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Executive Medical Director for Anti-Infectives at Shionogi Inc.

Christine Slover, PharmD discussed cefiderocol's effectiveness against challenging infections, including those caused by multi-drug resistant bacteria.

Shionogi's Strategies for Addressing Antibiotic Efficacy and Resistance

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

the panel discusses therapies and care around inpatients including mechanical ventilation, extracorporeal membrane oxygenation (ECMO), and remdesivir.

COVID-19 THERAPY Roundtable: Addressing Inpatient Clinical Care

According to the Centers for Disease Control and Prevention, the week ending November 30, 2024, there has been a rate of 0.8 hospitalizations per 100,000 people, and this shows a good downward trend over the last few weeks.

Although the number of hospitalizations have decreased significantly since the beginning of the pandemic, there are waves where incidence rates increase and a number of people who are contracting severe cases of COVID-19 need to be hospitalized.

During the height of the pandemic and before the development of vaccines and therapies, there were therapeutic limitations and patients could be put on mechanical ventilation or extracorporeal membrane oxygenation (ECMO).

ECMO was utilized more frequently in a time when there was not other treatments. And in some select cases, roundtable panelist James Wilson, DO, FACP, FAWM, CTropMed, says ECMO did show some benefit, and there might be some select situations where it might be warranted but overall he says treatment protocols have changed considerably since 2020.

“If they're breathing at 40 times a minute for more than an hour, you're going to have to do it [ECMO],” Wilson. “But now we have modalities to treat those patients.”

One of the treatments that emerged was remdesivir for inpatients with severe COVID-19.

“I triage COVID between requiring oxygen and not requiring oxygen,” said Scott Roberts, MD, associate medical director of Infection Prevention, Yale School of Medicine. “And then once you become severe enough to require it, we really start remdesivir as soon as we can in the inpatient setting. And we know from many studies at this point there are reductions in mortality in those who do receive remdesivir. We use it for all really severe patients.”

This is episode 2 of our 4-part series. Check back for future episodes.

Reference
1.COVID Tracker. CDC. Accessed December 10, 2024.
https://covid.cdc.gov/covid-data-tracker/#covidnet-hospitalization-network

In this week's episode, the panel discusses therapies and care involving inpatients, including mechanical ventilation, extracorporeal membrane oxygenation (ECMO), and remdesivir.

COVID-19 Therapy Roundtable: Addressing Inpatient Clinical Care 

Jason M Pogue, PharmD, BCPS, BCIDP discusses the findings, pharmacokinetics, why ceftolozane-tazobactam may be the preferred choice for resistant infections, and more.

CACTUS Study Compares Ceftolozane-Tazobactam vs. Ceftazidime-Avibactam for MDR Pseudomonas

A newly published study, the CACTUS Study, compares the effectiveness of ceftolozane-tazobactam (CT) and ceftazidime-avibactam (CZA) in treating multidrug-resistant (MDR) 

 infections. The findings show that CT and CZA have similar clinical outcomes: 62% of CT-treated patients achieved clinical success, compared to 55% of CZA-treated patients. The overall 30-day mortality rates were also similar: 20% for CT and 19% for CZA.

In this first part of our interview with Jason M Pogue, PharmD, BCPS, BCIDP, clinical professor at the University of Michigan and investigator of the CACTUS Study we discuss the background and purpose of the study. The study involved 420 patients, with 210 matched pairs, ensuring robust statistical power to compare the two drugs’ efficacy.

Pogue discussed how CT and CZA are cephalosporins that have shown superior efficacy over older, more toxic treatments such as polymyxins and aminoglycosides, which have been previously used to treat resistant Pseudomonas infections. “Both of these agents are recommended in guidelines for the treatment of drug-resistant Pseudomonas. The reason they're included in these guidelines is that they have been shown to be superior to older treatments that were used before the availability of these novel cephalosporins.”

Before the CACTUS Study, some smaller studies compared CT and CZA, but these studies had significant limitations. Many had small sample sizes, inconsistent susceptibility testing, and heterogeneous patient populations. “Some of the studies haven’t routinely tested susceptibility to these two drugs, so you don’t even know whether or not they’re active all the time in patients who got it,” Pogue said.

Also, disease state could play a role in how patients respond to therapy. “Some disease states are more or less likely to respond to nuanced differences in therapies,” Pogue explained. For instance, if patients with urinary tract infections were included, any differences between the two drugs might not be observed, as both drugs concentrate well in the urine.

The CACTUS Study was designed to address these issues by focusing specifically on pneumonia and bloodstream infections, conditions where treatment could have a significant impact on patient outcomes. In addition, pharmacokinetics (PK) and pharmacodynamics (PD) differences between CZA and ceftolozane-tazobactam could influence treatment success, making these infection types ideal for comparison.

“We wanted to limit it to disease states where we thought therapy might have a big impact on outcomes,” said Pogue, adding that pneumonia was chosen due to these potential PK/PD differences. To ensure high-quality data, the study included 28 US sites with leading researchers in resistant gram-negative infections. “The reason we did that is because we were going to get good data, and that allows you to get significantly more numbers,” Pogue said.

One challenge with observational studies like CACTUS is dealing with biases such as indication bias or residual confounding, which can affect the interpretation of results. To minimize bias, the study used a matched-pair design. “For every CZA patient, they had a matched ceftolozane-tazobactam patient, and they were matched on severity of illness, infection type, and time to treatment initiation,” Pogue explained.

Patients treated with CT were more likely to receive longer infusions of the drug (≥3 hours), with 36% of patients receiving the prolonged infusion compared to just 19% of those on CZA (P=0.005). However, no significant differences were found between the two drugs regarding microbiologic failures, recurrent infections, or resistance development.

“We hypothesized that ceftolozane-tazobactam would be superior because of some of these PK/PD advantages,” said Pogue. “We adequately powered the study to show if there was a difference.” Despite the similar outcomes, the study’s robust design helps provide a clearer understanding of these two treatments and their comparative effectiveness.

Stay tuned for the next parts of our interview with Pogue, where we dive deeper into clinical success, mortality rates, treatment-emergent resistance, and more.

Shields RK, Abbo LM, Ackley R, et al. 1109. A multicenter, observational study to compare the effectiveness of Ceftazidime-Avibactam versus Ceftolozane-Tazobactam for multidrug-resistant Pseudomonas aeruginosa infections in the United States (CACTUS). Open Forum Infect Dis. 2023;10(Suppl 2):ofad500.082. Published 2023 Nov 27. doi:10.1093/ofid/ofad500.082

The CDC has confirmed the first severe human case of avian influenza (H5N1) in the US, involving a patient from Louisiana with a history of exposure to backyard poultry. This follows global patterns of severe illness associated with poultry contact. 

The patient is the first such case in the US to be severe enough for the person to be hospitalized. Thus far, all previous patients in confirmed cases have had mild symptoms not requiring hospitalization. The case was confirmed by the CDC on December 13, and the Louisiana Department of Health has not released additional information about the patient, citing privacy concerns.

The patient’s infection was identified as the D11 genotype of the virus, which is commonly found in wild birds and has previously been linked to severe cases in regions like Canada and Washington state. Unlike the B313 strain, which has caused milder symptoms in dairy workers exposed to infected cattle, the D11 genotype appears to be more serious.

Genetic testing is ongoing to assess whether any mutations indicate increased danger or potential human-to-human spread, but no other related cases have been reported so far. The CDC continues to assess the risk as low to the public. It is important to note that although the D11 genotype appears to be more virulent, there has been no person-to-person transmission of the virus detected.

 recently spoke to NIH’s National Institute of Allergy and Infectious Diseases (NIAID) Director Jeanne Marrazzo, MD, MPH, about mutations and human-top human transmission.

“The virus would still likely need to acquire additional mutations to acquire the ability to spread effectively among humans,” Marrazzo said.

With this first severe case, the US now has 61 confirmed human cases of H5N1. Last week there were 58 cases, with the overwhelming majority of cases confirmed in California. Just yesterday, California Governor Gavin Newsom declared 

“This proclamation is a targeted action to ensure government agencies have the resources and flexibility they need to respond quickly to this outbreak. Building on California’s testing and monitoring system—the largest in the nation—we are committed to further protecting public health, supporting our agriculture industry, and ensuring that Californians have access to accurate, up-to-date information. While the risk to the public remains low, we will continue to take all necessary steps to prevent the spread of this virus,” Newsom said in a statement.

In California, there have been 34 human exposure incidents in the state overall and all but 1 of the cases have been linked to commercial agriculture and related operations. The one outstanding case was classified as having an unknown source. These figures reflect the overall exposure risk in the state tied to agricultural and animal operations.

The proclamation follows the detection of additional bird flu cases in dairy cows. While the risk to the public remains low, the declaration aims to provide state and local agencies with the resources and flexibility needed to respond swiftly and effectively. 

For the Louisiana case, it has been determined that the patient had exposure to sick and dead birds in backyard flocks. This is the first case of avian infleunza in the US that has been linked to exposure to a backyard flock. A sporadic case of severe H5N1 bird flu illness in a person is not unexpected; avian influenza infection has previously been associated with severe human illness in other countries during 2024 and prior years, including illness resulting in death.

Reference
1. CDC Confirms First Severe Case of H5N1 Bird Flu in the United States. CDC press release. December 18, 2024. Accessed December 19, 2024.


https://www.cdc.gov/media/releases/2024/m1218-h5n1-flu.html


2. Governor Newsom takes proactive action to strengthen robust state response to Bird Flu. Published December 18, 2024. Accessed December 18, 2024. 

https://www.gov.ca.gov/2024/12/18/governor-newsom-takes-proactive-action-to-strengthen-robust-state-response-to-bird-flu/


3.Avian Influenza (Bird Flu). H5 Bird Flu: Current Situation. CDC. Updated December 17, 2024. Accessed December 18, 2024. 

https://www.cdc.gov/flu/avianflu/index.htm

The Centers for Disease Control and Prevention (CDC) has reported a case in Louisiana where the patient is hospitalized due to the virus, and had a history of exposure to backyard poultry.

The First Severe Case of Avian Influenza Confirmed in the United States

the panel weighs in on treatments not specifically indicated for COVID-19 treatment, including metformin, and concerns around using medications in this way.

COVID-19 Roundtable: Considering Off Label COVID Therapies

During the earliest stages of the pandemic, and before the development of antivirals and other therapies, clinicians were struggling to find ways to treat their patients. As providers began to use off-label treatments, small studies began to surface around various therapies including hydroxychloroquine, the antimalarial therapy, and the antibiotic, azithromycin. One published paper found these 2 therapies used in combination could help reduce viral loads.

And while clinicians quickly realized these therapies were not reducing symptoms or mortality, both disinformation and misinformation was prevalent enough and making the therapies out to be wonder drugs. These therapies’ efficacy for COVID-19 treatment were debated on social media for way too long.

Just this week, that aforementioned paper about hydroxychloroquine and azithromycin was finally retracted.The paper had been published in the 

International Journal of Antimicrobial Agents

 back in 2020, and the lead author was Philippe Gautret of the Hospital Institute of Marseille Mediterranean Infection. In the paper, it was claimed that hydroxychloroquine was able to reduce virus loads in COVID-19 patients, and that used in combination with azithromycin, was even more effective.

This year, there has been some studies looking at metformin as an off-label treatment for COVID-19. However, with limited data showing efficacy and potential adverse effects, our roundtable panel believes it is better to prescribe FDA approved therapies.

“I don't think there's an overwhelming amount of data that would support it. With metformin, there were two studies together that pretty much showed it wasn't effective,” said Michael Curulewski, PharmD, BCPS, BCIDP, BCGP infectious diseases and antimicrobial stewardship pharmacist, Endeavor health, Northwest Community Hospital. “One thing to keep in mind is anytime that we use an off-label therapy or a therapy that's not supported by a large amount of data, [or even] the safety profile is a major one for me—because a lot of the medications are not benign. Metformin, for example, we have to watch out for patients who have renal dysfunction, IV contrast exposure, and drug-drug interactions. So, without that data to support it, I would say I don't routinely endorse or recommend off-label therapies.”



This is episode 3 of our 4-part series. Check back for the last episode next week.

Reference
1. O’ Grady C. Infamous paper that popularized unproven COVID-19 treatment finally retracted. 

December 17, 2024. Accessed December 17, 2024. https://www.science.org/content/article/infamous-paper-popularized-unproven-covid-19-treatment-finally-retracted

In this week's episode, the panel weighs in on treatments not specifically indicated for COVID-19 treatment, including metformin, and concerns around using medications in this way.



Canonical

COVID-19 Roundtable: Should Clinicians Consider Off Label COVID Therapies?

Antibiotic- or antimicrobial-resistant (AMR)

 bacteria cause highly difficult to treat infections, draining both money and hospital resources. AMR develops after systemically treating bacterial infections with various unnecessary 

. Bacterial infections are usually treated dynamically, with antibiotics rapidly switched mid-treatment.

, sought to understand the effects of frequently changing antibiotic therapies in individual patients. “Clinicians often try a certain antibiotic for a defined time and then switch to a different antibiotic,” said study author Gregory Priebe, MD, “but how switching therapies affects antibiotic resistance is unknown.”

To track the changes and frequencies of AMR mutations over time, the investigators used a new technique they call resistance-targeted deep amplicon sequencing (RETRA-Seq). RETRA-Seq combines whole-genome sequencing with deep-sequencing. “RETRA-Seq tests the bacterial population as a whole, so it can detect these rare antibiotic-resistant bacteria with much higher sensitivity than routine clinical methods,” said Alex McAdam, MD, PhD, a co-author of the study.

samples collected serially from 7 patients. The sample donors were hospitalized at Boston Children’s and required mechanical ventilation at the onset of respiratory infection. Testing commenced at infection onset and continued for 4-11 days, during the course of antibiotic treatments. From the patients’ sputum samples, the investigators sequenced 420 cultured bacterial colonies.

The investigators found that small-scale antibiotic resistance waxed and waned as treatment therapies were changed. 

gene mutations changed rapidly, with AMR mutations emerging after antibiotic treatment began and disappearing within days of switching to another treatment.

The RETRA-Seq method revealed rare resistance mutations not previously detectable by clinically administered culture-based gene sequencing. The investigators found antimicrobial resistance could increase nearly 40-fold in 5-12 days in response to changing the patients’ antibiotics regimen.

Our results suggest that antibiotic cycling might be more effective at the level of individual patients,” said Priebe. “We are looking to use genomic surveillance to inform initial antibiotic therapy — both the type of antibiotic and the timing — and then to inform switches in antibiotic as the frequencies of antibiotic resistance mutations change.”

This study, and the RETRA-Seq technique, may pave the way for choosing an antibiotics course that will not drive antimicrobial-resistant gene mutations in dangerous bacterial infections. Such research is vital to prevent the growing threat of antibiotic-resistant bacteria and bolster 

Using real-time genetic surveillance, investigators found bacterial infections rapidly develop resistance to antibiotics, only to have these gene mutations disappear within a few days of switching to a different treatment.

Christine Slover PharmD

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