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Every time I hear the term “candida,” I flash back to the 1970s, hearing Tony Orlando and Dawn singing. But I doubt it was an ode to these invasive yeasts.

The genus candida are regular denizens of our microbiome, operating in a happy symbiosis with us and our other gut bugs. Any fungal overgrowth is generally held in check by our immunological response. But as with all things in our digestive tract, it doesn’t take much to get the community balance out of whack; if we experience a change in diet, an uptick in stress, a new medical condition, or our immune system goes sideways for any one of a host of reasons, then our healthy bacteria’s numbers can take a precipitous slide. Candida takes advantage of this loss with all the enthusiasm of a four-year-old offered unlimited chocolate cake, proliferating like rabbits on Viagra.

S. A. Syed wrote how “alterations in gut flora and gene regulation raise the risk of opportunistic fungal infections in cases of immune system weakness or following antibiotic usage. Due to its ability to stick to tissues and create enzymes that dissolve barriers, candida thrives. Low immunity, improper use of antibiotics, chemotherapy, and endocrine or  nutritional  problems  are some  of  the  contributing causes to candida’s growth.”

Although  Candida  albicans gets all the press, Chung and associates wrote in the journal

Oncotarget that at least 15 others also colonize our bodies. According to Syed, “the five most prevalent pathogens— Candida albicans, Candida glabrata, Candida tropicalis, Candida parapsilosis, and Candida krusei—account for more than 90% of invasive diseases.”

It’s candida’s adaptability to its host that allows it to catch fire with immunocompromised patients, and it’s not picky about its incubator. Chung and associates wrote, “CI frequently involves the mouth, vagina, glans penis, esophagus, liver, gastrointestinal tract, respiratory tract, and skin.”

In the vagina, candida causes vaginal candidiasis; in the mouth, it’s known as thrush. The overgrowth can appear in the bowel movements of sufferers as white, yellow or brown mucus; a white, yellow or brown string-like substance; froth or foam; or diarrhea. Candida granuloma—severe and chronic— can appear on the skin, scalp, mouth or fingernails, while cutaneous candidiasis manifests as an itchy, raised red patch of pustules on folds of skin under the arms and breasts or in the groin area. Symptoms can also include white patches in the mouth, swelling, a burning sensation and cottage cheese– like vaginal discharge.

When candidiasis is at its worst, it becomes systemic: Invasive candidiasis is a serious infection of the blood or on the membranes that line the heart or brain, affecting some 25,000 U.S. patients per year.

And everyone’s a candidate. No one is immune to the possibility of overgrowth, but some folks make better hosts: pregnant people (thanks to the fluctuating hormones), diabetics, babies, hospitalized patients, and those with dentures and catheters are all at higher risk of candidiasis. In a patient with immune deficiency, candida can bloom like a wildfire out of control.

For most of us, an overgrowth of candida is mostly annoying, causing itching and discomfort. Systemic symptoms can include headache, fatigue, stomachache, flatulence, itchy skin and craving for sweets. If a patient who is receiving treatment for candidiasis develops a fever and chills, they should immediately call a doctor.

No one should shrug off these symptoms; untreated, candida can turn invasive and can even cause precancerous conditions that slide into cancer. Chung and associates wrote, “CI is not an infrequent complication of cancer and cancer-related therapy, and it may also play an active role in cancer development. The relationship between microbial infection and cancer is of great concern.”

They  argued  that  “several plausible mechanisms” support this  premise.  “First, Candida can produce compounds such as nitrosamines, which are identified carcinogens that play a role in oral cancer initiation,” they wrote. “Second, a previous study suggested that C. albicans promotes cancer through a proinflammatory response, mediated by an increase in cytokine production and adhesion-molecule expression. It is increasingly clear that the tumor microenvironment, which is largely orchestrated by inflammatory cells, is an indispensable participant in the neoplastic process. Other hypotheses, such as the induction of Th17 response and molecular mimicry, have also been proposed to explain the mechanism by which C. albicans might promote cancer progression.”

The First Date

For many women, our first experience with candidiasis showed up when we started taking oral contraceptives. For others, symptoms developed as side effects of various other medications: antibiotics, steroids, proton pump inhibitors, or medicines that cause dry mouth or “turn off” healthy bacteria. Additional triggers include a diet high in refined carbohydrates and sugar; uncontrolled diabetes, HIV, smoking, cancer, or anything that compromises the immune system; hormonal changes; and stress.

Candida isn’t contagious, exactly, but it can be spread by physical contact. Breastfeeding mothers can pick it up from babies who have thrush, and spouses can transfer it back and forth through sexual contact, including via oral sex. The disease seems to have no affiliation for gender or age; while the average age of infected patients is 57.4 years, other factors can influence its proliferation.

Practitioners diagnose candidiasis via tests and examination, including a physical exam and culture test. Average folks can chase off an outbreak with over-the-counter meds and a little time. Other at-home remedies include keeping the skin dry; limiti ng the use of anti bioti cs and hormone-disrupti ng birth-control methods; limiti ng sugary foods and keeping blood sugar in check; quitti ng smoking; and avoiding stress and heavy alcohol consumpti on. Oft en, this is enough to keep the proliferati on in check.

But for those with a compromised immune system, candidiasis is a whole other story.

Open Up Wide

The innate immune barrier in the esophagus is where the defense against candida begins, with the nonkeratinized strati fi ed squamous epithelium. If a pati ent has a candida overgrowth in the esophagus, it will show up as yellow-white patches, or plaques that cannot be removed, oft en in combination with oral thrush. Although herpes simplex virus and cytomegalovirus are among the other nasties that can cause infectious esophagitis, the most common type is esophageal candidiasis. While the oropharynx has the dubious distinction of being the most susceptible part of the GI tract to candida infection, the esophagus is second in line. And plaques can be found throughout the esophagus, or localized in the upper, middle, or distal areas.

Symptoms can include pain or difficulty swallowing, nausea, pain in the sternum area, heartburn, vomiting, weight loss, diarrhea, and melena, depending on the extent of esophageal damage. Abdimajid Ahmed Mohamed and associates wrote in the Canadian Journal of Gastroenterology and Hepatology that diagnosis may indicate

“(1) acute infection: extremely weak immunosuppression patients often die of acute fungal infection; (2) subacute infection: subacute infection may result in esophageal stricture or pseudodiverticulum; (3) chronic infection: usually from childhood, chronic infection is often associated with submucosal fungal infection and immunodeficiency.”

After confirming candida via endoscopic examination and subsequent biopsy, practitioners can contain the overgrowth with systemic oral antifungal drugs. However, “It is important to differentiate esophageal candidiasis from other forms of infectious esophagitis such as cytomegalovirus, herpes simplex virus, gastroesophageal reflux disease, medication-induced esophagitis, radiation-induced esophageal injury, and inflammatory conditions such as eosinophilic esophagitis,” Mohamed wrote. Complications can include necrotizing esophageal candidiasis, fistula and sepsis.

Further along in the gut, candida can cause gas, abdominal pain, diarrhea, nausea, bloating and cramps, among other symptoms. Patients who have some manner of compromise in the digestive tract—for example, Crohn’s disease, ulcerative colitis, gastric ulcers, duodenal ulcers and perforated ulcers—are more likely to present with candidiasis.

Syed wrote, “The three main risk factors for GI candidiasis are radiation, intestinal inflammation, and recurrent GI surgery.” But anything that compromises the immune system, including leukemia and lymphoma, or the use of cytotoxic drugs, corticosteroids or antibiotics, can cause a flare.

And candida’s toxic effects are increasing morbidity and mortality worldwide. According to Zhe Feng and associates in Frontiers in Cellular and Infection Microbiology, “When the human immune system is compromised, C. albicans can rapidly transition from nonpathogenic to pathogenic fungi, resulting in superficial or deep candidiasis, including thrush and candidemia.” Severe candidiasis kills approximately a million people worldwide every year—no small source of concern to healthcare practitioners.

Testing, 1, 2, 3

Diagnosing an overgrowth can be tricky; histological evidence can’t be determined from sputum or stool specimens, simply because candida is a normal part of the GI tract’s normal flora. An endoscopic biopsy sample “may exhibit pathological characteristics, including multiple abscesses and an acute inflammatory response. Pseudohyphae and fungal spores are typically observed, with neutrophils predominating,” Syed wrote.

Generally, a combination of clinical symptoms and notable growth is enough for a diagnosis. And if therapy helps, you know you’re on the right track. “The alleviation of dysphagia and substernal pain that occurs after systemic anticandidal therapy is indicative of candidal esophagitis,” Syed wrote. “Because dysphagic individuals run the danger of developing strictures, esophagoscopy is advised.”

Clinicians have three popular weapons in their arsenal against candidiasis: the small-molecule antifungal medications polyenes, azoles and echinocandins. However, each has limitations.

While polyenes like amphotericin B and nystatin have been around since the 1950s, they “can induce significant adverse effects as a result of the structural resemblance between the intended target, ergosterol, and cholesterol, a sterol found in mammalian cell membranes,” Zhe Feng and associates wrote. However, as Darius Armstrong-James wrote in Parasite Immunology, “antifungal resistance to this class of drugs has not significantly emerged during this time, although there are some fungal species with intrinsic resistance, such as Aspergillus terreus and Candida lusitaneae.”

Echinocandins (caspofungin, anidulafungin and micafungin) boast a commendable safety profile and are efficient fungicides, but cost, IV administration and narrow antifungal range inhibit their practical use. Armstrong James wrote, “They target beta-1,3-D glucan synthase, inhibiting the production of beta-1,3-D glucan, an essential fungal cell wall component.”

Azoles, with their low toxicity and broad antifungal efficacy, are a popular choice. They “have the advantage of a better toxicity profile and, importantly, are available orally. Fluconazole has specific utility for Candida albicans and Cryptococcus neoformans but no activity for Aspergillus species and patchy utility across dermatophytes and endemic mycoses,” Armstrong-Hames wrote.

In addition, according to Feng, “their fungistatic effects in certain species have led to the emergence of azole-resistant isolates.” Also, the effectiveness of these treatments decreases in patients who are immunocompromised.

Other options include terbinafine, “an ergosterol inhibitor with good oral bioavailability and activity against dermatophytes and dematiaceous (black) moulds,” Armstrong-Hames wrote, and flucytosine, a flurouracil pro-drug that suffered a rapidly emerging resistance that has limited it to adjunctive use.

A recent study in the journal Microbiology Research investigated the antifungal efficacy of vitamin D₃ (VD₃) against candida. The authors, Junwen Lei and associates, concluded that VD₃ may have “multitarget effects,” reducing the fungal burden in the liver, kidneys and small intestine. They wrote, “these findings suggest a new antifungal mechanism for VD₃ and indicate that VD₃ could be an effective therapeutic agent for use in [intra-abdominal candidiasis] treatment.”

While other antifungals are in the research pipeline, there’s just no magic bullet. And the need to find one is growing.

A New Attitude

One possible therapy addresses the patient’s immune system itself. Generally, the immune system will target the fungal invader, producing inflammatory factors and activating phagocytes to attack the infection. Feng, et al., wrote, “[In] addition to playing a crucial role in initiating early defense against fungal infections, the innate immune system also triggers various responses promoted by the adaptive immune system through [dendritic cells].” Two types of adaptive immunity—cell-mediated immunity and humoral immunity— combine to build a powerful immune defense against candida… when the immune system is working properly.

When it isn’t, Feng wrote, “immunotherapeutic approaches exhibit potential as a novel strategy for treating candidiasis, owing to the significant involvement of the human immune system in managing this condition. Immunotherapies encompass therapeutic approaches aimed at targeting and impacting the immune system of the body, thereby enhancing the host’s ability to combat infections (Qadri et al., 2023). These methodologies encompass various strategies, such as augmenting the population of phagocytes, activating innate defense pathways in phagocytes and DCs, and stimulating antigen-specific immunity through means like vaccines and monoclonal antibodies.”

Antibody-based medications, Feng wrote, have exhibited positive outcomes; compared to small molecule drugs, antifungal antibodies “present a diminished occurrence of adverse reactions and a broader array of choices.” And combining antifungal medications with monoclonal antibodies provides a one-two punch against the drug resistance seen in candida.

This also “enhances specificity,” potentially becoming an asset to better patient outcomes. Novel immunomodulatory techniques integrating the regulation of recombinant cytokines with monoclonal antibodies may enhance those antibodies’ therapeutic efficacy, according to Feng. “Moreover,” they write, “emerging technologies offer promising avenues for the treatment of life-threatening invasive fungal infections.”

This immunotherapeutic approach must always take into account the immunocompromised condition of the patient, as it’s necessary to customize the therapeutic intervention. Candida-generated proteins can be effectively targeted by antibody-based medications; a side benefit is fewer adverse reactions and a “broader array” of choices, according to Feng. When combined with antifungal medications, the monoclonal antibodies can help combat rising drug resistance in candida. And because the monoclonal antibodies are patient-specific, they hold the potential for improved clinical outcomes.