, then the survival rate can be as high as 90%. The first symptom is always severe facial pain. As you can see, the survival rate varies in a huge range, but the main problem is that it takes just a few weeks to reach from 90% to 1%. The takeaway is high-risk patients who can get black fungus need to be aware of the first symptom and should reach an ENT doctor as soon as they have doubt. Then there will be a very high chance of survival, and recovery will also be quicker. Dr. K. R. Meghanadh