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Brian Lu, PharmD, is a PGY-2 infectious diseases pharmacy resident at Stanford Health Care.

There is limited and conflicting data regarding the role of combination antifungal therapy for treatment of invasive mucormycosis.

Combination Antifungal for Invasive Mucormycosis: Yay or Nay?

Along with a 1 reported case in Massachusetts, the

New Hampshire Department of Health and Human Services (DHHS) has confirmed a person infected with eastern equine encephalitis (EEE) has died. The public health agency said the person was hospitalized due to severe central nervous system disease. The last reported human EEEV infection in New Hampshire was in 2014, when DHHS identified 3 human infections, including 2 fatalities. In the same statement, DHHS mentions there has been 1 confirmed case in Vermont this summer.

On August 16, the Massachusetts Department of Public Health (MDPH) released a statement discussing the confirmation of the first human case of EEE in the state this year. The confirmed case was discovered in an 80 year old man who was exposed to the vector borne disease in Worcester County. As a result, the risk level in the local communities of Douglas, Oxford, Sutton, and Webster has been raised to critical, and in Dudley, Northbridge, and Uxbridge the risk is increased to high.

Additionally, the neighboring communities of Auburn, Charlton, Grafton, Leicester, Mendon, Millbury, Millville, Southbridge, and Upton are now considered at moderate risk according to MDPH.

“This is the first time we have seen a person infected with EEE in Massachusetts since 2020,” Public Health Commissioner Robbie Goldstein, MD, PhD, said in a statement. “EEE is a rare but serious disease and a public health concern. We want to remind residents of the need to protect themselves from mosquito bites, especially in areas of the state where we are seeing EEE activity.

Though very rare, EEE is serious and a potentially fatal disease that can affect people of all ages. EEE is generally spread to humans through the bite of an infected mosquito. There were 12 human cases of EEE in Massachusetts in 2019 with 6 deaths, and 5 human cases with 1 death in 2020. There were no human cases of EEE in Massachusetts in 2021, 2022, or 2023.

EEE has a fatality rate of 33% to 70%, with most deaths occurring 2–10 days after the onset of symptoms.

In addition to a high mortality rate, long-term physical and mental complications, including permanent neurological deficits have been identified in many people who survive EEE.

Plymouth is approximately 40 miles south of Boston along the coast, and Worcester County is in the middle of the state, so the 2 areas are not in close proximity, but due to the elevated risk locally, the town of Plymouth decided to take action in response to outdoor parks. As of last Friday, all town public parks and fields are close daily from dusk until dawn.

“As Mass DPH has now elevated Plymouth’s EEE risk status to high, it is important to take extra precautions when outdoors and follow state and local health guidelines to avoid unnecessary risk to exposure to EEE. The health and safety of our community, residents, and visitors remain our priority,” Plymouth’s Commissioner of Health and Human Services, Michelle Bratti, said in a statement.

According to the Centers for Disease Control and Prevention (CDC) most people who are infected with the virus do not develop symptoms; however, for those that do, the date from the bite to the onset of the illness is 4 to 10 days. EEE can also result in fever or neurologic disease. The type of illness will depend on the age of the person and other factors. Those who are infected can develop meningitis.

There are no FDA-approved treatments for EEE and for patients who develop severe cases, they can be hospitalized to receive supportive treatment.

Over the weekend, MDPH detailed plans of spraying for mosquitos including aerially in areas of Plymouth County, and truck-mounted spraying in parts of Worcester County. As of Saturday, 10 communities in Massachusetts were raised to high or critical risk for EEE virus.

“The risk from EEE is high in parts of Plymouth County and critical in parts of Worcester County,” State Epidemiologist Catherine M. Brown, DVM, said in a statement. “In addition to recommending that people use mosquito repellent with an EPA-registered active ingredient and clothing to reduce exposed skin, we also recommend that evening outdoor events be rescheduled to avoid the hours between dusk and dawn. The mosquitoes most likely to spread EEE are most active during the dusk to dawn hours.”

There are preventative strategies to avoid EEE, and the MDPH has listed such measures 

For those who live in Massachusetts and want more information on EEE, it can be found 

 or by calling the DPH Division of Epidemiology at 617-983-6800.

1.NH DHHS Identifies Person Infected with Eastern Equine Encephalitis Virus in New Hampshire.The New Hampshire Department of Health and Human Services. August 27, 2024. Accessed August 28, 2024.
https://www.dhhs.nh.gov/news-and-media/nh-dhhs-identifies-person-infected-eastern-equine-encephalitis-virus-new-hampshire
2. State health officials announce season’s first human case of Eastern Equine Encephalitis in Massachusetts. MDPH. August 16, 2024. Accessed August 27, 2024.
https://www.mass.gov/news/state-health-officials-announce-seasons-first-human-case-of-eastern-equine-encephalitis-in-massachusetts
3.Plymouth to Close all Public Parks and Fields from Dusk to Dawn. Town of Plymouth. August 23, 2024. Accessed August 27, 2024. PDF.
4. Eastern Equine Encephalitis: Symptoms, Diagnosis, and Treatment. CDC. May 15, 2024. Accessed August 27, 2024.
https://www.cdc.gov/eastern-equine-encephalitis/symptoms-diagnosis-treatment/index.html
5. State officials announce plans to spray for mosquitoes in sections of Worcester and Plymouth counties due to EEE. MDPH. August 24, 2024. Accessed August 27, 2024. 
https://www.mass.gov/news/state-officials-announce-plans-to-spray-for-mosquitoes-in-sections-of-worcester-and-plymouth-counties-due-to-eee



The town of Plymouth decided to prohibit people from using the parks from dusk to dawn due to concerns over eastern equine encephalitis after a man contracted the rare disease in the state.

Concerns Over Mosquito-Borne Illness Causes Massachusetts Town to Create Curfew for Parks, Spraying in Counties

In 2024, there were many news updates in the world of respiratory infections, ranging from updates in vaccinations to new data on the long-term effects of some of these illnesses on patients. The 

 team followed it all, and spent our time speaking with experts from major institutions, pharmaceutical companies, and the federal agencies who are working together to push medical science forward.

Here, we'll be providing a list of stories that resonated with our audience in 2024 in the area of respiratory infections. As expected, a number of COVID-related updates made their way into this list, among other news items that were of interest to readers. 

Click the headlines to read more from these stories.

During the Pandemic, 75% of Hospitalized COVID-19 Patients Received Antibiotics, Despite Only a Minority Needing Them

In the early days of the pandemic when hospital ICUs were filling up with severe COVID-19 patients, clinicians had no therapeutic agents, and no one had any form of immunity to fight the virus, thus health care turned to a familiar form of treatment: antibiotics.

New data from the WHO offers further information on the scope of this treatment challenge that happened in the first years of the pandemic.

Although only 8% of hospitalized patients with COVID-19 had bacterial co-infections requiring antibiotics, 75% of patients were treated with antibiotics ‘just in case’ they helped, according to the WHO research. The highest rate of antibiotic use was seen among patients with severe or critical COVID-19...

COVID-19 Vaccination Associated with Reduced Risks of Thromboembolic, Cardiovascular Complications

One of the ongoing concerns of COVID-19 vaccines has been reports around thromboembolic and cardiovascular events. There have been reports of blood clots following adenovirus-based COVID-19 vaccines, with an association that was further assessed in observational studies. Later on, mRNA-based vaccines were found to be associated with the risk of rare myocarditis events. Contrary to these past associations, a new study published in the journal, 

, reported there was a major reduction of risk (45–81%) for post-acute COVID-19 venous thromboembolism (VTE), arterial thrombosis/thromboembolism (ATE) and heart failure (HF) in patients who had been vaccinated...

Healthcare Workers Who Received Additional Vaccine Dose Had Lower Odds of Symptoms at 6 Weeks

The early days of the Omicron predominant period continued to see high incidence rates of COVID-19 that included severe infections, hospitalizations, and mortality. For their part, healthcare workers (HCWs) were always in close proximity to patients with severe infection, and consequently in harm’s way. As such, HCWs saw a large incidence rate of active infection as a population.

According to 1 study done in the early period of the pandemic beginning from the time no vaccines were authorized, and extending through until nearly a year after the vaccines had been initially rolled out (December 2020), HCWs took up a large percentage of confirmed cases...

The US Will Transition to Trivalent Vaccines for Next Year's Influenza Season

The FDA’s Vaccines and Related Biological Products Advisory Committee recommended that all US flu vaccines transition from quadrivalent to trivalent vaccines for the 2024-2025 flu season. The trivalent vaccines’ formula will still contain the influenza A(H1N1), A(H3N2), and B/Victoria-lineage vaccine virus, but omit the influenza B/Yamagata virus because it is no longer actively circulating.

“FDA has been engaging and interacting with manufacturers of FDA-approved seasonal flu vaccines and providing scientific and regulatory advice to them to facilitate the timely availability of approved safe and effective trivalent seasonal flu vaccines for the 2024-2025 US flu season,” said the FDA in a news release...

COVID-19 Vaccination During Early Pandemic Years Shown to Reduce Risk for Heart Attacks, Strokes

The incidence rates for both heart attacks and strokes (arterial thromboses) were lower after COVID-19 vaccination than before or without vaccination during the earlier years of the pandemic, according to a new study from England.

Heart attacks and strokes were up to 10% lower in the 13 to 24 weeks after the first dose of a COVID-19 vaccine. And post-second dose, the incidence was up to 27% lower after receiving the AstraZeneca vaccine and up to 20% lower after the Pfizer/Biotech vaccine...

Japan Approves Updated Self-Amplifying mRNA COVID-19 Vaccine

Japan has approved the CSL and Arcturus Therapeutics' Updated self-amplifying (SA) mRNA COVID-19 Vaccine, ARCT-154 (Kostaive). The updated vaccine is targeted to protect against the JN1 lineage of omicron subvariants for adults 18 years of age and older. "We are pleased to receive the updated approval from Japan's Ministry of Health, Labor and Welfare, and remain on track to distribute Kostaive in time for the October COVID-19 vaccination campaign," Emmanuelle Lecomte-Brisset, senior vice president and head of Global Regulatory Affairs, CSL, said in a statement...

In a retrospective cohort study published in 

 investigators evaluated the incidence of certain symptoms and conditions associated with long COVID, potentially indicative of PASC, within 31 to 150 days after a SARS-CoV-2 test in both adults and children, comparing those with positive and negative results. Individuals infected with SARS-CoV-2, particularly those who required hospitalization, faced an increased risk of being diagnosed with specific symptoms and conditions following their acute infection phase.

Following adjustments for baseline covariates, adults and children who were hospitalized and tested positive showed higher odds of receiving a diagnosis of ≥1 symptom...

CDC Updated COVID-19 and Influenza Vaccination Guidelines for 2024-2025 Season

During the CDC's Advisory Committee on Immunization Practices (ACIP) meeting held on June 27, 2024, voting members recommended the authorized 2024-2025 COVID-19 vaccines for those 6 months of age and older and reaffirmed the influenza vaccination guidelines. The CDC discussed that the 2023-2024 COVID-19 vaccination has proven effective in protecting against various aspects of the virus, including asymptomatic SARS-CoV-2 infections, COVID-19-related visits to emergency departments and urgent care facilities, and hospitalizations. While showing waning patterns over time, it continues to provide notable protection against illness...

Internal Tremors: Adding to the List of Long COVID Symptoms

Long COVID has a laundry list of symptoms — and a lesser-known but troubling one is the sensation of having internal tremors, often with no outward evidence that this is happening. In a new, Yale-based Long COVID study, over one-third of participants report experiencing this strange symptom, which feels as if tremors are occurring 

Long COVID remains one of the most poorly-understood aspects of the SARS-CoV-2 pandemic. Since shortly after the pandemic began in 2020, health professionals have had to come to terms with the fact that some patients who overcome their initial COVID-19 infection never completely recover. People with Long COVID have developed a variety of symptoms that range from gastrointestinal issues to chronic fatigue...

As 2024 winds to a close, take a look back on some of the biggest stories Contagion was following around respiratory infections.

Contagion's 2024 Top Stories: Respiratory Infections

New research suggests the sympathetic nervous system (SNS) or flight or fight response can shape the severity of 

 infection. In an animal study, a group of investigators found if they disrupted specific receptor activity in the sympathetic nervous system, a significant reduction in both intestinal inflammation and mortality was seen.

The affected portion of the SNS is the alpha 2-adrenergic receptors (α2-ARs) which are cell surface-based, and play a role in fight or flight responses including blood pressure, anxiety and stress, and inflammation.

“The discovery of the α2AR as a major driver of disease was somewhat unexpected, considering that the α2AR is a well-known negative regulator of sympathetic activity,” the investigators wrote in their study, which was published in 

“Neurons are the first responders that coordinate defenses against toxic attacks. Sometimes those responders don’t recruit the right size and kind of artillery and that can make things worse,” said study author David Tyus, PhD, a neuroscience graduate student at University of Virginia (UVA), in a news release. “Interestingly, the receptor we identified as important in 

 infection [the alpha 2 adrenergic receptor] has also been linked to irritable bowel syndrome.

Tyus and study author William A. Petri Jr., MD, PhD, of UVA's Health’s Division of Infectious Diseases and International Health, evaluated the role of SNS in 

 the study's authors explain that blockade of alpha 2-adrenergic receptors downstream may stop disease progression of 

Can you explain the concept of using therapies to quiet the “fight or flight” response to potentially prevent a severe case of C difficile?
Petri and Tyus:

 Our results suggest that sympathetic nervous system activity contributes to the severity of disease in 

infection. Part of that determination was observing that blockade of specific receptors downstream of the sympathetic nervous system could curb disease progression 

infected mice. Theoretically, receptor blockade in patients could do the same but further study is needed to determine whether this approach could be safely applied prophylactically or after symptoms occur.

What are the important takeaways from your study?
Petri and Tyus:

The biggest takeaway from the study is that the sympathetic nervous system seems to be an important part of the disease process when one is infected with 

With the backdrop of many studies in the field focusing on barrier and immune functions, this study is a new example of neuronal contributions to 

What would you like to see in terms of next steps for your research?
Petri and Tyus:

 We would like to determine which cells downstream of the sympathetic nervous system mediate its effects in the hopes of finding more resolved mechanisms and therapeutic targets. Additionally, we would like to test the role of the sympathetic nervous system in recurrent disease, a hallmark issue of 

There are a number of reasons to study recurrent infection, including the possibility of a patient's diminished quality of life as well as mortality. Factors such as advanced age, use of antibiotics, gastric acid suppression, and infection with a hypervirulance are some reasons people infected have more severe bouts or even recurrence with 

“We are very excited to think about how our findings translate to clinic and how the sympathetic nervous system might play a role in recurrent infection. I hope that this study sets the foundation for future findings of how neurons affect the course of 

infection outcomes,” Petri said in a news release. 

References
1. Tyus D, Leslie JL, Naz F, Uddin MJ, Thompson B, Petri WA Jr. The sympathetic nervous system drives hyperinflammatory responses to Clostridioides difficile infection. 

. 2024;5(10):101771. doi:10.1016/j.xcrm.2024.101771
2. Belfer I, Buzas B, Hipp H, et al. Haplotype-based analysis of alpha 2A, 2B, and 2C adrenergic receptor genes captures information on common functional loci at each gene. 

. 2005;50(1):12-20. doi:10.1007/s10038-004-0211-y
3. Zhang SJ, Lai G, Griffis CA, Schiltz M, Aroke EN. α

-Adrenergic Receptor Agonist, an Attractive but Underused ERAS Component in Improving Fast-Track Recovery and Surgical Outcomes. 

. 2021;89(6):529-537.
4. Faulty ‘Fight or Flight’ Drives Deadly C. Difficile. UVA News release. 


https://newsroom.uvahealth.com/2024/10/10/faulty-fight-or-flight-drives-deadly-c-difficile/

 Infection: Risk Factors, Treatment, and Prevention. 

Investigators at the University of Virginia are examining the potential link between the “sympathetic” nervous system and the role of the seriousness of the infection.  

Could the Flight or Fight Response Trigger Severe C difficile?

Jose Alexander, MD, ABMM, ABAIM, FCCM, CIC, ASCP, BCMAS, and his team discovered the klebsiella pneumoniae variant, KPC-31, 

Identifying a Novel Variant of Klebsiella Pneumoniae 

Jose Alexander, MD, ABMM, ABAIM, FCCM, CIC, ASCP, BCMAS, medical director for the microbiology laboratory at AdventHealth in Orlando, FL has a unique perspective. As someone who has been both a practicing physician in the past and a current laboratorian, he is able to utilize both his clinical and diagnostic experiences and apply them to individual cases. This dual professional experience helped him earlier this year when he and his lab team at AdventHealth were able to diagnose a novel variant of 

, called KPC-31, in a patient which was possibly the first case ever diagnosed in the state of Florida.

The detection of this mysterious and unusual pathogen was discovered utilizing various diagnostics tools including whole genome sequencing (WGS) as well as multi-locus sequence typing (MLST).

“We've been lucky enough in the last two years that we've been working with whole genome sequencing, which brings us a direct, rapid clinical tool for identification,” Alexander said. “But now we have it implemented as a clinical tool for identifying mycobacteria, fungi, and some bacteria,” Alexander said.

The case identifying the KPC-31 variant stems from a patient that they were familiar with at his institution who had previously battled 

After discovering the isolate, it was rapidly tested against ceftazidime/avibactam, meropenem/vaborbactam, and imipenem/relebactam. Alexander and his team were surprised because the isolate was resistant to ceftazidime/avibactam, and susceptible to meropenem/vaborbactam, and imipenem/relebactam. He said they also found meropenem and imipenem were susceptible without inhibitors.

“We decided to do whole genome sequencing. And then after we did that, we started evaluating and the first thing that we did was ask what is the MLST of this strain? So, we found that it was strain 307 that is  hypervirulent, and has been reported both globally and in some regions in the US.”

Alexander sees the adoption of Matrix-Assisted Laser Desorption/Ionization Time-of-Flight (MALDI-TOF) mass spectrometry in microbiology being an important tool because it can identify microorganisms within 24 hours. Along with identifying the pathogen, he stresses the importance of differentiating between the antimicrobial resistance and susceptibility in these cases. And knowing the organism before setting up susceptibility testing is a significant development.

“I seeing antimicrobial testing not only from the treatment perspective, but also from the perspective of having a more comprehensive screening. This is something that we've been talking with some of the manufacturers about to try to have this approach, because we want to make sure that we are able to account for those new challenges that constantly are arising.”

Lastly, he says it is important for good communication between pharmacists, other clinicians, and laboratory professionals to work together through challenging cases.

“If we know that we have a problem with a specific antimicrobial resistant organism, let's say 

being able to understand it phenotypically— what are the best agents that in vitro we know have clinical activity or indicated for, having that cumulative data can actually drive antimicrobial therapy before susceptibility tests are available,” Alexander said. “I think using cumulative data to create a laboratory algorithm can be triggered just by a specific pattern. We can also alleviate the over calls to the laboratory asking for additional testing, asking for confirmation, and the pharmacy and the physician can escalate treatment immediately.”

Jose Alexander, MD, ABMM, ABAIM, FCCM, CIC, ASCP, BCMAS, and his team discovered the klebsiella pneumoniae variant, KPC-31, in a patient by sequencing the entire genome through a series of different diagnostics, which not only led to identifying the strain, but to a greater understanding of its antimicrobial susceptibility. 

From Pathogen to Infectious Disease Diagnosis: Identifying a Novel Variant of Klebsiella Pneumoniae 

Jason Pogue discussed ceftolozane tazobactam’s effectiveness over Ceftazidime Avibactam, particularly in pneumonia patients, where it reduced the likelihood of recurrent infections.

Ceftolozane Tazobactam Linked to Increased Clinical Success in Pneumonia

The CACTUS study found a 10% improvement in clinical success with ceftolozane tazobactam (CT), which was linked to a 1.5-fold increased chance of clinical success. After adjusting for residual differences between the treatment arms, the likelihood of success was nearly twice as high with CT. Despite these findings, mortality rates were similar between the two arms, and both therapies, CT and ceftazidime avibactam (CZA) showed high rates of resistance development.

The study's primary outcome was clinical success at day 30, defined as the patient being alive, free from the initial infection (with no escalation of therapy), and without infection recurrence within 30 days.

with Jason M Pogue, PharmD, BCPS, BCIDP explained, "What we found in the study was that CT was associated with about a 10% absolute improvement in that variable of clinical success. They weren’t great rates of clinical success in either arm. It was about 61% in the CT arm and 52% in the CZA arm. And so, if you got CT you had about a one-and-a-half-fold increased chance of having clinical success. Once we adjusted for residual differences between the two groups, it was about a two-fold increased chance.”

Although this difference might seem modest, the results suggest that CT offered a 1.5-fold increased chance of success. After adjusting for residual differences between the two groups, the chance of clinical success was approximately twice as high for patients treated with CT. Pogue further emphasized, "I like the idea of a therapy being twice as likely to have a positive outcome, but I think it’s very fair to note that success rates still weren’t optimal. We still need to think about ways to further improve outcomes for these patients.”

Mortality rates were similar across both arms of the study. The 30-day mortality rates ranged between 20-25%, and 90-day mortality rates were around 35%. These rates align with findings from other studies on drug-resistant 

Regarding mortality, Pogue commented that there was no difference observed between the two treatment arms. “When we looked at mortality, we saw no difference between the two arms,” he said. “When we looked at resistance development, we saw high rates in both treatment arms. So neither therapy was perfect, but CT was associated with increased clinical success.”

The study’s findings were particularly notable in pneumonia patients, where CT showed a clear benefit in reducing recurrent infections. Pogue shared, “When we looked at the nitty-gritty of the data, it was really driven by pneumonia patients. That’s where you really saw the effect, and the biggest driver was actually being less likely to have recurrent pneumonia after therapy. And again, that’s very consistent with our hypothesis, because if there was a place we thought this PK/PD (pharmacokinetics/pharmacodynamics) was most likely to manifest itself as clinically meaningful, we would have thought it would have been in pneumonia patients.”

This observation confirms the importance of pharmacokinetics and pharmacodynamics in shaping treatment outcomes, particularly for infections that involve the lungs.

While the clinical success rates were not optimal, Pogue acknowledged limitations due to the severely ill patient population. Over three-quarters of the cohort were in the ICU, mechanically ventilated, and on vasopressors. The average age was over 60 years, and many patients had significant comorbidities, including solid organ transplants and immunosuppressive conditions.

Pogue explained, “This cohort was incredibly ill, complicated patients... you do, to some degree, just have a really complicated patient population. And you would expect for a hard outcome like mortality, infection is certainly a piece of the story, but there’s a lot of other things that are going on in this patient population as well.”

He noted that the severity of illness in these patients makes it difficult to show the impact of the drug on mortality, as a superior therapy can only significantly impact mortality rates in a “sweet spot” patient population. “The amount of mortality rates that can be impacted by a superior therapy is really going to be limited to a sweet spot patient population,” he explained. “They have to be sick enough where they are going to die if you don't effectively treat them, but not too sick, where they probably won’t get better either way.”

Pogue suggested that more patients are needed to truly test the mortality hypothesis and emphasized the importance of subgroup analysis for gaining insights into mortality differences. “If you take a look at the supplemental table 2, we actually look at mortality rates compared between the two arms for different subgroups of populations. There are some interesting little nuggets that I think are in there.”

Looking ahead, Pogue discussed the potential for more research in the area of resistant infections. While the current study provided valuable observational data, a randomized controlled trial would be ideal to further validate these results. “The key thing you want to do now is design a randomized control trial where you actually put patients in these two arms. Unfortunately, I think that’s probably pretty unlikely, just because you'd need someone to support such a trial. It’s a complex study to do, and the chances of that occurring are quite low, in my opinion.”

Pogue emphasized that the current evidence should still influence clinical practice. “I believe pretty strongly that this is probably the best evidence we’re going to get… and I do think it should influence how we treat these patients.”

Part 1 of our interview introducing The CACTUS study: 

Jason M Pogue, PharmD, BCPS, BCIDP  discussed ceftolozane tazobactam’s effectiveness over ceftazidime avibactam, particularly in pneumonia patients, where it reduced the likelihood of recurrent infections.

Brian Lu, PharmD

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