Although several pathogenic fungi can be found in the surrounding environment, Candida, which is a natural human commensal, is found in our own gastrointestinal tract. However, these organisms can become sources of deadly infection in immune-compromised patients, especially patients who undergo organ or stem cell transplantation or cancer chemotherapy. Candida is a primary cause of fungus-related morbidity of these patients. For this reason, patients at risk of invasive fungal infection are given anti-fungal prophylaxis with echinocandins or triazoles.
Although C. albicans is the most common species of Candida, C. glabrata has emerged as a principle cause of invasive infections in hematopoietic stem cell transplant recipients who are normally put under prophylactic antifungal regimens. Additionally, reports in recent years have described multidrug-resistant C. glabrata isolates in the United States. The multidrug-resistant isolates have demonstrated resistance to two or more classes of antifungal drugs, i.e. echinocandins, polyenes and triazoles.
The gastrointestinal (GI) tract is a principle site of Candida colonization, which upon host immunosuppression can become a source for systemic infection. The GI tract has also been proposed as the principle reservoir of antimicrobial resistance and a likely source of drug-resistant mutants. For this reason, resistant isolates obtained from a patient’s internal organs or blood could originate from the GI tract, where inadequate drug exposure could play a role in sub-therapeutic activity.
Researchers at the Public Health Research Institute (New Jersey Medical School, Rutgers Biomedical and Health Sciences) in the United States led by Professor David S. Perlin have investigated the importance of the GI tract as a source of drug resistance. They developed a new mouse model of C. glabrata GI colonization and systemic breakthrough with an objective of understanding how antifungal therapy affects the yeast burden colonization and the occurrence of drug resistance within the GI tract, as well as breakthrough causing systemic dissemination upon immunosuppression. Their study demonstrated a clear relationship between drug exposure and development of genetically stable drug resistant mutants in the GI tract and was a proof of principle that the GI tract could harbor resistance among the colonizing organisms. Their research work is published in the peer reviewed journal Antimicrobial Agents and Chemotherapy.
The research team focused on treatment with caspofungin, a first-line agent, which is a member of the echinocandin class of antifungals (other echinocandins include micafungin and anidulafungin). In their studies the researchers found that daily doses of caspofungin at equivalent humanized levels (5 mg per kg of the body weight) led to no reduction in fecal burdens, resistance rates comparable to those found clinically (0 to 10%), and organ breakthrough rates comparable to those of untreated control groups. However, when the authors applied a treatment with higher dose caspofungin (20 mg/kg) initial reduction of fecal burdens was temporarily observed. Unfortunately, a rebound effect ensued following 5 to 9 days of treatment led to high level of resistance. Due to the elevated GI tract burdens prior to immunosuppression, dissemination rates were observed to increase within this phase. Importantly, the authors recovered the same genetically resistant mutants from the organs that were first identified within the gut.
In a move to negate drug tolerance that leads to resistance, the authors co-treated mice daily with caspofungin and the chitin synthase inhibitor nikkomycin Z, which also targets enzymes within the fungal cell wall. They recorded the largest reduction (3 log) in GI burdens within 3 to 5 days of treatment with 20 mg/kg of caspofungin in conjunction with nikkomycin.
Therapeutic levels of caspofungin (5 mg/kg) together with nikkomycin treatment significantly decreased organ breakthrough rates, but GI burdens remained unchanged. As such, the authors observed that single-dose pharmacokinetics demonstrated low levels of drug penetration into the GI lumen post treatment with 5 mg/kg of caspofungin. Generally, this study showed that C. glabrata echinocandin resistance can develop within the GI tract and that resistant mutants can disseminate following immunosuppression.
The new mouse model developed by Kelley Healey and colleagues is expected to be a valuable and powerful tool to better understand factors that promote and prevent anti-fungal drug resistance. It may also rapidly and efficiently accelerate drug discovery and help researchers find new drug targets for Candida treatment or prophylaxis.
Dr. Kelley Healey
She received her PhD degree from Drexel University College of Medicine in 2013. Kelley then joined the Public Health Research Institute (PHRI), which is affiliated with Rutgers New Jersey Medical School. Since joining PHRI, Kelley has studied the molecular mechanisms associated with Candida glabrata pathogenesis and antifungal resistance and is the recipient of an Arnold O. Beckman postdoctoral fellowship from the Arnold and Mabel Beckman Foundation.
Dr. Yanan Zhao
She received her PhD degree in 2005 from Fudan University in China. She joined the Public Health Research Institute (USA) in 2006 and started working on molecular diagnostics on fungal and bacterial infections since then. She was appointed as assistant professor in 2015. Her current research interests include rapid diagnostics of drug resistant fungal infections and efficacy and tissue distribution studies of antifungal and antibacterial compounds.
Professor David S. Perlin
Professor David S. Perlin, PhD is Executive Director of the Rutgers University and New Jersey Medical School’s Public Health Research Institute (PHRI), a 77-year-old specialized center for global infectious diseases. He is also a Professor in the Department of Microbiology, Biochemistry and Molecular Genetics.
Dr. Perlin is a highly-accomplished medical researcher who studies ways to diagnose and overcome drug resistant bacterial and fungal infections in high-risk patients, and he is widely regarded as a global leader in antifungal drug resistance and molecular diagnostics.
Kelley R. Healey, Yoji Nagasaki, Matthew Zimmerman, Milena Kordalewska, Steven Park, Yanan Zhao, and David S. Perlin. The Gastrointestinal Tract Is a Major Source of Echinocandin Drug Resistance in a Murine Model of Candida glabrata Colonization and Systemic Dissemination. Antimicrobial Agents and Chemotherapy, December 2017, Volume 61 Issue 12 e01412-17.