The Gastrointestinal Tract is a Major Source of Antifungal Drug Resistance

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.