Candida

Will Rezafungin Data for Serious Candida Infections Sway FDA Panel?

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Agency reviewers highlight limited clinical trial data, neurotoxicity concerns

FDA ADCOMM rezafungin over a computer rendering of candida albicans fungus.

Ahead of an advisory committee meeting on Tuesdayopens in a new tab or window, FDA staff raised concerns over whether the potential benefits of weekly rezafungin injections for adults with candidemia and invasive candidiasis (IC) outweigh any potential risks, including neurotoxicity.

According to an agency briefing documentopens in a new tab or window for the Antimicrobial Drugs Advisory Committee, potential approval of the investigational, long-acting echinocandin for candidemia and IC caused by susceptible Candida species hinges on a single phase III non-inferiority study (ReSTORE), along with data from the dose-finding phase II STRIVE study.

“The key issues for consideration in the benefit-risk assessment of rezafungin include the presumed ability to meet an unmet need in the context of generally similar (to current treatment options) effects on survival, the ability to mitigate any identified risks such as neurotoxicity, and the acceptable tradeoffs between the benefits and risks to patients,” FDA staff wrote.

Candidemia and IC affect about 25,000 people per year in the U.S., according to the CDCopens in a new tab or window. The in-hospital all-cause mortality rate among people with candidemia is approximately 25%.

“There are three FDA-approved echinocandins, all of which are available only as intravenous (IV) formulations dosed once daily,” FDA staff noted. “Antifungal therapy is usually continued for 2 weeks after documented clearance of Candida spp. from the blood in the case of candidemia or following adequate source control and clinical response in IC.”

In the ReSTORE trial, which involved 187 subjects, rezafungin was found to be noninferior to caspofungin in the primary endpoint of all-cause mortality at 30 days in the modified intention-to-treat population, with rates of 23.7% in the rezafungin group versus 21.3% in the caspofungin group. Rezafungin was given as a 400-mg IV loading dose followed by weekly 200-mg IV doses for up to 4 weeks — the proposed clinical dose.

The safety dataset for rezafungin, submitted by sponsor Cidara Therapeutics, included 151 patients from ReSTORE who were given the proposed clinical dose and 81 patients from STRIVE given a higher dose (400 mg administered weekly).

In this dataset, tremor was observed in 2.6% of those receiving the proposed rezafungin dose compared with zero patients receiving caspofungin. Tremor was also reported in early nonhuman primate studies.

While the ReSTORE/STRIVE data “show a similar safety profile to the FDA-approved echinocandins, the size of the dataset limits the ability to identify rare adverse reactions that may be unique to rezafungin,” according to agency staff.

Although tremor has been reported to be an uncommon adverse reaction in the labeling of other echinocandins for candidemia/IC, the FDA noted that the trial data need further scrutiny.

“The review team’s assessment is that the Applicant has not provided sufficient data to support the position that rezafungin provides improved activity against Candida spp. with reduced susceptibility to FDA-approved echinocandins or provides improved tissue penetration,” the FDA wrote in its briefing document. “Overall, the review team finds that rezafungin is primarily distinguished from FDA-approved echinocandins by its extended half-life but welcomes the committee’s input on whether rezafungin may have additional benefits that would extend treatment options for patients with candidemia/IC to address an unmet need.”

All of the currently approved echinocandins, including caspofungin, anidulafungin, and micafungin, come with warnings for hypersensitivity reactions and hepatic adverse reactions in their labeling. Micafungin also has a warning for hematologic effects, renal effects, and infusion and injection site reactions, and anidulafungin has warnings related to risks associated with two of the inactive ingredients in its formulation.

“None of the echinocandins have warning statements related to neurotoxicity, and the only nervous system adverse reaction reported in >5% of patients in clinical trials was headache,” the FDA wrote.

Tremor was reported as an adverse reaction occurring in less than 5% of 68 pediatric patients in an open-label non-comparative study of anidulafungin, and in the pooled safety experience from 34 studies of caspofungin in adult and pediatric patients or volunteers (n=1,951).

During the planning of the ReSTORE trial, the FDA recommended safety measures to mitigate the risk of neurotoxicity, including the exclusion of patients “with a history of neuropathy, history of tremors, or [those] receiving neurotoxic medication; addition of safety assessments for neuropathy, ataxia, and tremor; and review of safety information by the data safety monitoring board.”

Currently, four classes of antifungals (echinocandins, azoles, amphotericin B formulations of polyenes, and flucytosine) have shown clinical effectiveness for the treatment of candidemia/IC. The Infectious Diseases Society of America recommends echinocandins as first-line therapy, except when infections affect the central nervous system, the eyes, or the urinary tract. The other antifungals are considered alternatives in the case of drug intolerance, drug-resistant pathogens, or as adjunctive therapy for refractory cases.

Tools for Detecting a “Superbug”: Updates on Candida auris Testing

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ABSTRACT

Candida auris is an emerging yeast species that has the unique characteristics of patient skin colonization and rapid transmission within health care facilities and the ability to rapidly develop antifungal resistance. When C. auris first started to appear in clinical microbiology laboratories, it could be identified only by using DNA sequencing. In the decade since its first identification outside of Japan, there have been many improvements in the detection of C. auris. These include the expansion of matrix-assisted laser desorption ionization–time of flight mass spectrometry (MALDI-TOF MS) databases to include C. auris, the development of both laboratory-developed tests and commercially available kits for its detection, and special CHROMagar for identification from laboratory specimens. Here we discuss the current tools and resources that are available for C. auris identification and detection.

SUMMARY

As more laboratories have focused on the identification of C. auris, the number of available tools for detection and identification has increased. However, not all laboratories can implement a laboratory-developed test, and many do not have access to MALDI-TOF MS or a Vitek 2 system. The number of alternative commercially available tests is still quite limited, which leaves definitive identification of C. auris as a send-out test in many facilities. An especially glaring deficiency is the lack of a point-of-care test for detection of C. auris colonization. This would be an important tool for the identification of colonized patients, which plays an important role in the implementation of infection control practices, especially in cities where C. auris has become endemic. Candida auris continues to spread across the United States and across the world, and it has become a notifiable disease in many U.S. states and municipalities. While we may only be able to slow the spread, more tools for its detection and identification will allow us to combat it at the point of individual patient care.

Coconut Oil Fights Deadly Yeast Infections, Candida, Research Suggests

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Coconut Oil Fights Deadly Yeast Infections, Research Suggests

A common food oil has been found to have potent antifungal properties that could literally save lives. 

The coconut palm is perhaps the world’s most widely distributed and versatile food-medicine, and has been prized and even revered by indigenous cultures for a wide range of health complaints since time immemorial. Increasingly, scientific evidence is emerging validating its traditionally ascribed health benefits, and more, including supporting brain health, protecting the heart, and even reducing stress and depression.

But what of anecdotes referring to the presumed antifungal activity of coconut oil? Is there any basis in scientific research to make such claims? 

Indeed, a recent study led by researchers at Tufts University has found that coconut oil is highly effective at controlling the overgrowth of the opportunistic fungal pathogen Candida albicans in mice.

Published in the American Society for Microbiology’s journal mSphere, and titled “Manipulation of Host Diet to Reduce Gastrointestinal Colonization by the Opportunistic Pathogen Candida Albicans,” the study identified C. albicans as the most common human pathogen, with a mortality rate of about 40% when causing systemic infections.

C. albicans is normally present in the human gastrointestinal tract, but antibiotics can destroy commensal bacteria that normally keep Candida populations within a healthy range. According to the study, compromised immunity is also a major cause of C. albicans overgrowth, and “systemic infections caused by C. albicans can lead to invasive candidiasis, which is the fourth most common blood infection among hospitalized patients in the United States according to the CDC.”

Additionally, in a recent article we wrote on the topic of Candida albicans and cancer, we explored the implications of a paper published in Critical Reviews in Microbiology, titled “Candida albicans and cancer: Can this yeast induce cancer development or progression?“, wherein compelling evidence is presented that C. albicans overgrowth may play a significant role in carcinogenesis. If this is true, clearly natural ways to keep C. albicans levels at bay are needed by a global population increasingly afflicted by cancer as a primary cause of morbidity and mortality.

Like conventional cancer treatments like chemotherapy, conventional anti-fungal drugs carry with them significant risk of adverse effects, and their repeated use leads to the development of drug resistant strains of fungal pathogens, making natural approaches all the more attractive. The researchers hypothesized that a coconut-based dietary intervention might reduce Candida infection in mice. The study design and results were reported on ScienceDaily.com as follows:

“The team, led by microbiologist Carol Kumamoto and nutrition scientist Alice H. Lichtenstein, investigated the effects of three different dietary fats on the amount of C. albicans in the mouse gut: coconut oil, beef tallow and soybean oil. A control group of mice were fed a standard diet for mice. Coconut oil was selected based on previous studies that found that the fat had antifungal properties in the laboratory setting.

“A coconut oil-rich diet reduced C. albicans in the gut compared to a beef tallow-or soybean oil-rich diet. Coconut oil alone, or the combination of coconut oil and beef tallow, reduced the amount of C. albicans in the gut by more than 90% compared to a beef tallow-rich diet.

“Coconut oil even reduced fungal colonization when mice were switched from beef tallow to coconut oil, or when mice were fed both beef tallow and coconut oil at the same time. These findings suggest that adding coconut oil to a patient’s existing diet might control the growth of C. albicans in the gut, and possibly decrease the risk of fungal infections caused by C. albicans,” said Kumamoto, Ph.D., a professor of molecular biology and microbiology at Tufts University School of Medicine and member of the molecular microbiology and genetics program faculties at the Sackler School of Graduate Biomedical Sciences.”

These preliminary results have profound implications for the practice of medicine, according to a statement made to ScienceDaily by Alice H LIchtenstein, D.Sc., director of the Cardiovascular Nutrition Laboratory at the Jean Mayer USDA Human Nutrition Research Center on Aging at Tufts University:

“This study marks a first step in understanding how life-threatening yeast infections in susceptible individuals might be reduced through the short-term and targeted use of a specific type of fat. As exciting as these findings are, we have to keep in mind that the majority of adult Americans are at high risk for heart disease, the number one killer in the U.S. The potential use of coconut oil in the short term to control the rate of fungal overgrowth should not be considered a prophylactic approach to preventing fungal infections.”

The first author of the study, Kearney Gunsalus, Ph.D. an Institutional Research and Academic Career Development (IRACDA) postdoctoral fellow at the Sackler School in Kumamoto’s lab, also offered his opinion on the study implications:

“We want to give clinicians a treatment option that might limit the need for antifungal drugs. If we can use coconut oil as a safe, dietary alternative, we could decrease the amount of antifungal drugs used, reserving antifungal drugs for critical situations.”

Previous research, available to view on GreenMedInfo.com, indicates that coconut oil is also an effective anti-fungal agent against the growth of dermatophytes, a type of yeast which can cause infections of the skin, nails, and hair because they can utilize keratin.

In Emergency Situations, a Fecal Transplant May Be a Lifesaving Option .

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Probiotics, i.e. beneficial gut bacteria have been heavily featured in the media lately, and for good reason. Researchers are increasingly realizing just how essential your intestinal microflora really is to your health.

The easiest way to improve the makeup of bacteria in your gut is to include traditionally fermented foods in your diet, but in an emergency situation, a novel procedure called fecal microbiota transplant may be the difference between life and death.

Who Knew a Fecal Transplant Could Be a Life Saving Procedure?

Such was the case with Kaitlin Hunter, a California woman who developed a potentially lethal bacterial infection in her colon after spending a month in the hospital recuperating from a serious car accident.

As reported by CNN Health:1

“In the hospital after her accident, doctors followed standard care and put Hunter on antibiotics to prevent an infection. In spite of the antibiotics – or possibly because of them – Clostrium difficile (C. diff) infected her colon, causing severe stomach pain, diarrhea and vomiting…

It’s believed that antibiotics, which kill harmful infection-causing bacteria, also weaken the beneficial, healthy bacteria percolating in the colon. With the colon’s defenses down, C. diff grows rampant, releasing a toxin and inflaming the colon.

C. diff infections kill about 14,000 people in the United States every year, according to the Centers for Disease Control and Prevention, and the number and severity of total cases have increased dramatically over the past decade.”

A fecal microbiota transplant (FMT) involves taking donor feces (the donor is typically a spouse or relative; in the Kaitlin’s case, it was her mother) and transferring it to the patient during a colonoscopy. In this way, the patient receives a transplanted population of healthy bacteria that can combat the overgrowth of pathogenic bacteria.

Recent research has shown the procedure to be very effective against recurrent Clostridium difficile infections. In a study2 published earlier this summer, FMT had a 91 percent primary cure rate, meaning resolution of symptoms without recurrence within 90 days of FMT. The secondary cure rate was 98 percent. Here, resolution of symptoms occurred after one additional course of vanomycin either with or without probiotics and/or a repeat FMT.

Antibiotics Without Probiotics Can Be a Dangerous Proposition

Kaitlin had received nine rounds of antibiotics, so it’s no wonder such a dangerous infection could get foothold in her colon. In this particular case, the fecal transplant likely saved her life.

However, I would dissuade you from thinking this procedure is a magical route to fix less than life threatening conditions. Furthermore, it’s important to understand that you have the power to prevent such a dangerous condition from occurring in the first place. It would certainly be nice if more doctors understood the importance of reseeding the gut with probiotics during and after a course of antibiotics, to reduce the health risks to their patients. However, as in so many other instances, many doctors still overlook this critical step, and this is where knowledge and self-responsibility comes into play.

Any time you take an antibiotic, it is important to take probiotics to repopulate the beneficial bacteria in your gut that are killed by the antibiotic along with the pathogenic bacteria. And you certainly don’t need a doctor’s prescription or permission for this.

If you’re in a hospital setting, you’re not likely to be served fermented foods, but you could have a family member or friend bring some in, or ask your doctor to sign off on a probiotics supplement. Outside a hospital setting, your best bet is to incorporate traditionally fermented foods in your diet, so you’re constantly maintaining a healthy bacterial balance.

Other Infections that Can Be Treated with Probiotics

Clostridium difficile infections are very serious, and since the cure rate with beneficial bacteria is so high for this type of infection, it can give you an idea of the power of probiotics for other, far less lethal ailments. For example, another type of infection that is far more common than C. diff. is Candida albicans.

An overgrowth of Candida, a type of yeast, can cause a variety of chronic health problems in both men and women. Under normal circumstances Candida albicans is a harmless part of your skin, intestines, and for women, your vagina. But Candida cells develop rapidly, and if your system is out of balance from eating unhealthy foods, taking certain prescription drugs, or fighting an illness for example, Candida can quickly grow out of control.

Vaginal yeast infections tend to occur when the normal acidity of a woman’s vagina changes, allowing the yeast to multiply. It’s estimated that up to 75 percent of women have had at least one vaginal yeast infection in their lifetime, which typically is accompanied by intense itching, burning with urination and sometimes a thick, white discharge. Up to 80 million Americans – 70 percent of them women – suffer from yeast-related problems, and if you suffer from yeast infections (especially if they’re recurrent) you should also be on the watch for other symptoms of Candida overgrowth, such as:

Chronic fatigue Weight gain
Food allergies Irritable bowel syndrome
Migraines PMS

 

As with all yeast-related problems, the infection occurs because your system has become run down or out of balance, allowing the Candida that already exists in your body to multiply out of control, causing illness. You may also fall into the trap of treating the infection with an over-the-counter anti-fungal cream, and then assuming that when the symptoms disappear the problem is cured. However, these creams only treat the symptoms and do nothing about the underlying yeast overgrowth that caused the problem to begin with.

How to Harness Your Gut Bacteria for Better Health

Do you suffer from gas and bloating? Constipation or diarrhea? Fatigue? Headaches? Sugar cravings? All of these are signs that unhealthy bacteria of one type or another have taken over too much real estate in your gut, which is actually quite common considering how vulnerable your gut bacteria are to environmental insults. It’s important to realize that your lifestyle can and does influence your gut flora on a daily basis. Therefore, to protect your microflora, you’ll want to avoid:

Poor diet is another enemy to healthy gut bacteria. Sugar is enemy number one, as it actually nourishes the bad or pathogenic bacteria, yeast, and fungi in your gut. Hence, dramatically limiting or eliminating sugar and fructose is an essential step to optimize your gut health. Processed foods also promote bad bacteria – partly due to the high fructose content in most processed foods, but also because of the processing, which essentially “kills” the food.

One of the major side benefits of eating a healthy diet like the one described in my nutrition plan is that it helps your beneficial gut bacteria to flourish. A critical part of a healthful diet is fermented foods, as they will actively “reseed” your body with good bacteria, and can do so far more effectively and inexpensively than a probiotic supplement. It’s unusual to find a probiotic supplement containing more than 10 billion colony-forming units.

But when my team tested fermented vegetables produced by probiotic starter cultures, they had 10 trillion colony-forming units of bacteria. Literally, one serving of vegetables was equal to an entire bottle of a high potency probiotic! So clearly, you’re far better off using fermented foods. Again, when choosing fermented foods, steer clear of pasteurized versions, as pasteurization will destroy many of the naturally-occurring probiotics. Examples of traditionally fermented foods include:

  • Fermented vegetables
  • Lassi (an Indian yoghurt drink, traditionally enjoyed before dinner)
  • Fermented milk, such as kefir (like fermented vegetables, a quart of unpasteurized kefir also has far more active bacteria than you can get from a probiotic supplement)
  • Natto (fermented soy)

Learn to Make Your Own Fermented Vegetables

Fermented vegetables are my favorite as they’re both easy to make, and one of the tastiest types of fermented food. To learn how to inexpensively make your own, review the following interview with Caroline Barringer, a Nutritional Therapy Practitioner (NTP) and an expert in the preparation of the foods prescribed in Dr. Natasha Campbell-McBride’s Gut and Psychology Syndrome (GAPS) Nutritional Program. In addition to the wealth of information shared in this interview, I highly recommend getting the book Gut and Psychology Syndrome, which provides all the necessary details for Dr. McBride’s GAPS protocol.

Although you can use the native bacteria on cabbage and other vegetables, it is typically easier to get consistent results by using a starter culture. Caroline prepares hundreds of quarts of fermented vegetables a week and has found that she gets great results by using three to four high quality probiotic capsules to jump start the fermentation process. If you’re not quite ready to make your own, Caroline also prepares the vegetables commercially. I used hers for a month before I started making my own batches. You can find her products on www.CulturedVegetables.net or www.CulturedNutrition.com.

How to Reduce Chances of “Healing Crisis”

There is one precaution that needs to be discussed here, and that is the potential for a so-called “healing crisis,” provoked by the massive die-off of pathogenic bacteria, viruses, fungi, and other harmful pathogens by the reintroduction of massive quantities of probiotics. It can significantly worsen whatever health problem you’re experiencing, before you get better.

The reason for this is because when the probiotics kill off the pathogens, those pathogenic microbes release toxins. These toxins are what’s causing your problem to begin with; be it depression, panic attacks, rheumatoid arthritis, multiple sclerosis, or any other symptom. When a large amount of toxin is suddenly released, your symptoms will also suddenly increase. So, if you’ve never had fermented foods before, you need to introduce them very gradually.

Dr. Campbell-McBride recommends starting off with just ONE TEASPOON of fermented vegetable, such as sauerkraut, with ONE of your meals, and then wait for a couple of days to see how you react. If it’s manageable, you can have another helping, and gradually increase your portion. If you feel worse, stop. Let the side effects subside, and then have just a tiny amount again. Some may even need to start with just a teaspoon of the juice ferment to start. Then move on to two teaspoons per day, and so on.

It’s important to realize that besides containing massive amounts of beneficial bacteria, fermented foods also contain many active enzymes, which act as extremely potent detoxifiers. As Dr. Cambell-McBride explains:

“Healing goes through two steps forward, one step back, two steps forward, and one step back. But you will find that the next layer is smaller. The die off and the detox will not last as long as the previous one… We live in a toxic world, and many of us have accumulated layers and layers of toxicity in our bodies. The body will clean them out, but you will find that each layer will last shorter and not be as severe… Eventually, you will come to complete, radiant health. You will feel 100 percent healthy, no matter how ill you were before.”

Source: Dr. Mercola