Olorofim - a promising new antifungal candidate for aspergillosis treatment.
Olorofim represents a significant advancement in treating aspergillosis, particularly for patients who cannot tolerate or do not respond to existing antifungal therapies. Here’s why it’s important:
1. Novel Mechanism of Action
- Olorofim is the first antifungal in a new class called orotomides. It inhibits dihydroorotate dehydrogenase, an enzyme essential for fungal pyrimidine biosynthesis.
- This mechanism is entirely distinct from existing antifungal classes (azoles, polyenes, and echinocandins), making it effective against strains resistant to current treatments
2. Broad Spectrum and Potency
- It has demonstrated activity against azole-resistant Aspergillus species and other difficult-to-treat moulds, addressing a major gap in antifungal therapy
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This includes rare and often lethal fungal infections like Scedosporium, Lomentospora, and Fusarium, as well as chronic conditions like Chronic Pulmonary Aspergillosis (CPA) and invasive aspergillosis.
3. Oral Administration
- Unlike many current treatments that require intravenous administration (e.g., amphotericin B), olorofim is taken orally, improving convenience and accessibility for patients needing long-term therapy.
4. Targeting Unmet Needs
- Aspergillosis, particularly invasive aspergillosis, has high morbidity and mortality rates, especially in immunocompromised patients (e.g., those with cancer, transplant recipients).
- Current treatments face challenges like resistance, toxicity, and drug-drug interactions. Olorofim addresses these limitations by offering a safer and more tolerable alternative
5. Regulatory Recognition
- The drug has been granted Breakthrough Therapy Designation and Orphan Drug Status by the FDA and EMA, underscoring its potential to meet urgent medical needs
Future Implications
Olorofim's availability for treating Chronic Pulmonary Aspergillosis (CPA) depends on its successful progression through clinical trials and regulatory approval. Here's a summary of its current status and potential timeline:
- Current Status:
- Olorofim is in Phase 3 clinical trials (OASIS trial) for invasive fungal diseases, including invasive aspergillosis, a related but more acute condition than CPA.
- Although the drug has shown promising results in earlier studies, the FDA recently issued a Complete Response Letter, indicating that additional clinical data is required before it can be approved in the U.S.
- CPA is not explicitly listed as a primary indication in current trials, but success in related aspergillosis treatments could lead to future trials or off-label use for CPA.
- Timeline to Approval:
- If the ongoing Phase 3 trial and additional studies satisfy regulatory agencies, olorofim could receive an approval within 2–3 years for its initial indications (e.g., invasive aspergillosis).
- For CPA specifically:
- Additional trials may be needed to confirm efficacy and safety, potentially extending approval timelines by 3–5 years.
- Off-label use might occur sooner, depending on clinician judgment and availability in regions with less restrictive policies.
Given the high unmet need in CPA and the novelty of olorofim’s mechanism, it is closely watched by both the medical community and regulators. If you're a patient with CPA, keeping in touch with your healthcare provider about ongoing trials and compassionate use programs may help you access new treatments sooner.
Understanding How Our Lungs Fight Fungus
Airway epithelial cells (AECs) are a key component of the human respiratory system: The first line of defence against airborne pathogens such as Aspergillus fumigatus (Af), AECs play a crucial role in initiating host defence and controlling immune responses and are important in maintaining respiratory health and preventing infections that can lead to conditions such as aspergillosis. Research by the University of Manchester’s Dr Margherita Bertuzzi and her team sought to understand how AECs combat Af and what leads to vulnerabilities in these defences, particularly in individuals with underlying health conditions.
Previous work by Dr Bertuzzi and her team demonstrated that AECs are effective in stopping the fungus from causing harm when they are functioning well. However, in people who are at higher risk, like those with weakened immune systems or existing lung conditions, if these cells are not working correctly, the fungus can take advantage of this situation.
This new research by Dr Bertuzzi and her team aimed to explore how AECs stop the fungus in healthy people and what goes wrong in people who get sick. The team looked closely at the interaction between the fungus and lung cells from both healthy individuals and those with certain diseases. Using advanced scientific methods, the team was able to observe the interactions between the lung cells and the fungus at a very detailed level.
What They Found
Experiments showed that the stage of fungal growth was important and a surface carbohydrate – mannose (a sugar) also had a role in the process.
Specifically, they discovered that the fungus is more likely to be taken up by lung cells when it has been growing for a few hours compared to when it’s just a fresh spore. Swollen fungal spores that were locked at 3 and 6 hours of germination were 2-fold more readily internalised than those locked at 0 hours. They also identified that a sugar molecule called mannose on the surface of the fungus plays a big role in this process.
Mannose is a type of sugar molecule that can be found on the surface of various cells, including those of pathogens like Aspergillus fumigatus. This sugar plays an important role in the interactions between the fungus and the host’s cells, particularly the AECs lining the lungs. In a healthy immune response, mannose on the surface of pathogens can be recognised by mannose receptors on immune cells, triggering a series of immune responses aimed at eliminating the pathogen. However, Aspergillus fumigatus has evolved to exploit this interaction, allowing it to adhere to and invade lung cells more effectively. The presence of mannose on the fungus’ surface facilitates its binding to mannose-binding lectins (MBLs) (proteins that bind specifically to mannose) on the surface of lung cells. This binding can promote the internalisation of the fungus into the lung cells, where it can reside and potentially cause infection.
The research highlighted the possibility of manipulating this interaction as a means to combat fungal infections. By adding mannose or mannose-binding lectins like Concanavalin A, researchers could significantly reduce the fungus’s ability to invade lung cells. This reduction was accomplished by essentially “competing” with the fungus for the binding sites on the lung cells or by directly blocking the fungal mannose, thereby inhibiting the interaction that facilitates fungal infection.
Why does it matter?
Understanding these interactions gives us important insights into how our lungs protect us from fungal infections and what goes wrong in people who are vulnerable to such infections. This knowledge could help in creating new treatments against pathogens like Aspergillus fumigatus.
You can read the full abstract here.
Learning to control antifungal drug resistance from the environment
Spores of fungi including Aspergillus fumigatus, the main species that causes aspergillosis, have been found to propagate the growth of strains of fungi that are already resistant to those antifungal medications most commonly used in medical clinics to treat aspergillosis. This can render the most common treatments for aspergillosis useless, which is a concern for doctors.
Where do these strains come from? Most experts suggest that the use of commercial fungicides by farmers exposes the fungus to pesticides that closely resemble the antifungal drugs used by doctors. This exposure is likely to enrich the numbers of resistant spores found in the environment ie in compost, soil, and of course in/on the plant material produced by the farmers e.g. food crops, and flowering plants.
Can we stop using these antifungal chemicals as pesticides? A multi-disciplinary meeting designed to bring together experts from all sides of the debate took place in London on 13th July and those representing the growers outlined how important it is that farmers use these fungicides to prevent crop damage and to produce enough food to feed us all! Completely stopping their use on crops does not seem to be an option.
Given that it seems that there will be antifungal-resistant spores in the environment we live in for the foreseeable future we need to:
- know where they are
- know how to avoid inhaling them
Where might patients come into contact with most antifungal-resistant spores?
Farmers use antifungal pesticides on many crops including:
- Fruits: Apples, grapes, peaches, strawberries, and tomatoes
- Vegetables: Potatoes, onions, corn, and soybeans
- Grains: Wheat, corn, and rice.
- Nursery crops: Roses, trees, and shrubs
Researchers have found antifungal-resistant Aspergillus fumigatus spores on many of these crops or the soil around them, at low levels (0 - 10% of samples).
Is this level of antifungal-resistant spores increasing?
When scientists looked at spore numbers they found that the number of resistant spores increased during the growing season as antifungal pesticides were applied to the crops, but this resistance did not survive the winter (1) and levels were back down to where they were the previous year.
It is apparent that handling crops, or the soil around them is a potential way to come into contact with some spores that are resistant to antifungal medications given in the clinic.
What is the likelihood of these spores causing an antifungal-resistant infection?
Researchers (1) have looked at how resistant the resistant spores are to the level of antifungal medication they will be exposed to in a patient and found that the proportion of the isolates that were resistant to the levels of antifungal medication used in patients was 1-4% - so very low.
Which crops are worst affected?
The most common material found to contain antifungal-resistant material was plant material waste originating from cut flowers and flowering bulbs and other types of waste produced in the industry in The Netherlands (2), so it is clear that composting can promote the growth of resistant spores. Ways to prevent this from happening are under development.
Other materials tested were household waste, wheat grain, poultry manure, cattle manure, horse manure, maize silage & fruit waste and of those antifungal-resistant spores were found only in fresh household waste.
Other researchers across the world (3) have detected antifungal-resistant spores in a range of crops and soils. Highest numbers of resistant spores (or perhaps in places where most research has been done) tend to be in India (rice), China (maize, some house plants, potato), USA (wheat, roses, apples), The Netherlands (orchids), Spain (onions, strawberries), Colombia (carrots) & Italy (grapes).
These were not exhaustive studies and we know that Aspergillus fumigatus (i.e. not antifungal-resistant) itself is found on far more plants/fruits/vegetables, so it stands to reason that if they are treated with antifungal pesticides then it may be possible to isolate resistant spores from them. It is clear that although there is a risk of inhaling antifungal-resistant spores from this plant material, the risk to the domestic consumer is low. Nonetheless, out of an abundance of caution, it might be best to take a few precautions:
a. Avoid handling cut flowers and flowering bulbs from The Netherlands
b. After purchase wash fruit and vegetables prior to storage in the home
c. Dispose of household waste in a timely manner
Action is being proposed and taken nationally and internationally to reduce the risk to aspergillosis patients in particular of inhaling antifungal-resistant spores of A. fumigatus and other fungi (4). Research is ongoing to learn more about what are the causal factors responsible for the increase in resistant spores, which are the main risks to human health and what we can do about it.
In time we should be able to prevent the growth of resistant isolates, ensuring that we have useful antifungal medication for years to come.
1. Effects of Agricultural Fungicide Use on Aspergillus fumigatus Abundance, Antifungal Susceptibility, and Population Structure
Authors: Amelia E. Barber https://orcid.org/0000-0002-3399-1037, Jennifer Riedel, Tongta Sae-Ong, Kang Kang, Werner Brabetz, Gianni Panagiotou, Holger B. Deising, Oliver Kurzai https://orcid.org/0000-0002-7277-2646AUTHORS INFO & AFFILIATIONS
DOI: https://doi.org/10.1128/mbio.02213-20
2. Emerg Infect Dis. 2019 Jul; 25(7): 1347–1353. doi: 10.3201/eid2507.181625
Environmental Hotspots for Azole Resistance Selection of Aspergillus fumigatus, the Netherlands
Sijmen E. Schoustra, Alfons J.M. Debets, Antonius J.M.M. Rijs, 1 Jianhua Zhang, Eveline Snelders, Peter C. Leendertse, Willem J.G. Melchers, Anton G. Rietveld, Bas J. Zwaan, and Paul E. Verweij
3. Azole-resistant Aspergillus fumigatus in the environment by cburks817 · MapHub
4. Nat Rev Microbiol. 2022; 20(9): 557–571.
Published online 2022 Mar 29. doi: 10.1038/s41579-022-00720-1
Tackling the emerging threat of antifungal resistance to human health
Matthew C. Fisher,1 Ana Alastruey-Izquierdo,2 Judith Berman,3 Tihana Bicanic,4 Elaine M. Bignell,5 Paul Bowyer,6 Michael Bromley,6 Roger Brüggemann,7 Gary Garber,8 Oliver A. Cornely,9 Sarah. J. Gurr,10 Thomas S. Harrison,4,5 Ed Kuijper,11 Johanna Rhodes,1 Donald C. Sheppard,12 Adilia Warris,5 P. Lewis White,13 Jianping Xu,14 Bas Zwaan,15 and Paul E. Verweij11,16
Fungal vaccine developments
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The numbers of people at risk of fungal infections are increasing due to an aging population, increased use of immunosuppressive medications, pre-existing medical conditions, environmental changes, and lifestyle factors. Therefore, there is a growing need for new treatments or preventative options.
Current treatment options for fungal infections often involve the use of antifungal medications, such as azoles, echinocandins, and polyenes. These medications are generally effective in treating fungal infections, but they can have drawbacks. For example, some antifungal drugs can interact with other medications, leading to potentially harmful side effects. Additionally, overuse of antifungal drugs can contribute to the development of antifungal drug resistance, which can make treatment more challenging.
There has been a growing interest in the development of fungal vaccines as an alternative treatment. A fungal vaccine works by stimulating the immune system to produce a specific response against the fungus, which can provide long-term protection against infection. The vaccine could be given to at-risk individuals before exposure to the fungus, preventing infection from occurring in the first place.
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A recent study by researchers from the University of Georgia demonstrated the potential for a pan-fungal vaccine to protect against multiple fungal pathogens, including those that cause aspergillosis, candidiasis, and pneumocystosis. The vaccine, called NXT-2, was designed to stimulate the immune system to recognize and fight against several types of fungi.
The study found that the vaccine was able to induce a strong immune response in mice and additionally protect them from infection with several different fungal pathogens, including Aspergillus fumigatus, which is the main cause of aspergillosis. The vaccine was found to be safe and well-tolerated in the mice, with no adverse effects reported.
This study demonstrates the potential for a pan-fungal vaccine to protect against multiple fungal pathogens. While the study did not specifically address the use of the vaccine in patients with pre-existing aspergillosis infections, the findings suggest that the vaccine has potential to prevent aspergillosis infection in high-risk individuals.
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In summary, while the development of antifungal vaccines offers a promising potential alternative to the challenges posed by current treatment options for fungal infections, further research is needed to determine the safety and efficacy of the vaccine in humans, including those with aspergillosis, before it can be considered as a treatment option.
Original paper: https://academic.oup.com/pnasnexus/article/1/5/pgac248/6798391?login=false
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Developments in Biologic and Inhaled Antifungal medications for ABPA
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ABPA (Allergic Bronchopulmonary Aspergillosis) is a serious allergic disease caused by a fungal infection of the airways. People with ABPA usually have severe asthma and frequent flare-ups that often require long-term use of oral steroids and antibiotics to treat secondary bacterial infections.
The two main treatments for ABPA are antifungal medication and oral steroids. Antifungal medication work by targeting the fungi causing the infection, limiting its growth and spread. This can help reduce the frequency of flare-ups and stabilize the condition but may also cause side effects such as nausea and, more rarely, liver damage. Oral steroids work by reducing inflammation and suppressing the immune system's response to the allergen, which can help control the symptoms of ABPA. However, long-term use can cause significant side effects, including weight gain, mood swings, and adrenal insufficiency.
These side effects can greatly impact quality of life, but both treatments may be necessary to prevent the disease from worsening. Therefore, new or improved treatments are needed.
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Fortunately, there have been recent developments in managing ABPA, and a review by Richard Moss (2023) highlights two promising types of treatment:
- Inhaled antifungal medication treat fungal lung infections by delivering the drug directly to the site of infection. This allows for a higher concentration of the drug to be delivered to the affected area while limiting the exposure of the rest of the body and therefore reduces side effects. For instance, inhaled itraconazole has been shown to reach concentrations high enough to kill or inhibit fungus growth. Further trials will be completed this year (2023) to assess its safety and effectiveness. Although still in development, these drugs offer hope for more effective and better-tolerated treatment options for patients with ABPA.
- Biologic medication is a completely new type of treatment that uses synthetic antibodies to target specific cells or proteins of our immune system instead of using a chemical compound. Omalizumab, a type of biologic, binds to immunoglobulin IgE and deactivates it. IgE is involved in the allergic response our bodies launch against foreign invaders and plays a big role in ABPA symptoms. Deactivation of IgE has been shown to reduce allergic symptoms. In clinical trials omalizumab has been shown to significantly (a) reduced the number of flare-ups compared to pre-treatment, (b) reduced the need for oral steroid use and lowered its necessary dose, (c) increased wean off steroids, (d) improved lung function and (e) improved asthma control. Additionally, other Monoclonal antibodies (Mabs) such as mepolizumab, benralizumab, and dupilumab have shown a reduction in flare-ups, total IgE and a steroid-sparing effect.
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According to Moss (2023), these new treatment approaches are highly effective in reducing hospital visits. Biologics seem highly effective, with up to a 90% reduction in flare-ups for ABPA patients and up to 98% efficacy in reducing the amount of oral steroid needed by the patient. If these new treatments continue to work well, it could potentially offer a new, higher quality of life for individuals with ABPA . Overall, these findings are promising, but further research is needed to confirm the effectiveness of these treatments specifically for ABPA.
Original paper: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9861760/
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Drug Induced Photosensitivity
What is drug-induced photosensitivity?
Photosensitivity is the abnormal or heightened reaction of the skin when exposed to ultraviolet (UV) radiation from the sun. This leads to skin that has been exposed to the sun without protection becoming burnt, and in turn, this can increase the risk of developing skin cancer.
There are several medical conditions like lupus, psoriasis and rosacea that can increase a person's sensitivity to ultraviolet light. A more comprehensive list of known conditions can be found here.
Drug-induced photosensitivity is the most common type of skin-related adverse drug reaction and can occur as a result of topical and oral medications. Reactions happen when a component of the medication combines with UV radiation during sun exposure, causing a phototoxic reaction that appears as severe sunburn, identified by swelling, itchiness, profuse redness and in the worst cases, blistering and oozing.
Patients taking antifungal medications, in particular, Voriconazole and Itraconazole (the former being more widely known for causing reactions), are often aware of the increased risks of photosensitivity; however, these are not the only drugs that can induce an abnormal response to UV exposure. Other drugs that have been reported to cause photosensitivity are:
- NSAIDs (Ibuprofen (oral and topical), naproxen, aspirin)
- Cardiovascular medication (furosemide, ramipril, amlodipine, nifedipine, amiodarone, clopidogrel – just a few)
- Statins (simvastatin)
- Psychotropic drugs (olanzapine, clozapine, fluoxetine, citalopram, sertraline – just a few)
- Antibacterial medications (ciprofloxacin, tetracycline, doxycycline)
It is essential to note that the above list is not exhaustive, and reported reactions range from rare to frequent. If you think a medication other than your antifungal is causing a reaction to the sun, speak to your pharmacist or GP.
How to protect yourself
In most cases, patients can't stop taking the medication that can predispose them to photosensitivity. Staying out of the sun isn't always possible either - quality of life is always an important consideration; therefore, extra care should be taken to protect their skin while outside.
There are two types of protection:
- Chemical
- Physical
Chemical protection is in the form of sunscreen and sunblock. However, it is important to remember that sunscreen and sunblock are not the same. Sunscreen is the most common type of sun protection, and it works by filtering the sun's UV rays, but some still get through. Sunblock reflects the rays away from the skin and prevents them from penetrating it. When buying sunscreen, look for a sun protection factor (SPF) of 30 or above to protect against UVB and at least a UVA protection rating of 4 stars.
Physical protection
- NHS guidance advises staying in the shade when the sun is strongest, which in the UK is between 11am and 3pm from March to October
- Use a sunshade or umbrella
- A wide-brimmed hat that shades the face, neck and ears
- Long-sleeved tops, trousers and skirts made of close-weave fabrics that stop sunlight from penetrating
- Sunglasses with wraparound lenses and wide arms that conform to the British Standard
- UV protective clothing
Links to further information
Adrenal insufficiency
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Cortisol and aldosterone are important hormones our bodies need in order to stay healthy, fit and active. They are produced by the adrenal glands which are sited at the top of each of our kidneys. Sometimes our adrenal glands may not be able to produce enough cortisol and aldosterone, for example when the glands are mistakenly attacked and destroyed by a person’s immune system – this is Addison’s disease (see also addisonsdisease.org.uk). The lost hormones can be replaced by medication from an endocrinologist and the patient can live a normal life. This form of adrenal insufficiency is not a feature of aspergillosis.
Unfortunately, people who take corticosteroid medication (e.g. prednisolone) for longer periods of time (more than 2-3 weeks) can also find that they have low levels of cortisol as their corticosteroid medication can suppress the production of their own cortisol, especially if high doses are taken.
Once the corticosteroid medication is stopped your adrenal glands will usually re-activate but it may take some time which is why your doctor will tell you to slowly taper down your dose of corticosteroid carefully over several weeks, to allow your adrenal glands to recover.
What has this got to do with aspergillosis?
People with chronic forms of aspergillosis & asthma can find themselves taking corticosteroid medication for quite long periods of time in order to control their breathlessness and allow comfortable breathing. Consequently, they may find that they have to take care when reducing their dose of corticosteroid and proceed gradually to allow their own natural cortisol production to resume safely. Reducing too quickly can cause a range of symptoms including fatigue, fainting, nausea, fever, dizziness.
These are powerful drugs and must be handled with care so if you have any concerns contact your GP without delay.
Other medication you may be taking to treat aspergillosis has also rarely been associated with causing adrenal insufficiency e.g. some azole antifungal medication, so it is worthwhile to remain vigilant for relevant symptoms (see list above). However, note that symptoms such as fatigue are very common in someone with aspergillosis.
For other details on taking corticosteroid medication see the steroids page
Steroid Emergency Card
The NHS has issued a recommendation that all patients who are steroid dependant (i.e. should not abruptly stop corticosteroid medication) carry a Steroid Emergency Card to inform health practitioners that you need daily steroid medication in the event you are taken into hospital and are unable to communicate.
Information on obtaining a card can be found here.
NOTE patients attending the National Aspergillosis Centre in Manchester can collect a card at pharmacy
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Antifungal Drug Pipeline
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Many of our patients already know of the increasing need for new antifungal drugs; treatments for fungal diseases like aspergillosis have significant limitations. Toxicities, drug-drug interactions, resistance, and dosing are all issues that can complicate therapy; therefore, the more treatment options we have, the more likely we are to find an optimal therapeutic option for patients.
Developing antifungal drugs is difficult because of the biological similarities between people and fungi; we share many of the same biological pathways as fungi, creating issues in developing safe antifungals. To develop new antifungal drugs, researchers must look at how they can exploit some of the differences we do have.
Below is a layman’s breakdown of a recently published review that looked at seven antifungal drugs currently in various stages of development. The majority of new antifungals have been new versions of old drugs, but the ones discussed in this review have new mechanisms of action and different dosing regimens, so, if approved, these drugs could provide a ray of hope in the not so distant future in terms of treatment.
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Rezafungin
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Rezafungin is currently in phase 3 of development. It is a member of the echinocandin class of drugs, including micafungin and caspofungin; Echinocandins work by inhibiting a fungal cell wall component essential to homeostasis.
Rezafungin has been developed to retain the safety benefits of its echinocandin predecessors; while enhancing its pharmacokinetic and pharmacodynamic properties to create a unique, longer-acting, more stable treatment that allows for weekly intravenous rather than daily administration, potentially expanding treatment options in the setting of echinocandin resistance.
Fosmanogepix
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Fosmanogepix is known as a first-in-class drug (so first of its kind antifungal) that blocks the production of an essential compound that is important for the construction of the cell wall and self-regulation. Blocking the production of this compound weakens the cell’s wall enough that the cell can no longer infect other cells or evade the immune system. It is currently in Phase 2 clinical trials and is showing promising results in the oral and intravenous treatment of multiple invasive fungal infections, demonstrating efficacy in multi-drug resistant and other difficult-to-treat infections.
Olorifim
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Olorifim falls under an entirely new class of antifungal drugs called orotomides. The orotomides have a distinct mechanism of action, selectively targeting a key enzyme in pyrimidine biosynthesis. Pyrimidine is an essential molecule in DNA, RNA, cell wall and phospholipid synthesis, cell regulation, and protein production, so when Olorofim targets this enzyme, it profoundly affects the fungi. Unfortunately, Olorifim isn’t broad spectrum, and it only kills a few fungi – pertinently, Aspergillus, and the fungus that causes valley fever (which affects the brain), Coccidioides. Since its discovery, it has progressed through pre-clinical studies and phase 1 human trials and is currently an ongoing phase 2 clinical trial testing its use orally and intravenously.
Ibrexafungerp
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Ibrexafungerp is the first of a new class of antifungals called Triterpenoids. Ibrexafungerp targets the same essential component of the fungal cell wall that the echinocandins do, but it has an entirely different structure, making it stabler and meaning it can be given orally; differentiating Ibrexafungerp from the three currently available echinocandins (caspofungin, micafungin, andulafungin), which can only be given intravenously limiting their use to hospitalised patients and those with indwelling venous access.
There are two ongoing phase 3 trials of ibrexafungerp. The most extensive enrolling study to date is the FURI study, which evaluates the efficacy and safety of Ibrexafungerp among patients with severe fungal infection and who are unresponsive or intolerant of standard antifungal agents. The oral formulation was recently approved by the USA’s Food and Drug Administration (FDA) for the treatment of vulvovaginal candidiasis (VVC).
Oteseconazole
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Oteseconazole is the first of several tetrazole agents designed with the goal of greater selectivity, fewer side effects, and improved efficacy compared to currently available azoles. Oteseconazole has been designed to tightly bind to an enzyme called cytochrome P450. When we discussed earlier fungi and humans being similar, cytochrome P450 is one of those similarities. Human cells contain various species of cytochrome P450, which are responsible for many important metabolic functions. Therefore, if azole antifungal agents inhibit the human cytochrome P450, the result can be adverse reactions. But, unlike other azole antifungals, Oteseconazole only inhibits the fungal cytochrome p450- not the human one because of its affinity for the target enzyme (cytochrome P450) is greater. This should mean fewer drug-drug interactions and less direct toxicity.
Oteseconazole is in phase 3 of development and is currently under FDA consideration for approval to treat recurrent vulvovaginal candidiasis.
Encochleated Amphotericin B
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Many of our patients will already be aware of Amphotericin B, which has been around since the 1950s. Amphotericin B falls under the class of drugs called Polyenes- the oldest class of antifungal drugs available. They kill fungi by binding to ergosterol which acts to maintain cell membrane integrity. The drug works by stripping away the ergosterol, causing holes in the cell membrane, making it leaky enough to fail. But, polyenes also interact with cholesterol in human cell membranes, meaning they have significant toxicities. Encochleated Amphotericin B has been developed to avoid these significant toxicities – its novel lipid nanocrystal design allows for drug delivery directly to the infected tissues, shielding the body from unnecessary exposure – and it can be given orally, potentially reducing hospital stays.
Encochleated Amphotericin B is currently in phases 1 & 2 of development, so a little way off. Still, it promises the potential of an oral drug with little, if any, of the typical toxicities of amphotericin B.
ATI-2307
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ATI-2307 is in the very early stages of development and is a new antifungal drug with a unique mechanism of action. ATI-2307 inhibits mitochondrial function (mitochondria are structures within cells that convert food to energy), decreasing the production of ATP (adenosine triphosphate), which is the molecule that carries energy, leading to growth inhibition.
As mentioned earlier, ATI-2307 is still in the early stages. Still, researchers have completed three Phase 1 clinical studies that demonstrated it was well tolerated in humans at anticipated therapeutic dose levels. Thus, the clinical role for ATI–2307 is unclear; however, its broad in vitro activity against a host of important fungal pathogens, including multi-drug resistant organisms, could translate into a critical role for this compound, especially for fungal infections due to drug-resistant organisms such as azole-resistant Aspergillus species.
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Therapeutic drug monitoring (TDM)
[et_pb_section fb_built="1" admin_label="section" _builder_version="4.16" global_colors_info="{}" theme_builder_area="post_content"][et_pb_row admin_label="row" _builder_version="4.16" background_size="initial" background_position="top_left" background_repeat="repeat" global_colors_info="{}" theme_builder_area="post_content" custom_margin="7px|auto|7px|auto|true|false"][et_pb_column type="4_4" _builder_version="4.16" custom_padding="|||" global_colors_info="{}" custom_padding__hover="|||" theme_builder_area="post_content"][et_pb_text admin_label="Text" _builder_version="4.16" background_size="initial" background_position="top_left" background_repeat="repeat" global_colors_info="{}" theme_builder_area="post_content"]Therapeutic drug monitoring (TDM) is a branch of clinical chemistry and clinical pharmacology that specializes in the measurement of medication levels in blood. Its main focus is on drugs with a narrow therapeutic range, i.e. drugs that can easily be under- or overdosed.
When prescribing and managing oral antifungal medication, each needs to be carefully managed for each patient - the table below gives some standard guidelines as used at the UK National Aspergillosis Centre by its specialist pharmacists.
