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European agencies warn that non-medical fungicide use may be fueling resistance in A fumigatus, a mold responsible for severe human infections.

Azole Fungicides in Agriculture Linked to Rising Resistance in Aspergillus fumigatus

Children with invasive candidiasis had successful outcome  whether IV antifungal treatment was completed or converted to enteral to reduce risk of infusion site infections and costs.

Children with Invasive Candidiasis Do Well After Switching IV Antifungal to Enteral

Kansas is experiencing the largest tuberculosis outbreak in decades, a preview into vaccines and treatments up for FDA approval this winter/spring, and more.

Advancing STOP2030 Treatment in Global Health

Investigators developed a novel prognostic model around this subset of patients treated for this fungal infection. 

Identifying Clinical Characteristics, Mortality in Nonimmunodeficiency Individuals With Aspergillosis 

GAFFI is working to address fungal diagnostic gaps in Africa by raising awareness, implementing successful models, and advocating for shifts in resources and collaboration, while facing challenges in funding, infrastructure, and political commitment.

GAFFI Continues Efforts to Raise Awareness and Improve Fungal Diagnostic Capabilities

Fungal infections affect over 1 billion people globally, causing an estimated 11.5 million life-threatening infections and more than 1.5 million deaths annually. Despite their impact, fungal diseases remain under-recognized and underfunded in global health. In response, the Global Action Fund for Fungal Infections (GAFFI) launched the "95-95 by 2025" initiative, aiming to diagnose and treat 95% of serious fungal infections by the end of 2025.

David W Denning, FRCP, FRCPath, FMedSci, professor of infectious diseases and global health at the University of Manchester, and a key figure in GAFFI, discussed the organization's ongoing efforts to address gaps in fungal diagnostics, particularly in Africa, where many countries lack adequate testing infrastructure.

"As of 2025, GAFFI is continuing its journey in addressing global fungal diagnostic gaps," Denning said. "Surveys have documented the availability of fungal tests in different regions. For example, there was a good survey in South America, two surveys conducted in multiple centers across Asia, and a large survey in Africa in 2002. This survey looked at lab tests and sample collection procedures across all of Africa, including North Africa."

Denning explained that many countries, especially in Africa, face barriers to diagnosing fungal infections. One example he highlighted was testing for fungal eye infections, which can occur in regions with high contact lens use or ocular injuries. "The question is whether the country performs corneal scraping (as required) and whether they consider fungal infection as a potential cause, with the appropriate lab tests available."

GAFFI published the findings of this survey in a report in 2002 and presented it at the African Centers for Disease Control’s public health meeting in Kigali that December. The results showed significant diagnostic gaps across Africa. “Morocco and Tunisia are doing well with testing, and South Africa has a good setup except for Aspergillus disease, which isn’t well recognized there,” Denning explained. “Some countries have patchwork testing, and places like South Sudan and Equatorial Guinea have virtually no testing available at all—no pathology for cancer diagnosis, let alone fungal testing.”

To raise awareness of these gaps, GAFFI sent the report to every medical school in Africa, addressing the deans, in the hopes of improving education and training in this area. "I don’t know whether they’ve done anything with it, but we hope that they at least could see that their country had a problem," Denning said. "We’ve worked with Africa CDC to raise awareness and also with the industry to help them understand where the gaps are and provide links to these countries. We’ve conducted numerous webinars and educational sessions as well."

Looking ahead, Denning shared GAFFI’s goal of replicating its model from Guatemala in an African setting. "One of our future goals is to replicate the successful model we implemented in Guatemala in an African setting," Denning noted. "While we may not focus solely on HIV, a possible area of focus could be HIV and lung disease. However, implementing this in larger, less organized countries like Kenya, Tanzania, and Mozambique presents challenges."

He stressed that this initiative will take time and resources. "This initiative will take two to three years and is not a trivial task. It's not just about diagnostics; we need to provide education, monitor the progress, and collect data as well."

A key factor in improving fungal diagnostic capabilities, according to Denning, is shifting how resources are allocated. "Currently, in Africa, most diagnostics are paid for by the patients or their families, except for HIV or TB testing. But fungal tests are not covered, which poses a problem," Denning explained.

Denning concluded by noting that GAFFI cannot tackle this issue alone. "GAFFI alone can’t tackle these issues. Collaboration with other stakeholders is essential to drive these changes forward."

Listen to the first part of our conversation with Denning about the "95-95 by 2025" initiative, which aims to diagnose and treat 95% of serious fungal infections globally by 2025. The discussion highlights efforts to improve access in underserved regions and the impact of the campaign, with successes in countries like Uzbekistan and Guatemala, where improvements in diagnostic tools have helped address fungal infection challenges.

https://www.contagionlive.com/view/fungal-infections-invisible-until-it-s-too-late

https://www.contagionlive.com/view/fungal-infection-diagnosis-misdiagnoses-and-global-health-initiatives

1. Denning DW. The ambitious '95-95 by 2025' roadmap for the diagnosis and management of fungal diseases. Thorax. 2015;70(7):613-614. doi:10.1136/thoraxjnl-2015-207305

2. Gaffi. IMPROVING OUTCOMES FOR PATIENTS WITH FUNGAL INFECTIONS ACROSS THE WORLD A ROAD MAP FOR THE NEXT DECADE. February 2025. Accessed January 20, 2025. chrome-extension://efaidnbmnnnibpcajpcglclefindmkaj/https://gaffi.org/wp-content/uploads/GAFFI_Road_Map_interactive-final0415.pdf

GAFFI is addressing fungal diagnostic gaps by raising awareness, implementing models, and advocating for resource shifts, despite challenges in funding, infrastructure, and political support.

Research into new antifungal treatments, including drugs in phase two and three trials, offers hope for patients who do not respond to current therapies.

Immune Deficits in Some Valley Fever Patients Hinder Response to Antifungal Treatment

 fungi, remains a serious concern, particularly in regions like California and Arizona. Antifungal treatments are effective for many patients, but for others, they’re not enough. George Thompson, MD, professor of infectious disease at UC Davis Medical Center, sheds light on this issue and the ongoing research efforts to better understand and treat valley fever.

Thompson explains that despite the availability of antifungal drugs, some patients, even when treated with the correct medication, simply do not respond. “We know what the susceptibility is in the lab, but for whatever reason, it just doesn’t work. The patient doesn’t respond and clear the infection,” Thompson says.

This challenge is particularly pronounced in patients with severe disease manifestations, such as bone, brain, or skin infections, where the body’s immune system has failed to effectively control the infection. “There’s a key defect somewhere,” Thompson said. “They don’t all have HIV or AIDS or are on immunosuppressive medications. It’s a very small innate immune deficit that is probably only significant for valley fever. Most commonly, it’s just valley fever that they suffer with.”

In response to these treatment challenges, Thompson and a group of researchers from UC San Diego, UCLA, Texas, and Northern Arizona University (NAU) have spent the past years focusing on the host response to valley fever. By better understanding why certain patients fail to clear the infection, the team aims to improve treatment strategies and explore preventative measures. “If we really understand how we control the infection, perhaps we can create a vaccine that will prevent it completely. That would be just fantastic,” Thompson said. He emphasizes that understanding the nuances of the immune system’s response to valley fever is a key step in making significant progress for treatment and future vaccine development.

Thompson notes that patients diagnosed early in the course of their illness tend to have better outcomes, “The infection really hasn’t fully established itself, so to speak, and they generally do better the earlier they’re diagnosed,” he said. Educational initiatives and heightened awareness have been key to improving early diagnosis. Efforts led by the state and the CDC have significantly contributed to raising awareness about valley fever, prompting more patients to seek testing sooner. In Arizona, patients can even order their own valley fever tests without needing a doctor’s referral, which Thompson believes is a major step forward in facilitating earlier diagnosis, “The goal is to move up the diagnosis date and not allow the disease to establish itself for weeks or even months before it comes to clinical attention,” he said.

While much of the focus has been on diagnosis and immune response, there is also news in the development of new antifungal treatments. Thompson highlights two promising drugs currently in phase two and three clinical trials, 

 While these drugs are not yet available on the market, early results have been promising, and they are already being used in compassionate use programs for patients who have failed standard therapies. “These drugs are really needed, and we’re hopeful they’ll be available soon,” said Thompson. Until then, the medical community continues to rely on existing therapies, though these new options could offer hope for patients whose infections do not respond to current treatments.

Thompson also emphasizes the importance of a comprehensive patient history, especially when dealing with respiratory illnesses. Valley fever is often diagnosed outside its traditional regions of California and Arizona. He advises healthcare providers to take a thorough travel history when patients present with pneumonia or other respiratory symptoms that don’t respond to initial antibiotic treatments. “Think about not only valley fever but also other fungal infections like 

, as well as atypical bacteria,” he advises. By considering these factors, doctors can improve diagnosis and treatment outcomes for patients who might otherwise be misdiagnosed.

The impact of the "95-95 by 2025" campaign and successes in countries like Uzbekistan and Guatemala, where action to improve diagnostic tools has addressed fungal infection challenges.

Fungal Infection Diagnosis, Misdiagnoses, and Global Health Initiatives 

David W Denning, FRCP FRCPath FMedSci, professor of infectious diseases and global health at the University of Manchester, and a key figure in GAFFI, discussed the ongoing challenges in diagnosing and treating fungal infections. He also highlighted the goals and successes of the "95-95 by 2025" campaign, which seeks to address global care gaps for fungal infections.

“When we started asking our colleagues, the GAFFI ambassadors, and others about which drugs they had available, we found that many countries didn’t have them (testing),” Denning explained. “One of the things GAFFI did was to register a number of diagnostics and antifungal drugs as essential for the WHO. Once these drugs are listed, it becomes incumbent on the governments to make them available to their populations. Uzbekistan took immediate action, applied, and within six months, they had all the generic antifungal drugs approved, something that hadn’t happened before.”

Denning gave another example, “In Nigeria we’ve been working with late-stage HIV patients. Our ambassador there has trained hundreds of clinicians across the country on how to diagnose cryptococcal meningitis and histoplasmosis. These tests have now been rolled out, and as a result, more diagnoses are being made, allowing doctors to give the correct treatment earlier,” Denning explained. “Although the survival benefit isn’t yet formally demonstrated, these diagnostic efforts have been integrated into national AIDS treatment guidelines, ensuring broader access to life-saving treatments.”

Indonesia and India are also witnessing shifts in how fungal infections are diagnosed. In both countries, where tuberculosis (TB) is highly prevalent, many patients with chronic chest diseases are being misdiagnosed with TB when, in fact, they are suffering from fungal infections. Denning noted that this misdiagnosis is common in areas where fungal diseases are not part of the standard diagnostic thinking. “We are starting to see more fungal infections being diagnosed instead of TB, especially in patients with chronic chest disease. The key here is awareness—awareness from both lab professionals and clinicians,” he said.

The project’s success in Guatemala, with the country now seeing an increase in correct fungal diagnoses and a reduction in mortality rates for late-stage HIV patients. Denning emphasized that the results are clear: “The number of fungal diagnoses has increased, and this is leading to better treatment and survival outcomes for patients.”

Denning noted that there are various clinical scenarios where fungal infections are still overlooked, resulting in poor patient outcomes. “A common scenario is a patient who presents with symptoms that could be TB, such as a cough or chest pain,” Denning explained. “They’re often sent to a TB clinic, where they undergo TB tests, and even if those tests are negative, they are still treated for TB. This is because the clinicians aren’t considering fungal infections, which leads to unnecessary treatments and contributes to AMR.”

Denning emphasized “To really make a difference, clinicians need to be aware of the differential diagnosis for infections. Is it a fungus? Is it bacteria? Is it a virus? Is it cancer? Accurate diagnostics and timely treatments are critical,” Denning said.

Fungal Infections: Invisible Until It’s Too Late

Stay tuned for more updates on GAFFI’s progress and other initiatives focused on improving global health in the next part of our conversation.

George Thompson of UC Davis explains a sharp rise in valley fever cases in the Central Valley, with concerns about increased virulence, ICU admissions, and the impact of droughts and wildfires on fungal spread.

Dusty Fungal Threat: Valley Fever Spreads as Conditions Change

George Thompson, MD, professor of infectious disease at UC Davis Medical Center, has been tracking the increase in coccidioidomycosis (Valley fever) and discussing the current trends and contributing factors. "We've seen a big increase in the number of cocci cases over the last two to three years. The central valley looks like there may even be a 200% increase in cases over the last year in some areas," he said. "And then we're really concerned that it's become more virulent. And what I mean by that is some of the patients really appear to have more aggressive disease."

Thompson noted that not only are there more cases, but there is also a higher incidence of severe cases. “We haven't typically had this many patients with valley fever in the ICU at one time. And we've talked with other sites in Northern California, and they're seeing the same thing. So we're concerned that not only are there more cases, but there's more severe cases,” he said.

Valley fever primarily affects the respiratory system, but in some cases, it can cause meningitis or spread to other organs. "The majority of people with valley fever have some type of respiratory illness. So some of those most severe manifestations are really bad pneumonia,” Thompson explained.

“Those are even people on the ventilator or that need assistance to oxygenate their blood. And so that's sort of the most severe pulmonary manifestation. In about 1% of people, valley fever will leave the lungs and go to some other site, skin, bone or brain and cause meningitis. And we've, we've seen more meningitis cases over the last few years as well," Thompson said.

For some patients, antifungal treatments are not effective, making treatment more difficult. "Some of those patients don't respond to any agent, and that's really a challenge for” how are we going to improve these patients?" Thompson said. In such cases, immunotherapy may be used to try to enhance the immune response.

Thompson also discussed the role of weather conditions in the spread of Valley fever, “In the soil, 

 exists as sort of a mold form. And during periods of heavy precipitation, when we get a good amount of rainfall, we think it grows into a higher quantity within the soil,” Thompson said. “And then during drought conditions, every other cell dies and spores are formed. And those spores are what we breathe in for the infectious form of coccidioidomycosis.”

The increasing number of wildfires in California is another factor that may contribute to the spread of Valley fever. "Long droughts are associated with fires, of course, too. So we’re still sort of working on, are those fires related to valley fever or just coincident?” Thompson said. “But fire can create its own weather. It kind of updrafts air, and we’re concerned that those that large updraft might throw valley fever into the air and really facilitate spread into the surrounding region."

George Thompson, MD, explains a rise in Valley fever cases in CA, with concerns about increased virulence, ICU admissions, and the impact of droughts and wildfires on fungal spread.

David W. Denning outlines the "95-95 by 2025" initiative, aiming to diagnose and treat 95% of serious fungal infections globally by 2025, with a focus on improving access in underserved regions.

In 2015, fungal infections affected over 1 billion people globally each year, leading to an estimated 11.5 million life-threatening infections and more than 1.5 million deaths annually. Despite their significant impact, fungal diseases have historically been under-recognized and underfunded in global health efforts. In response, the Global Action Fund for Fungal Infections (GAFFI) launched a global initiative called "95-95 by 2025," which aims to diagnose and treat 95% of individuals with serious fungal infections by the end of 2025.

David W Denning, FRCP, FRCPath, FMedSci, professor of infectious diseases and global health at the University of Manchester, played a key role in developing GAFFI’s initiatives. Denning, also former chief executive of GAFFI, discussed the challenges of diagnosing and treating fungal infections and the goals of the 95-95 by 2025 initiative.

“We convened a meeting alongside one of the International AIDS meetings in Seattle in 2015 with about 60-70 people, including people from all over the world,” Denning said. “Some from Africa, South America, Asia, as well as people from the WHO and other major funding agencies to address the problem of how we're going to stop people dying of fungal disease. One of the problems with fungal disease is that it’s fairly invisible until it’s too late. You have to start looking for it in at-risk patients. So, examples of patients with AIDS, patients who have a transplant, patients with really complicated lung disease, patients with leukemia, lymphoma, that sort of group of patients."

Denning highlighted the lack of diagnostic infrastructure in many regions, particularly in Sub-Saharan Africa and Asia. He noted, “We learned that many countries, particularly in Sub-Saharan Africa, but also in many parts of Asia, don’t have a diagnostic service for fungal disease, and many of them don’t have any of the modern treatments for fungal disease. So, we ended up writing a roadmap that included a very basic summary of how many infections there might be in the world with these problems, and also the approaches, the diagnostics, and the treatments that are relevant to that."

Denning explained their goal, “Our aspiration 10 years ago now was that 95% of the world's population would have access to these diagnostics, and 95% would have access to the relevant anti-fungal therapies, particularly the generic anti-fungal therapies that are less expensive than the more recently issued ones."

Denning discussed the barriers to achieving this goal, including drug approval delays and the lack of resources in many countries. Denning explained, “For example, in South Africa, 

 was on the roster for approval for five years before they finally approved it, and yet it’s a core drug for fungal meningitis in AIDS. As you know, South Africa has the largest population of HIV patients per capita in the world.”

Denning noted that these delays are just one example of the challenges in ensuring access to affordable treatments. He said, “There are lots of different tests. There's lots of different lab approaches to handling those tests, and the registration processes for drugs are complicated in many countries.”

Denning discussed the progress made in countries like Guatemala, where GAFFI helped fund a project in 13 centers across the country. Denning described the process, “In Guatemala, we funded a small demonstration project and helped run it with about 13 centers across the country looking after patients with HIV and AIDS. We provided the wherewithal for them to run a rapid diagnostic service for two important fungal infections which are common: histoplasmosis and cryptococcal meningitis, in tandem with diagnostics for TB, which is also common there.”

The program successfully improved diagnostic accuracy, reduced misdiagnosis of tuberculosis as fungal infections, and ultimately led to a decrease in mortality. Denning shared, “We diagnosed many fungal infections, we diagnosed fewer TB infections, and that was because they were misdiagnosed as TB when actually they were a fungus. The overall mortality from these late-stage patients went down by 8% in basically two and a half years. And that’s a really big change.”

Denning expressed hope that similar programs could be replicated in other regions facing similar challenges, “We’d like to reproduce that other places. The idea here was to show that if you applied these diagnostics, and you provided the results quickly, and you trained the clinicians in parallel, you could really make a difference.”

Stay tuned for the next part of our conversation where we dive deeper into the initiative.

David W Denning, FRCP, FRCPath, FMedSci, outlines the "95-95 by 2025" initiative to diagnose and treat 95% of serious fungal infections globally by 2025, focused on improving access in underserved regions.





In the second interview segment with George Thompson, MD, he provides feedback on patient profiles and prescribing practices for the antifungals.  

Considering Rezafungin For Candidemia and Invasive Candidiasis

The antifungal market is limited in terms of development, and when rezafungin (Rezzayo) was 

 back in 2023, it became the first new therapy approved to treat candidemia and invasive candidiasis in more than 10 years.

Since its approval, additional studies have been done, and in one pooled analysis study, rezafungin was shown to be 

 for candidemia and invasive candidiasis for 30 day mortality.

George Thompson, MD, professor of Medicine at the University of California, Davis, School of Medicine, was an investigator during the clinical trials and describes some of the benefits in specific patients.

“I think where we've seen the most rapid adoption is people with high grade candidemia. Our ICU patients are neutropenic patients, and those are the groups that have really gotten the most advocates for this very high front-loaded exposure with rezafungin,” said Thompson. "So I think that's where we've seen most of our use thus far. It also certainly can help if someone has 

and needs to go home, but still needs to stay on a echinocandin so that once a week infusion is certainly more convenient than a daily option.”

And in terms of safety, rezafungin is in a class of therapies that has shown to be have a favorable profile.

“That class as a whole, the majority of the side effects we see are with too rapid of an infusion. So if it's given as a push, instead of infused over an hour, patients get a kind of a histamine-like response,” Thompson said. “We think it's very safe. we have a lot of experience with it from the phase 2 and 3 trials. And with the availability on the market now, we're not seeing toxicity with rezafungin.”

In the second interview segment with George Thompson, MD, he provides feedback on patient profiles and prescribing practices for the antifungal.  

George Thompson, MD, offers some insights on 2 studies looking at these antifungals in patients with Candidemia and invasive candidiasis

Rezafungin is Noninferior to Caspofungin For All-Cause Mortality For Candida Infections

deeply into the body and develop into fungal infections, including candidemia and invasive candidiasis. These fungal infections can affect the bloodstream and internal organs. Candidemia, in particular, is a common infection found in hospitalized patients. In addition, there are some specific clinical challenges associated with them.

“There's really 2 major problems with candidemia and invasive candidiasis right now. One of them relies on diagnostics. We often don't make the diagnosis of 

 until several days after the infection has manifested. Blood cultures take a little bit to grow; at a minimum, probably 2 days—and that's improved by PCR availability. So, we do get the diagnosis earlier now, but we have to order the correct test, and that's not always done in clinical care,” said George Thompson, MD, professor of Medicine at the University of California, Davis, School of Medicine. “And the other aspect is, even when we do know the diagnosis, the associated mortality rate of candidemia is still high.”

One antifungal looking to address these infections is rezafungin (Rezzayo), which was 

 in 2023. It is a long-acting, next-generation echinocandin indicated for the treatment of candidemia and invasive candidiasis. Rezafungin was developed by Cidara Therapeutics, and it’s marketed by Melinta Therapeutics and Mundipharma. Melinta acquired the exclusive rights to commercialize the antifungal in the US. Cidara retains the rights to rezafungin in Japan and has licensed the commercial rights to Melinta Therapeutics in the US and Mundipharma in all other geographies.

The FDA’s approval was largely based on positive data from phase 3 clinical trials. Dosed once a week, rezafungin was determined to be statistically noninferior compared to once-daily caspofungin, the current standard of care.

A Long-Acting Injectable for the Treatment of 



Thompson was part of a team of investigators who conducted a pooled analysis of 2 trials—the phase 2 STRIVE and phase 3 ReSTORE studies— and they examined the all-cause mortality at day 30 of patients with these infections.

“In STRIVE, rezafungin was found to be efficacious with a similar safety and tolerability profile to that of caspofungin. In ReSTORE, once-weekly rezafungin (using a dosing regimen of 400 mg and 200 mg) was non-inferior for 30-day all-cause mortality to once-daily caspofungin (70 mg and 50 mg), with a similar safety profile,” the investigators wrote.

One of the important findings that was realized related to the rezafungin dosing regimen as patients treated with this antifungal saw an early benefit.

“It's once a week, so it gets this very high front-loaded exposure more rapidly, clears blood cultures, and probably tissue sites as well,” said Thompson. “In the analysis we saw, the ICU patients actually improved faster in the rezafungin group compared to caspofungin. So all of that makes some sense, I think, just from the PK/PD standpoint, from what we've seen on animal models. And so that was really pretty neat to see it carried forward into the clinical trials and the pooled analysis as well. I think it represents an incremental advance to have rezafungin available for the treatment of those patients.”

Stay tuned for the second installment of the interview this week, as Thompson will discuss patient profiles for rezafungin and prescribing considerations.



References
1. Cidara Therapeutics and Melinta Therapeutics Announce FDA Approval of REZZAYO™ (rezafungin for injection) for the Treatment of Candidemia and Invasive Candidiasis. Cidara Therapeutics press release. March 22, 2023. Accessed January 21, 2025.
https://www.cidara.com/news/cidara-therapeutics-and-melinta-therapeutics-announce-fda-approval-of-rezzayo-rezafungin-for-injection-for-the-treatment-of-candidemia-and-invasive-candidiasis/
2.Thompson GR 3rd, Soriano A, Honore PM, et al. Efficacy and safety of rezafungin and caspofungin in candidaemia and invasive candidiasis: pooled data from two prospective randomised controlled trials. 

. 2024;24(3):319-328. doi:10.1016/S1473-3099(23)00551-0
 

George Thompson, MD, offers some insights on 2 studies looking at these antifungals in patients with candidemia and invasive candidiasis.

Fungal Infections

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