Benjamin Park, MD, image credit CDC

At this week’s World AMR Congress, Benjamin Park, MD, senior advisor for Global Programs, Division of Healthcare Quality Promotion, CDC’s National Center for Emerging and Zoonotic Infectious Diseases (NCEZID), participated on a panel, titled, The Role of ID Surveillance to Reduce AMR. During the conference, Park spoke to Contagion and he provided information on the agency’s involvement in AMR, including some of its initiatives and educational resources.

Contagion: In terms of the scope of the problem, can you talk about the importance of AMR as a public health issue?
Park: Antimicrobial resistance is an urgent global public health threat. It has the potential to affect people at any stage of life, regardless of health status, and threatens our progress in health care, food production, and life expectancy. Antimicrobial resistance already affects all regions of the world. It is estimated to kill at least 1.27 million people worldwide each year, more than HIV/AIDS or malaria. Most of these deaths are occurring in low- and middle-income countries, especially sub-Saharan Africa.

Antimicrobial resistance happens when germs like bacteria or fungi develop the ability to defeat one or more of the drugs designed to kill them. Infections caused by antimicrobial-resistant germs can be difficult, even impossible, to treat. It can complicate nearly every health problem—from chronic conditions to infectious diseases. Modern medicine depends on antibiotics, including for joint replacements, organ transplants, cancer therapy, and the treatment of chronic diseases like diabetes, asthma, and rheumatoid arthritis.

When antibiotics and antifungals lose their effectiveness, we lose the ability to treat infections and control these public health threats. Everyone should have antibiotics and antifungals that work when they are needed.

Contagion: You are on a panel at the World AMR Congress discussing the role of infectious disease clinicians and AMR. Can you talk about the strategies providers can employ to prevent resistance?
Park: CDC leads US public health efforts to combat antimicrobial resistance in support of the The US National Action Plan for Combating Antibiotic-resistant Bacteria, 2020-2025. CDC’s AR Solutions Initiative supports domestic and global programs to track infections, respond to outbreaks, and prevent infections, while building strong local relationships between public health and healthcare facilities that facilitate the implementation of actionable prevention strategies locally. Our goal is to protect people, animals, and our shared environment by preventing the spread of existing and emerging antimicrobial-resistant threats in, and into, the United States.

Prevention must be our first defense against antimicrobial resistant germs. Healthcare providers play an essential role in preventing infections and stopping the spread of germs. They can help protect patients and communities with these actions:

Follow infection prevention and control guidelines and access training resources, including screening at-risk patients when indicated.

Ensure your patients receive recommended vaccines. Talk to them and their families about:

• Preventing infections
• Keeping scrapes and wounds clean
• Managing chronic conditions
• Seeking medical care when an infection is not getting better.
• Understanding when antibiotics and antifungals are needed.
• Educate patients on ways to prevent spread of germs and infections, for example share ways to be a safe patient while in the hospital.
• Stay informed of current outbreaks.
• Ask patients if they have recently traveled or received care in another facility. Germs can spread easily when people move.
• Alert the receiving facility when transferring patients who are colonized or infected with antimicrobial-resistant pathogens.

Contagion: Can you offer an overview of the SECURE initiative and its plans to reduce AMR?
Park: CDC is not involved in the SECURE initiative. World Health Organization (WHO) and the Global Antibiotic Research & Development Partnership (GARDP) lead this effort and would be more suited to respond to your question.

Contagion: What is CDC’s role in reducing AMR?
Park: CDC leads the U.S. public health efforts to combat antimicrobial resistance with a global, One Health approach. The agency’s prevention efforts span healthcare settings, communities, the food supply, and the environment such as water and soil. Through CDC’s Antimicrobial Resistance Solutions Initiative, the agency invests in national infrastructure to detect, respond, control, and prevent antimicrobial-resistant infections. CDC supports efforts to slow the spread of resistance in all 50 state health departments, several local health departments, Puerto Rico, Guam, and the U.S. Virgin Islands.

CDC is also supporting innovative antimicrobial resistance projects and programs in more than 50 countries throughout the world to improve antibiotic and antifungal use, track resistance, and slow the spread of untreatable infections through infection prevention and control activities. Many of these investments, including CDC’s Global AR Laboratory and Response Network, and CDC’s Global Action in Healthcare Network, are highlighted in the AR Investment Map.

During her panel discussion at the World AMR Congress, Akhila Kosaraju, MD, CEO and President of Phare Bio, addressed strategies for modernizing incentive structures in antimicrobial development. The panel addressed the main barriers to antimicrobial development and explored innovative approaches to overcome these challenges.

One of Kosaraju’s key points was the concept of the “two valleys of death” in drug development.

The First Valley of Death: This is the gap between early-stage discovery and clinical trials. It represents the high-risk phase where a new drug has to transition from initial research and development (R&D into more advanced stages, including preclinical studies and clinical trials. This phase is challenging due to the high cost of development, technical uncertainties, and the significant risk of failure.

Kosaraju explained, “In terms of how we’re addressing it, in addition to the efficiencies and the precision and the opportunities that come from the AI platform itself, we’re also using a nonprofit model. So the reason that’s important is that we’ve decided to have this part of the valley of death be funded with philanthropic and grant funding, and by doing that, we can de-risk our compounds, push them forward through preclinical development, and then have those conversations with venture capitalists and Big Pharma when these compounds are much closer to the clinic and where the risk-reward is rebalanced.

The Second Valley of Death: This occurs after a drug has been approved and involves the challenge of commercialization. Even if an antibiotic successfully makes it through clinical trials and receives approval, it may still face difficulties in succeeding commercially. This can be due to factors such as inadequate market incentives, low profitability compared to blockbuster drugs in other fields, and difficulties in achieving market penetration

Kosaraju’s approach to overcoming this challenge involves, “ moving the entire field forward with what’s called pull incentives, so subscription models or other ways to really reinvigorate the marketplace for antibiotics, you then have more activity on the licensing co-development side. You have more investment in preclinical pipelines commercially, so it trickles all the way to early stage development. And so we think it’s absolutely critical that not only are we addressing the first valley of death in early stage R&D, but that this second, you know, pull incentive necessity is addressed as well.”

Kosaraju also discussed how AI and deep learning are impacting antibiotic discovery and development. “AI is particularly suited for this because it can help identify and prioritize novel chemical spaces for drug discovery. By focusing on finding new mechanisms of action, AI addresses the core issue of AMR, which is the overuse of old antibiotics leading to increased resistance.

Since 2017, Phare Bio has achieved significant milestones. Kosaraju brings awareness to these accomplishments, “discovering two novel classes of antibiotics, published in Cell and the other in Nature Chemical Biology. We are also incorporating new parameters into our AI platform, such as drug toxicity, oral formulation, and half-lives, which could lead to significant advancements,” she explains. “A proof of concept in Nature last December on this idea, suggesting that AI could lead to tailored drug discovery processes.

Addressing the challenges in antibiotic development requires push and pull incentives. Kosaraju emphasized the role of government policies, “the first key part is having some marketplace. If you have an approved product, especially one that has a novel mechanism of action against a high-priority pathogen that should be incentivized and rewarded.”

Legislation like the PASTEUR Act can stabilize the market for novel antibiotics by separating sales volume from pricing, while increased government grants for early-stage innovation are crucial for breakthrough discoveries.

In conclusion, addressing the challenges in antibiotic development requires both innovative strategies, such as AI-driven discovery and nonprofit funding models, and supportive government policies. These measures are important for revitalizing the antibiotic pipeline and combating antimicrobial resistance effectively.

The Pasteur Act has been in Congress for a few years now and seems to be in a holding pattern. This bill authorizes the Department of Health and Human Services (HHS) to enter into subscription contracts for critical-need antimicrobial drugs, provides $6 billion in appropriations for activities under the bill, and contains other related provisions.¹ Last year, Senators Michael Bennet (D-CO) and Todd Young (R-IN) and Representatives Drew Ferguson (R-GA) and Scott Peters (D-CA), reintroduced the Pasteur Act in Congress. The bill was initially introduced in Congress by Bennet and Young in September of 2020. Bennet and Young along with Representatives Mike Doyle (D-PA) and Ferguson reintroduced the bill in June 2021.

After the bill’s reintroduction last year, 5 national organizations: the Biotechnology Innovation Organization, the Cystic Fibrosis Foundation, the Infectious Diseases Society of America (IDSA), the Partnership to Fight Infectious Disease, and The Pew Charitable Trusts, issued a statement on the topic.

“Antimicrobial resistance is not a partisan issue. It is an increasingly challenging public health emergency that reverberates far beyond just health care settings. Every 15 minutes, a person in the United States dies from an infection resistant to treatment with existing antimicrobial drugs. This means that since PASTEUR’s last introduction on June 16, 2021, more than 64,000 Americans have died because they did not have adequate medications to treat their infections,” part of the statement read.

This week at the World AMR Congress meeting, Amanda Jezek, senior vice president for Public Policy and Government Relations at IDSA is participating at the meeting and serving as chair person of Impact, Policy, and Awareness as well as participating on a panel around antimicrobial resistance (AMR).

In-between activities, Jezek sat down with Contagion at the meeting to offer some Washington insider updates on the prospective bill as well as provide feedback about ongoing AMR initiatives that IDSA is working on.

Jezek does believe the Pasteur Act will pass and says it is better to do so now than deal with the consequences of increased mortality rates and the inability to perform procedures due to concerns over AMR. “I think it has to; the stakes are too high,” Jezek said. “Right now we are trying convince Congress to do the right thing, and pass this while we have a little bit of lead time to protect modern medicine.”

Jezek says that along with being a major supporter of the Congressional bill, IDSA is involved in other AMR-related activities including the US national plan to address AMR, and the United Nation’s meeting at the end of this month looking at AMR and a One Health approach. “IDSA has been really excited to have multiple opportunities to be able to brief UN leaders and other experts who are involved in this process.”

Reference
1. Summary: S.1355 — 118th Congress (2023-2024). Congress.gov. Accessed September 5, 2024.
https://www.congress.gov/bill/118th-congress/senate-bill/1355#:~:text=Introduced

Final Diagnosis

Invasive Fusarium sinusitis

History of present illness
A 74-year-old White man who initially presented at a local urgent care with a 2-day history of progressively worsening pounding frontal headache, generalized weakness, frontal/maxillary sinus tenderness, rhinorrhea, and bilateral blurring of vision. He was diagnosed with presumptive bacterial sinusitis and was sent home on amoxicillin/clavulanate 500 mg every 8 hours for 7 days. Despite being on antibiotics for 2 days, his symptoms progressively worsened, particularly his headache. He eventually developed subjective fevers and chills, prompting him to come to the emergency department.

Medical history
He had a history of high-risk myelodysplastic syndrome (MDS) on decitabine/cedazuridine. He was diagnosed with MDS 2 years ago, and his last cycle of decitabine/cedazuridine was approximately 1 month prior to his presentation. He also had a history of type 2 diabetes mellitus.

Key medications
• Decitabine 35 mg/cedazuridine 100 mg orally once a month
• Metformin 500 mg orally daily

Epidemiological history
He lived with his wife, daughter, and 5 grandchildren. He had 2 pet cats and no contact with any farm animals. He denied gardening, hiking, camping, fishing, and hunting. He had no known sick contacts and no recent travel. He was in the military approximately 50 years ago. He had never been incarcerated, and he denied illicit drug use, cigarette smoking, and alcohol intake. There was no active or recent renovation in his house.

Physical examination
The patient appeared older than his age, not in cardiorespiratory distress but visibly in pain. His vital signs were a blood pressure of 112/71 mm Hg, heart rate of 84 beats per minute, temperature of 98.1 °F (36.72 °C), and respirations of 18 breaths per minute. On physical examination, he had bilateral frontal and maxillary sinus tenderness, warmth, and erythema that was worse on the right. There was also mild but noticeable right-sided periorbital edema. His pupils were equal and reactive to light and accommodation with no pain in movement. The remainder of the physical examination findings were normal.

Studies
His white blood cell count was 0.5 K/μL (reference range, 4.40-11.30 K/μL), with neutrophils at 5%, no bands, lymphocytes at 75%, and monocytes at 10%. The absolute neutrophil count was 0. The hemoglobin was 7.7 g/dL (reference range, 13.8-17.4 g/dL) and hematocrit was 22.9% (reference range, 41%-51%). The platelet count was 39 K/uL (reference range, 150-450 K/μL). His creatinine was 0.88 mg/dL (reference range, 0.6-1.3 mg/dL), blood urea nitrogen level was 21 mg/dL (reference range, 7-20 mg/dL), and glucose was 105 mg/dL. His C-reactive protein level was 136 mg/L (reference range, < 5 mg/L), procalcitonin was less than 0.05, and ferritin was 3456.7 ng/mL (reference range, 26-388 ng/ml). Blood cultures did not grow anything.

Image credit: Ian Adrian F. Frani, MD, BSN

A CT scan (Figure 1) showed mucosal thickening in frontal sinuses, ethmoid air cells, and right maxillary sinus. No acute territorial infarct, intracranial hemorrhage, cerebral edema, or cerebral mass effect is seen. An MRI of the orbits (Figure 2) showed severe paranasal sinus disease involving frontal sinuses, ethmoid air cells, sphenoid sinuses, and right greater than left maxillary sinus. There is no evidence of intracranial or intraorbital extension or other complication. Orbits and brain are otherwise unremarkable.

Clinical course
Infectious diseases service was consulted, and because of his febrile neutropenia and concern for invasive sinusitis, he was started on intravenous liposomal amphotericin 4 mg/kg/day, vancomycin, and piperacillin/tazobactam to cover for fungal and bacterial sinusitis, respectively. Otorhinolaryngology evaluated the patient and took him to surgery for endoscopic sinus surgery with right maxillary antrostomy and right ethmoidectomy. A frozen section was done intraoperatively and noted fungal elements, with no obvious vascular invasion.

Image credit: Ian Adrian F. Frani, MD, BSN

Pathology of tissue samples showed necrotic tissue with numerous fungal organisms with long, thin hyphal forms with regular septations and acute angle branching (Figure 3). The tissue samples that were sent for culture grew mold and were eventually identified as Fusarium species. Empiric vancomycin and piperacillin/tazobactam were stopped, and voriconazole was added in addition to liposomal amphotericin B for 1 week post procedure and was eventually transitioned to voriconazole 200 mg orally twice-a-day monotherapy. Granulocyte colony-stimulating factor (G-CSF) was administered with consultation from oncology to shorten the period of neutropenia. Because of concerns for recurrence and the high risk of mortality associated with invasive fungal disease in this population, a decision was made to keep him on voriconazole long term with serum level monitoring for at least 3 to 6 months, or at least until immunosuppression and neutropenia have resolved whichever is the latest. His symptoms resolved a few days after debridement, and he was eventually discharged. Two weeks later, he was readmitted for a fever and worsening headache and periorbital pain. Repeat MRI showed worsening sinusitis without any intracranial and intraorbital extension. This time, his blood cultures showed Clostridium septicum. He was started on piperacillin/tazobactam and liposomal amphotericin B in addition to voriconazole. He was then transferred to a higher-level facility where he underwent endoscopic debridement twice prior to being discharged on voriconazole in addition to levofloxacin and acyclovir prophylaxis. Unfortunately, he was readmitted after 1 month with recurrent worsening sinusitis, and after a few weeks, his family opted for palliative and comfort care.

Image credit: Ian Adrian F. Frani, MD, BSN

Discussion
Fusarium species are widely distributed as water structure biofilms in soil and water and are important plant pathogens.1 They can cause hyalohyphomycosis similar to Aspergillus, Penicillium, and Scedosporium species, among others.2 Hyalohyphomycosis is a term used to described opportunistic fungal infections caused by molds whose basic tissue form is in the nature of hyaline, light-colored, hyphal elements that are branched or unbranched, occasionally toruloid, and without pigment in their wall.^2,3 Microscopically, they resemble Aspergillus species in that they have septated hyaline hyphae 3 to 8 μm in diameter that branch at acute or right angles and produce both fusoid macroconidia and microconidia, which is a characteristic of the genus Fusarium.² There are more than 50 species of Fusarium, but only 12 species cause human disease.¹ Fusarium solani complex is the most pathogenic of the species4 and is most frequently associated with human disease (approximately 40%-60% of cases), followed by Fusarium oxysporum (20%), Fusarium verticillioides (10%), and Fusarium moniliforme (10%).^1,5

Fusarium species can produce trichothecenes and other mycotoxins that can suppress humoral and cellular immunity, as well as cause tissue breakdown. Because of its virulence factors and interplay with the host’s immune system, particularly innate immunity and T-cell defenses, the clinical manifestation and its severity are largely dictated by the degree of immune suppression.1,4 Immunocompetent hosts usually have more localized presentation in contrast to more invasive and disseminated disease associated with immunocompromised hosts. Prolonged neutropenia and recent corticosteroid therapy are associated with poor outcomes in the immunocompromised population.^1,2,4 Mortality in the immunocompromised patients has been reported to range from 50% to 80%.^1,2

In a retrospective study by Nucci et al that included 84 patients with hematologic cancers and invasive fusariosis, factors associated with poor survival included persistent neutropenia and corticosteroid therapy. The actuarial survival rates in the study are 0% in patients with both prolonged neutropenia and recent corticosteroid therapy, 4% for those with only prolonged neutropenia, and 30% for those on recent corticosteroids.6 In this case, our patient is not on corticosteroids but is on decitabine/cedazuridine, which can cause myelosuppression and increase risk of infection.

Diagnosis is made by identification of the fungus via growth from a culture such as blood, skin, corneal scrapings, and lung/nasal tissues.^1,4 Fusarium grows readily on blood cultures but can grow 10 to 35 hours faster, depending on the subspecies, if grown on fungus-specific media.¹ This is in contrast with Aspergillus, which rarely grows on blood cultures (5% recovery rate in Aspergillus vs 50% in Fusarium).⁷ This characteristic of Fusarium to grow on blood cultures can be attributed to adventitious sporulation, which is the production of reproductive fungal structures in infected human tissue, including blood.⁷ Identification is important because Aspergillus and Fusarium can resemble each other morphologically and can both invade blood vessels, causing thrombosis, tissue infarction, and eventually necrosis.²

Management of fusariosis includes a combination of antifungal therapy, decreasing the immunosuppression, and, in cases of localized infection, surgical debridement. Fusarium species are intrinsically resistant to echinocandins.⁷ It can also develop resistance mechanisms such as changes in amino acid sequences and overexpression of genes that can both promote azole resistance and efflux pumps.⁷ Voriconazole and amphotericin B are the drugs of choice, with posaconazole being used for salvage therapy.^4,5 Because Fusarium is highly resistant and in vitro susceptibility to various antifungals are low and unreliable with no established minimal inhibitory concentrations, combination therapy is recommended, especially if susceptibility has not returned in immunocompromised patients with invasive or disseminated disease.^2,4,5 There are no defined guidelines for duration of therapy, but because of the high risk of relapse in immunocompromised patients, prolonged therapy with secondary prophylaxis is recommended.⁴ Administration of G-CSF should be considered to shorten the duration of neutropenia, although its benefit on mortality in this population has not been established.^1,2,4

Fusariosis has a wide variety of clinical manifestations that are directly related to the degree of immunosuppression.

As our patient highlights, there should be a high degree of suspicion for invasive or disseminated fusariosis in patients who are severely ill with prolonged neutropenia and significant immunosuppression because mortality is high, even on appropriate antifungal therapy, in this population.

References

1. Nucci M, Anaissie E. Fusarium infections in immunocompromised patients. Clin Microbiol Rev. 2007;20(4):695-704. doi:10.1128/CMR.00014-07

2. Dignani MC, Anaissie E. Human fusariosis. Clin Microbiol Infect. 2004;10(suppl 1):67-75. doi:10.1111/j.1470-9465.2004.00845.x

3. Ajello L. Hyalohyphomycosis and phaeohyphomycosis: two global disease entities of public health importance. Eur J Epidemiol. 1986;2(4):243-251. doi:10.1007/BF00419488

4. Tortorano AM, Prigitano A, Esposto MC, et al. European Confederation of Medical Mycology (ECMM) epidemiological survey on invasive infections due to Fusarium species in Europe. Eur J Clin Microbiol Infect Dis. 2014;33(9):1623-1630. doi:10.1007/s10096-014-211-1

5. Batista BG, Chaves MA, Reginatto P, Saraiva OJ, Fuentefria AM. Human fusariosis: an emerging infection that is difficult to treat. Rev Soc Bras Med Trop. 2020;53:e20200013. doi:10.1590/0037-8682-0013-2020

6. Nucci M, Anaissie EJ, Queiroz-Telles F, et al. Outcome predictors of 84 patients with hematologic malignancies and fusarium infection. Cancer. 2003;98(2):315-319. doi:10.1002/cncr.11510

7. Liu K, Howell DN, Perfect JR, Schell WA. Morphologic criteria for the preliminary identification of Fusarium, Paecilomyces, and Acremonium species by histopathology. Am J Clin Pathol. 1998;109(1):45-54. doi:10.1093/ajcp/109.1.45