Recently, the UN General Assembly held a High-Level Meeting to discuss an urgent, global public health problem: Antimicrobial resistance (AMR), which occurs when bacteria, viruses, fungi and parasites evolve to evade antibiotics and other medicines that are meant to kill them. Currently, antimicrobial resistance results in approximately 1.3 million deaths worldwide, including 35,000 in the United States each year, according to the Centers for Disease Control and Prevention. Antibiotic resistance can make infections more difficult to treat—and, unfortunately, due in part to overuse and misuse of antibiotics, antimicrobial-resistant infections are becoming more common.

The National Institute of Allergy and Infectious Diseases (NIAID), part of the National Institutes of Health, has prioritized AMR research for many years. For instance, through the Antibacterial Resistance Leadership Group (ARLG), the Institute has supported more than 60 AMR clinical research projects, involving more than 20,000 participants at sites around the world. The results of this work, combined with 10 years of coordinated efforts from across the U.S. government, have led to significant improvements in how public health officials consider antibiotics and how physicians can tackle difficult infections. As a global, evolving problem, AMR continues to demand new research and innovations from the public health sector.

One ongoing clinical trial is examining a particularly thorny facet of treating antimicrobial resistant (AMR) infections: when dealing with antibiotic-resistant infections, healthcare providers may need to try several different treatments before they identify an effective one, and tests to verify whether treatments will work can take days to complete. This delay can slow the patient’s recovery or lead to death. For example, ineffective therapy due to treatment delay is associated with high mortality among patients with bloodstream infections caused by Gram-negative bacteria. 

A new clinical trial sponsored by NIAID is currently evaluating whether the use of a rapid test of antibiotic susceptibility for bacteria growing in blood cultures improves clinical outcomes for patients with sepsis in settings that have high rates of antibiotic-resistant bacterial infections. The trial is being conducted by ARLG and will ultimately enroll roughly 900 hospitalized participants at seven locations around the world. 

The Fast Antibiotic Susceptibility Testing for Gram-Negative Bacteremia Trial (FAST) will test whether use of the VITEK^® REVEAL™ AST System, a direct-from-positive-blood-culture fast phenotypic susceptibility test (manufactured by Specific Diagnostics, San Jose, CA, a wholly owned subsidiary of bioMérieux, Inc., Salt Lake City, UT), can speed up the identification of effective antibiotics to treat bloodstream infections and lead to better patient outcomes. The VITEK^® REVEAL™ system is already available for clinical use in the European Union (and recently received FDA 510(k) Clearance (K230675) on June 20, 2024, and can identify phenotypic susceptibility of 10 different bacteria to 23 different antibiotics. Unlike standard of care susceptibility testing, which typically takes several days to provide results, the VITEK^® REVEAL™ test results are available in an average of 5.5 hours.

A recent clinical trial supported by NIAID through the ARLG showed that using a similar rapid test for antimicrobial susceptibility helped healthcare providers identify and use effective antibiotics faster than standard-of-care testing. However, that trial was unable to show whether using a rapid test led to better patient outcomes—possibly because the trial was carried out in areas with relatively low rates of antimicrobial-resistant infections. The researchers hope that data from the FAST trial will show whether the test improves outcomes in regions where many patients have antimicrobial-resistant infections.

The FAST trial has enrolled hospitalized participants with Gram-negative bacteria identified in their blood. Such bacteria include Klebsiella species and Escherichia coli. They have been randomized to one of two groups: half the participants are having their blood cultures tested with VITEK^® REVEAL™ as well as standard bacterial culture and antibiotic susceptibility testing. The other participants are serving as a control group and their blood cultures will undergo standard bacterial culture and susceptibility testing. The participants’ progress is being monitored for 30 days, as clinical staff record how quickly participants recover and whether they experience any negative effects, such as worsening or relapsing while still in the hospital, requiring readmission to the hospital later for the same problem, acquiring a new infection while in the hospital, or death.

Improved testing alone will not eliminate the threat of AMR infections. For that, healthcare providers will need better therapeutics, better means of keeping the infections from spreading, and other tools. However, when patients present to the hospital with severe infections, the initial hours of waiting for test results can make all the difference. Confirming that rapid tests actually improve patient outcomes is an important step on the road to fighting back against ever-changing pathogens.

To read more about this trial, search ClinicalTrials.gov using the identifier NCT06174649.

The world of fungi includes a wide range of organisms, such as mushrooms, molds, and yeast, that are common outdoors in water, soil, and air; indoors on surfaces; and on our skin and inside our bodies. Although many fungi are helpful—or even delicious, like some mushrooms—there are many others which can cause disease. Some fungal infections are more common in people with weakened immune systems or hospitalized individuals, while other fungal infections can infect anyone, including otherwise healthy people. According to the Centers for Disease Control and Prevention (CDC), more than one billion people worldwide get a fungal infection each year. There are four main classes of antifungal drugs, and the rising rate of antimicrobial resistance is limiting and complicating existing treatment options. Currently, there are no approved vaccines to prevent fungal infections.

NIAID conducts and supports basic, translational, and clinical research to understand how fungal pathogens cause disease and how the immune system responds to infection. NIAID researchers are exploring how fungal susceptibility and infection impact the function of immune cells. The following are examples of ongoing clinical trials supported by NIAID through the investigator-initiated clinical trial funding mechanism investigating various aspects of fungal disease. 

Stewardship in AMR – Examining a shorter treatment course for children

Immunocompromised patients are at risk for the development of fungal infections. Hospitalized patients can get severe, often deadly, fungal diseases like candidemia, a bloodstream infection caused by the Candida fungus. According to the CDC, candidemia is one of the most common bloodstream infections in the U.S. with an estimated 25,000 cases each year. The current treatment guidelines for invasive candidemia recommend 14 days of antifungal therapy.  This guideline is based on expert opinion rather than comparative data and the optimal treatment duration remains unknown. NIAID-funded researchers Drs. William J. Steinbach and Brian T. Fisher are conducting a clinical trial (NCT05763251) to examine whether a shorter 7-day treatment strategy is just as safe and effective as current practice. This trial is only enrolling pediatric patients at the study-site hospitals with uncomplicated cases of candidemia. A shorter treatment would significantly reduce the burden of care on sick and recovering pediatric patients, allowing families to come home earlier from the hospital, and could help combat the rising rates of antimicrobial resistance. This is the first randomized control trial to explore the efficacy of a shorter course treatment for any invasive fungal disease. The trial is supported through NIAID grant funding R01 AI 170385. 

Cryptococcus neoformans contributing to HIV/AIDS-related mortality 

Cryptococcus neoformans is a fungal pathogen that can cause cryptococcal meningitis. Those most at risk are immunocompromised, such as people/persons living with HIV/AIDS. Although Antiretroviral therapy (ART) has significantly reduced the incidence of HIV/AIDS in the United States, regions of the world with limited access to ART are still seeing tens of thousands of cases. According to the CDC, each year an estimated 152,000 people living with HIV experience cases of cryptococcal meningitis, of which an estimated 112,000 deaths occur, most in sub-Saharan Africa. In the weeks prior to the onset of meningitis, the cryptococcal antigen (CrAg) is detectable in the blood and is a good predictor of meningitis and death. NIAID-funded researcher Dr. Radha Rajasingham is leading a clinical trial (NCT03002012) to examine whether the treatment combination of liposomal amphotericin (AmBisome) and fluconazole for those who receive a positive CrAg antigen test effectively prevents cryptococcal meningitis and death. Dr. Rajasingham’s lab at the University of Minnesota is dedicated to improving cryptococcal meningitis treatment strategies and outcomes for people/persons living with HIV/AIDS and is supported through NIAID grant funding U01 AI 174978 and R01 AI162181. 

Though these conditions can be severe, they are not the only fungal diseases of concern for NIAID. From aspergillosis to Valley Fever, NIAID is committed to researching new treatments, diagnostics, and preventative measures for a wide array of fungal diseases, especially in the face of rising antifungal resistance.