Antifungals: A Prudent Perspective – Part 2
Lauren Tessier, ND
As discussed in the last installment of this article, there are numerous concerns with employing antifungals, including the growing issue of antifungal resistance and the complexities of how and when to use them appropriately. Part 1 of this article laid the foundation for a discussion regarding the process of choosing a suitable antifungal, as well as how to optimize its efficacy.
Can Testing Help or Hinder Antifungal Choice?
Choosing an antifungal is not as easy as it is made out to be and can be as complex as you wish it to be. There are numerous clinical considerations to take into account when employing an antifungal: location of colonization/infection, the type of fungus, and resistance patterns.
Being aware of location of the infection (or colonization) is important, as proper medication delivery can make or break a case. Fungi can inoculate the sinuses, skin, lungs, GI tract (mouth to anus), and urogenital tract. Information about localized complaints, such as facial pain, discharge, GI issues, skin rashes, discolored sputum, shortness of breath, and cough, can all point to localization. Similarly, imaging and culturing may also help inform localization. For instance, “fungal balls,” or mycetomas, may be seen in the hollow cavities of the body (eg, sinuses, urinary tract, etc) via CT or MRI.1,2 Moreover, invasive aspergillosis may appear on chest X-ray or CT as a ground-glass opacity or a nodule surrounded by a ground-glass halo.3-6 As a cautious aside, other pathologies may demonstrate the ground-glass appearance; therefore, if such a finding is found, the patient should ideally be appropriately directed to pulmonology and infectious disease for adjunctive care. Culturing of skin scrapings, sputum, stool, and urine not only allows for identification, but also localization. Keep in mind, when ordering a culture, it is imperative to be clear that a fungal culture is being requested. Fungal cultures can produce false negatives for numerous reasons, including inadequate sampling, incorrect growth medium, short growing duration, incorrect temperature, and general lack of lab awareness for fungal identification. In cases where a false negative is suspected, a histopathological sample may be of benefit7-8; however, it is not a fail-proof method for fungal pathogen identification.9-10 In some cases, PCR may be helpful for identification, although it is not applicable to all molds, and may not be available in all areas.
As for susceptibility testing, there are various types of lab methodologies that are used to determine resistance patterns, which may vary from lab to lab. Some labs are unable to test susceptibility of molds and are only able to test susceptibility of yeasts, while other labs limit their susceptibility testing to a handful of specific antifungals.
In some cases, serology testing may help to inform a case, so long as the physician is aware of its limitations. Not unlike like other serology testing, patients who struggle with immune compromise, deficiency, or dysregulation, may be unable to produce reliable levels of antibodies required to make an assessment. Moreover, antibody testing for individual molds has limitations in its sensitivity and specificity, as cross-reactivity to other fungi is possible. Moreover, IgM and IgG testing may not be available for the specific species in question. To further confound (or potentially enhance) IgM and IgG results, research has demonstrated that simple exposure alone, not just infection, can cause species-specific elevations in IgM, IgG, and IgA.11-13
Direct antigen testing may also be used to inform antifungal choice by means of narrowing the potential antigenic field. β-D-glucan, galactomannan, and glycoprotein assays are available through most large labs and are used primarily in the detection of life-threatening Candida and Aspergillus infections, but they also can be used in the diagnosis of Histoplasma, Pneumocystis, and Cryptococcus infections. These tests can analyze various types of samples, including serum, bronchial alveolar lavage, urine, etc. The biggest problem with these assays is that they suffer a wide-ranging sensitivity and specificity, depending on the study employing them.14-15
An exciting up-and-coming test centers around the identification of fungal-reactive T-cells. This minimally invasive test, although still considered investigational, may offer more diagnostic information, especially in the face of other negative laboratory findings.16-18 However, similar to serology testing, simple exposure to environmental molds is capable of producing activated T-cells in the absence of demonstrable infection.19
Finally, urine mycotoxin testing may be potentially helpful in identifying the mold for which one should be tested for antifungal consideration. For instance, literature demonstrates that gliotoxin is not only produced by Aspergillus fumigatus,20 but also by A terrus, A niger, and A flavus21 and by certain strains of Candida albicans.22-24 There is, however, the possibility that some yet-to-be-identified molds also produce specific mycotoxins. So, while urine mycotoxin testing is not fool-proof, it can still provide clues that help to inform a case.
A similar logic may be applied to known environmental exposure. Environmental testing using MSQPCR technology can identify fungal species in a living space, whereas air testing typically only identifies genus (due to limitations in methodology). Therefore, the highly specific data from an Environmental Relative Moldiness Index (ERMI) – which utilizes MSQPCR – of a client’s living space can help to inform a case. Let’s say you have a patient with a known exposure to Aspergillus fumigatus, as demonstrated by an ERMI. This result, paired with an elevated urine gliotoxin level, may warrant an Aspergillus fumigatus-specific work-up to help inform antifungal utility.
As one can infer, no single test is perfect; however, much can be obtained if the clinician truly understands information that a laboratory test is providing.
Types of Antifungals
Once you are aware of a patient’s specific environmental exposure, and perchance you have a lead on internal exposure by serology, culture, antigen detection, PCR, or otherwise, it is important to also assess for preexisting conditions of the liver and kidneys so that pathologies may be identified in advance and be monitored appropriately during the course of treatment. Once the aforementioned data points have been collected, it is time to match the case to an appropriate drug and delivery method. Drug delivery options can be systemic (oral or IV), topical (internal or external), intranasal, or nebulized. However, one must keep in mind that not all antifungals are safe or effective in all delivery methods.
There are 7 major classes of antifungals: azoles, polyenes, echinocandins, fluorinated pyrimidine, griseofulvin, morpholines, and allylamines.25 Systemic diseases are typically clinically treated with azoles, echinocandins, and polyenes, while superficial diseases can be addressed by morpholines, griseofulvin, and allylamine, in addition to the polyenes and azoles.25
The well-known fungistatic azole class of drugs interferes with the synthesis of ergosterol, an integral part of the fungal cell membrane, by inhibiting a fungal CYP450 enzyme that is responsible for its production.26-27 The azoles include the initially created subclass, imidazoles, which consist of clotrimazole, ketoconazole, and miconazole; these are most active for Candida, Cryptococcus, and dermatophytes.27,28 However, these drugs have been noted to have numerous side effects and drug-drug interactions due to their impact on the CPY450 pathway. In response to this, the first generation of the triazole subclass was developed, which initially included fluconazole and itraconazole. These medications offered a wider spectrum of activity, but ultimately failed in the treatment against Fusarium and Mucorales molds.29,30 Fluconazole, while widely used against species of Candida, Coccidioides, Cryptococcus, Histoplasma, and Blastomyces, is simply ineffective against molds.31-32 This is perhaps the most important clinical pearl in this entire discussion: Fluconazole does not have as extensive of a spectra as many assume, and therefore suffers many failures despite being widely used in the clinical setting for presumptive treatment. Meanwhile, the other first-generation triazole, itraconazole, is active against not only yeasts, but also some Aspergillus species.33-34 Compared to earlier iterations of azoles, the second generation of triazoles – voriconazole and posaconazole – are fungicidal35 and provide a wider spectrum of activity against filamentous fungi,36-37 a property only provided by amphotericin B38 prior to their invention nearly 20 years ago. The newest triazole, isavuconazole, has one of the widest spectra, as it is effective against Aspergillus, Cunninghamella, Rhizopus, and Mucor species of fungi.35
The polyene class of medications was the first class of antifungals, as made popular by amphotericin B; other polyenes include natamycin and nystatin. These drugs cause a disruption of the fungal cell membrane by means of pore formation, and are thus fungicidal in nature.39-45 They are considered broad-spectrum, as they are efficacious against most Aspergillus, Candida, Mucor, and dimorphic fungi, with considerably low rates of resistance.46-49 Amphotericin B is the most widely utilized polyene for systemic mycoses in its IV form. While highly efficacious, original formulations were also very toxic, resulting in infusion reactions, electrolyte imbalances, and renal and hepatic toxicity26,50 – hence its nickname “ampho-terrible.” Having been improved upon at the end of the last century, the lipid-based reformulation is now less renal-toxic than the previous iteration.48,51 Generally speaking, natamycin and nystatin are topically used, as they are not formulated to enter the bloodstream, thus their use in the treatment of fungal overgrowth or infection of the mouth, esophagus, GI tract, vagina, cornea, and skin.46
The echinocandins, a relatively new class of antifungals, consist of anidulafungin, caspofungin, and micafungin.38,52 These drugs inhibit the production of the polysaccharide β-1,3 glucan, which is integral to the health and functionality of the fungal cell wall.53 This medication class is effective against Candida and Aspergillus species,54-60 and is considered fungicidal and fungistatic,61 respectively. However, echinocandins are not effective against Cryptococcus, Fusarium, and Mucoraceae fungi.62-64 These drugs are typically delivered intravenously and are reserved for more serious invasive infections; however, they have poor penetrance into the central nervous system.65,66 In general, they demonstrate minimal drug-drug interactions, as well as minimal side effects, which include headache, infusion reaction, GI upset, and altered liver enzymes.55,56,66 Due to their general tolerability and efficacy, they have been called the “penicillin of antifungals.”67
Griseofulvin, allylamines (eg, naftifine and terbinafine), and morpholines (eg, amorolfine) are all effective topically against dermatophytes.25 Amorolfine also addresses Malassezia,68,69 while all of the above demonstrate efficacy against species of Candida.70-72 Terbinafine is also available in oral preparations,72 as it is able to be absorbed and delivered systemically by the bloodstream. It demonstrates efficacy against Aspergillus, Fusarium34,73 and other dimorphic fungi,72 as well as some dematiaceous fungi.74
Flucytosine, also known as 5-fluorocytosine of 5-FC is the only drug in the class of fluorinated pyrimidines that is used as an oral antifungal; as such, it interferes with nucleic acid synthesis and thus fungal protein synthesis.75 While this drug is active against some Cryptococcus and Candida species,38,76-79 it has little to no action against filamentous or dimorphic fungal species.63,80 Unfortunately, the efficacy of this particular drug is limited due to continually growing resistance when used as the only treatment agent,81-82; as such, it is now largely used in conjunction with other antifungal agents.77-79 Caution is required, as it may cause drug-drug interactions,38 liver toxicity, and bone marrow suppression.83 This particular medication may be useful for urinary system indications, as the medication is mostly excreted by the kidneys in a largely unmetabolized form.83 That said, careful attention should be paid to cases with renal insufficiency, wherein therapeutic drug monitoring should be considered.
As you can imagine from the above discussion, having a grasp of what fungi are in play can have a large impact on your choice of antifungal, and thus treatment outcome.
There are numerous ways you can maximize effectiveness of antifungal treatment.
Research has demonstrated that fungi occur naturally throughout the body, creating what we call the mycobiome,84-89 and that some of these fungi, including Aspergillus, Candida, and even Zygomycetes, produce biofilms85-101 which – like bacterial biofilms – may be capable of adding to their overall resistance.93,102-111
Certain drugs have mixed efficacy against various biofilms. Generally speaking, drugs in the azole class have poor activity against Candida biofilms,93,103,105-111 whereas caspofungin, micafungin, anidulafungin, and amphotericin B have demonstrated some efficacy against Candida biofilms.93,105,107,109-118 Therefore, agents active against biofilms should be considered as adjunctive treatment. This includes the aforementioned drugs, and also the various biofilm busters we have all come to know.
When we create a void in our natural flora, it is advantageous to fill that space with something beneficial that will act as a niche competition. Therefore, it is not uncommon to use probiotics when using antifungals. Some may opt to seed the niche with beneficial yeast such as Saccharomyces boulardii, which has been shown to mitigate the ill effects of ochratoxin119 and deoxinyvanol120-122 exposure in animals. However, some may decline to do so due to concerns about cross-reactivity and lack of control over studied vs commercially available strains.
Another way to help maximize effectiveness is being aware of the metabolism and mechanism of action of the medication you are using. As you are aware, many things impact drug kinetics, and thanks to analysis of single nucleotide polymorphisms (SNPs), we may be able to anticipate that a patient might have a higher likelihood of altered drug metabolism. As a result, it may be of benefit to review SNP analysis of patients prior to choosing an antifungal, as doing so may identify unexpected cases of necessary therapeutic drug monitoring. Additionally, keep in mind that natural products have the ability to modify the very CYP pathways that metabolize these medications. Therefore, it is always of benefit to reference drug-herb or drug-nutrient interactions, as these too may impact therapeutic drug levels.
SNP discussion aside, there is additional in-vitro research available discussing the impact of natural products on drug efficacy. For instance, there are numerous studies demonstrating the enhanced effect of amphotericin B when combined with essential oils of Cinnamomum cassia,123 Thymus vulgaris,124 Myrtus communis,125 and Coriandrum sativum.126 However, as these are in-vitro studies rather than in-vivo, one should tread cautiously in their translation to clinical application, as they too may modify metabolic pathways.
Why You Shouldn’t Fear Antifungals
While most of this 2-part piece proposes methodical and cautious decision-making in using antifungals, one should not be scared or dissuaded in doing so. There is a time and place for everything and, in some cases, antifungals may be the best course of action. In naturopathic medicine there is the concept of matching the level of interventions to the illness. If a client is clearly suffering from a problematic fungal infection, the best-match intervention may in fact be an antifungal drug. Moreover, an antifungal medication may be preferentially used in cases where treatment resistance to other antifungal classes or herbs has occurred, or potentially when insurance coverage for medications is a realistic part of the discussion. Finally, in quite a few cases, I have turned to pharmaceutical antifungals instead of antifungal herbs and nutraceuticals, as I have found that in most cases they work faster than herbs and, for some, are better tolerated.
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Lauren Tessier, ND, is a licensed naturopathic physician specializing in mold-related illness. She is a nationally known speaker and is the vice president of the International Society for Environmentally Acquired Illness (ISEAI) – a non-profit dedicated to educating physicians about the diagnosis and treatment of environmentally acquired illness. Dr Tessier’s practice, “Life After Mold,” in Waterbury, VT, draws clients from all around the world who suffer from chronic complex illness as a result of environmental exposure and chronic infections. Dr Tessier’s e-booklet, Mold Prevention: 101, has been widely circulated and its suggestions implemented by many worldwide.