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A review of the current literature and future directions.

Long-Acting Anti-MRSA Agents: One Dose to Cure?

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

CEO Larry Sutton discusses SIDIPREV, a novel oxygen-based therapy aimed at preventing C difficile infections, with a focus on high-risk elderly patients and regulatory strategies to accelerate access.

Fighting C difficile Before It Starts: Lopoxy Therapeutics Approach

, Inc has acquired assets from Xeno Biosciences Inc. to advance its therapy SIDIPREV for preventing 

) infections in hospitalized patients. The acquisition includes regulatory filings, FDA correspondence, CMC data, intellectual property, and data from Phase I and Ib clinical trials showing the safety of the active pharmaceutical ingredient. This deal allows LPOXY to begin a Phase II study of SIDIPREV under the FDA’s Limited Population Pathway for Antibacterial and Antifungal Development (LPAD).

Larry Sutton, MD, PhD, physician scientist and CEO of Lopoxy Therapeutics, is leading efforts to address this growing health crisis. In our interview with Sutton, he shares the science behind their innovative therapeutic, SIDIPREV, and how it could transform the way we combat this difficult-to-treat, highly recurrent infection.

Larry Sutton begins by explaining that Lopoxy's mission is not simply to treat 

, but to prevent it from ever happening. “There have been some people that have tried this,” he says. “Sanofi and Pfizer both tried to prevent 

 by making vaccines, but they didn’t work in phase three. Most of the other people are just kind of resigned to the fact that you have to get it and then try to treat it. But the problem is, it’s highly recurrent, and it’s difficult to treat.”

Lopoxy believes the solution is to intervene before the infection has a chance to develop. “We think that through our technology, through raising the oxygen concentration in the gut—which is toxic to these anaerobic pathogens—we will prevent them from happening in the first place,” Sutton said.

SIDIPREV is a metered-dose oxygen delivery system specifically designed to be co-administered with antibiotics, which is the number one risk factor for developing 

 infections. “You take these at the same time, and that increased concentration of oxygen, which is toxic to 

, will prevent it from causing an infection,” Sutton said.

“Anybody of any age on any antibiotic can get this infection, because it’s a spore-forming organism. We breathe in and swallow spores from fungi, pollen, and other things every day. But elderly patients are more likely to get it, not necessarily as an independent risk factor, but because the older we get, the sicker we get, and the more vulnerable we are," Sutton said.

He continued, “So the most urgent need is in hospitalized elderly patients, and that’s what we’re targeting first. There’s no other therapy to prevent these infections in this group.” Their initial clinical trials will focus on elderly patients hospitalized with pneumonia—an infection that increases the likelihood of contracting a secondary 

 infection, especially when combined with antibiotic use.

Although, Sutton also points out that the risk extends beyond the hospital. “There are antibiotics out in the community that cause this too,” he says. “For example, like clindamycin, there’s 16% of people on clindamycin who will get 

 infections. It’s a very high risk, and it’s a great antibiotic—it’s on the WHO’s essential medicines list—but physicians are a little reluctant to prescribe it because of the risk for 

An important step in bringing SIDIPREV to market involves navigating the regulatory process. Sutton highlights the FDA’s Limited Population Pathway for Antibacterial and Antifungal Drugs (LPAD) as an important strategy for getting this innovative treatment into the hands of those who need it most. “LPAD is for situations like this, where there’s a high-risk group of people who don’t have any other therapeutic options,” Sutton said. “It’s a way to do a pivotal clinical trial and get a limited label for these high-risk people.”

If successful in their clinical trials, Sutton’s team would secure approval for SIDIPREV, but only for the specific population it’s designed to protect. “For example, if we are successful with this in elderly patients with community-acquired pneumonia who are on fluoroquinolones or ceftriaxone, we wouldn’t get a label to give it to anybody. We could only give it to those people, because they’re the high-risk ones,” Sutton explained. “But at least it gets it out there and begins to protect people.”

While the approval would be limited at first, Sutton sees this as a critical step forward. “It doesn’t stop us from going on and developing it in the more traditional way through Phase III trials,” he added. “We will do that for broader indications. But the LPAD pathway gets a way to get something on the market quickly to protect people.”

Stay tuned for part 2 of our interview coming soon.

LPOXY Therapeutics, Inc. Acquires Key Assets from Xeno Biosciences Inc. to Advance C difficile Prevention Therapy. January 4, 2024. Accessed January 10, 2024. 

https://firstwordpharma.com/story/5925021

CEO Larry Sutton, MD, PhD, discusses SIDIPREV, a novel oxygen-based therapy aimed at preventing C difficile infections.

The fall and winter months signal an increase in viral infections circulating among children and families, including influenza, COVID-19, and respiratory syncytial virus (RSV). Although RSV is a public health concern for individuals of all ages, infants and toddlers, especially those born prematurely or with compromised immune systems, and older individuals have particular vulnerability to severe complications. Each year, RSV accounts for more than 2.1 million outpatient visits in children younger than 5 years and more than 60,000 hospitalizations, making it the most common cause of hospital admission in children younger than 1 year.¹ In vulnerable groups, RSV can lead to severe conditions such as bronchiolitis, often resulting in emergency department visits and hospitalization. 

In an effort to protect these populations with high risk, the US Food and Drug Administration approved nirsevimab-alip (Beyfortus) in July 2023. Nirsevimab-alip is a monoclonal antibody administered as a preventive measure for all infants younger than 8 months whose mothers did not receive an RSV vaccine during pregnancy.² Despite recent advances in RSV prevention, effective antiviral treatments remain unavailable. Current treatment guidelines emphasize supportive care, such as oxygen supplementation, fluid management, and nutritional support when needed. Although aerosolized ribavirin is available, its use is limited by significant drawbacks. Ribavirin requires prolonged administration, is expensive, and raises safety concerns for health care providers due to potential teratogenic effects. Consequently, its role in clinical practice is minimal. These limitations highlight the urgent need for more practical and effective antiviral therapies in RSV management, extending beyond preventive options.

Ziresovir (AK0529) is a potent, selective RSV F protein inhibitor aimed at reducing the severity and duration of respiratory symptoms, leading to shorter hospital stays and fewer complications.³ Ziresovir is dosed based on body weight, with a minimum dose of 2 mg/kg necessary to achieve the suggested trough concentration of at least 130 ng/mL, which has been shown to correlate with improvements in clinical symptom scores and reduced viral loads.⁴ A recent phase 3 trial conducted in China evaluated the efficacy and safety of ziresovir therapy in children hospitalized with RSV infection. 

This randomized, double-blind, placebo-controlled trial was conducted across 28 hospitals in China. Participants were children aged 1 to 24 months hospitalized with confirmed RSV infection within 36 hours prior to receiving their first dose of ziresovir or placebo. Infants were excluded if they had positive test results for HIV, were coinfected with influenza or bacterial pneumonia, or had a known or suspected immunodeficiency. Participants were randomly assigned 2:1 to receive either ziresovir (n = 164) or placebo (n = 80), with both treatments administered every 12 hours for 5 days. Doses ranged from 10 to 40 mg, depending on body weight. The primary efficacy end point was assessed using the Wang Bronchiolitis Severity Score, which evaluates symptoms such as wheezing, respiratory rates, and the child’s general condition, from baseline to day 3. Secondary end points included reductions in RSV viral loads, symptom remission, and length of stay in the intensive care unit, if applicable. The trial was divided into 2 parts: The first focused on safety and pharmacokinetics, whereas the second evaluated efficacy. The safety analysis (part 1) included 302 participants, whereas the efficacy portion of the trial (part 2) evaluated 244 participants. Part 2 of the trial was initiated after part 1 was completed. Participants received ziresovir or placebo for 5 days, with a 9-day safety follow-up period. 

Findings from the phase 3 trial demonstrated that ziresovir had significant efficacy compared with placebo, offering a promising therapeutic option for infants and toddlers hospitalized with RSV (TABLE). The adverse event profile of ziresovir was minimal and comparable to that of placebo, suggesting a favorable safety profile (adverse event occurrences, 61% vs 53%). Additionally, resistanceassociated mutations were identified in the ziresovir treatment group. However, no correlation was observed between these mutations and viral rebound, indicating that the presence of resistance mutations did not affect viral load recurrence in these patients. 

There are some limitations to the study worth noting. First, there was a lack of multinational enrollment, with approximately 89% of the intention-to-treat population identifying as Han Chinese. This may warrant further studies across diverse global populations to ensure the broader applicability of the findings. Second, a common end point for assessing treatment response, time to discontinuation of supplemental oxygen, was not included whereas end points such as change in Wang bronchiolitis score and viral load were included. The former is not yet validated for RSV infection, and the latter is not regularly used in clinical practice. 

Given these limitations, readers should interpret the findings with caution regarding applicability across diverse patient populations and should consider that an alternative clinical scoring tool might have provided a more optimal measure of treatment response. However, the variables assessed are intuitive and frequently used in clinical practice, lending relevance to the study’s findings. Ultimately, these data contribute promising insights toward the development of more effective RSV treatment options, an area of critical need. Considering that the median time from symptom onset to the first dose was 4 days—when viral load is naturally declining—the timing of intervention is a critical factor in interpreting the efficacy of the antiviral. 

Like most antivirals, earlier administration is generally associated with greater effectiveness, as early intervention can actively inhibit viral replication before substantial immune response and viral decline occur. Given the delayed dosing in this study, it raises the question of whether the observed antiviral effect was due to the treatment itself or was partially attributable to the natural course of infection. Therefore, readers should consider that although promising, these results might reflect the antiviral’s potential in later stages rather than its full efficacy if administered earlier, underscoring the need for further studies exploring optimal timing of treatment initiation. 

As the use of nirsevimab-alip continues to grow for RSV prevention, the development and approval of an effective antiviral treatment, such as ziresovir, would be a significant advancement in managing severe cases. Although further research is necessary to confirm the efficacy and safety of ziresovir in more diverse populations, findings from this trial highlight its potential as a valuable therapeutic option in the fight against RSV.

1.Surveillance of RSV. Centers for Disease Control and Prevention. Accessed October 15, 2024. http://www.cdc.gov/rsv/php/surveillance/index.html
2.Dalton M. Respiratory syncytial virus (RSV). National Foundation for Infectious Diseases. September 14, 2024. Accessed October 15, 2024. http://www.nfid.org/infectious-disease/rsv/
3.Zheng X, Gao L, Wang L, et al. Discovery of ziresovir as a potent, selective, and orally bioavailable respiratory syncytial virus fusion protein inhibitor. 

. 2019;62(13):6003-6014. doi:10.1021/acs.jmedchem.9b00654
4.Zhao S, Shang Y, Yin Y, et al; AIRFLO Study Group. Ziresovir in hospitalized infants with respiratory syncytial virus infection. 

. 2024;391(12):1096-1107. doi:10.1056/nejmoa2313551

Findings from a recent phase 3 trial show promising results for
the approval of ziresovir in the treatment of respiratory syncytial virus in infants.

Publications

Respiratory Syncytial Viral Infection: Treatment With Ziresovir in Infants

The National Institutes of Health (NIH) updated its risk assessment for highly pathogenic H5N1 avian influenza A virus (HPAI H5N1) saying the risk to the general public remains low.

The NIH’s National Institute of Allergy and Infectious Diseases (NIAID) leadership including NIAID Director Jeanne M. Marrazzo, MD, MPH, and Michael G. Ison, MD, MS, chief of the Respiratory Diseases Branch in NIAID’s Division of Microbiology and Infectious Diseases said in a new commentary published in the 

, that people should find a balance between enhanced vigilance and “business as usual” with respect to avian influenza.

In the commentary, they discuss 4 strategies in how we can respond to the threat including:

1. “Collaboration among investigators in human and veterinary medicine, public health leadership, health care providers, and occupational authorities;

2. the urgent need for vigilant surveillance of emerging mutations and assessment of the threat of human-to-human transmission;

3. pursue development and testing of medical countermeasures; and

4. precautions to prevent infection are critical, including the use and optimization of PPE in occupational settings and education about the risk of contact with sick birds and animals.” 

(See below for some infection prevention strategies from Marrazzo.)

Thus far, the overwhelming majority of cases have been in farm workers who are working with cattle and poultry. All cases in the United States, except 1 have been classified as mild. The single case of severe avian influenza has been reported in a 65-year old person who had a different genotype of the virus, D11.

commentary, Marrazzo and Ison point out a case in Canada of a young girl who also had the D11 genotype and was hospitalized with a very severe case including having to be put on venovenous extracorporeal membrane oxygenation (ECMO). She had existing mild asthma and obesity and presented with conjunctivitis and fever and had progression to respiratory failure. After ECMO and treatment with antivirals, she recovered.

As of today, January 3, 2025, there have been 66 cases of avian influenza in the US according to the CDC’s website. And the agency points out there have only been zoonotic transmissions in humans and no human to human transmission. 

 recently who offered infection control prevention strategies for both farm workers and the general public.

“The CDC recommends avoiding direct contact with wild birds or other wild animals, especially if they appear to be sick or dead. Wild birds can also be infected with H5N1 and not appear sick, so it is better to observe them from a distance. People who live and work alongside domesticated animals which may be potentially infected, such as poultry or dairy cattle, can take extra precautions to avoid contact with infected animals and their contaminated environments. For example, wearing personal protective equipment can help dairy farm workers reduce exposure to infectious milk,” Marrazzo said.

“While there are no documented cases of humans directly catching H5N1 influenza from drinking raw unpasteurized milk, raw milk produced by cattle infected with H5N1 contains high levels of the virus. Fortunately, pasteurization appears to kill the flu virus. Because of the risk of exposure to the H5N1 flu virus, as well as other harmful diseases, people should not consume raw milk or products, such as fresh cheese, that are made with raw milk.”

In their commentary, Marrazo and Ison succinctly offer their assessment of where we are today at the beginning of 2025 as it regards to this strain of influenza.

“The CDC still designates the risk of HPAI A(H5N1) to most Americans as low. We do have candidate vaccines and antivirals available to try to mitigate severe influenza in the case of wider spread… The past weeks have seen more cases detected in more states as well as more persons with respiratory illness acquired through exposure to poultry or from an unknown source. Without a clearer understanding of the extent of exposure, infection, viral evolution, and transmission, we will be unable to properly protect our communities from a pathogen that has proven to be a formidable challenge to human and animal health,” they write.

1.Ison MG, Marrazzo J. The Emerging Threat of H5N1 to Human Health. 

. Published online December 31, 2024. doi:10.1056/NEJMe2416323
2. Parkinson J. CDC: Genetic Mutations of Avian Influenza Emerge in First Severe US Case Contagion. December 28, 2024. Accessed January 3, 2025. 


https://www.contagionlive.com/view/nih-mutation-in-avian-influenza-protein-could-enable-easier-human-infection-but-risk-of-infection-remains-low


3. H5 Bird Flu: Current Situation. CDC. January 3, 2025. Accessed January 3, 2025.
https://www.cdc.gov/bird-flu/situation-summary/index.html

The federal health agency stresses the importance of finding the balance between vigilance and enjoying normal activities. 

NIH Offers Updated Risk Assessment on Avian Influenza

In the United States, there are approximately 2 million outpatient visits related to community-acquired pneumonia (CAP) in the pediatric population as well as approximately 124,000 hospitalizations for children, annually.

 And CAP continues to be one of the most common reasons for hospitalizations in this patient group.

With concerns around CAP hospitalizations, investigators from the Children's Hospital of Philadelphia (CHOP) studied an intervention utilizing clinician feedback reports to evaluate the appropriate usage for antibiotics for CAP inpatients.

Typically, in the outpatient pediatric setting, these feedback reports have been used as a stewardship tool looking at individual performance says, study first author Kathleen Chiotos, MD, MSCE, assistant professor of Anesthesiology, Critical Care, and Pediatrics at the University of Pennsylvania Perelman School of Medicine and an attending physician in Critical Care Medicine and Infectious Diseases at CHOP. She explained using these reports in the inpatient setting and including group-level performances were novel concepts.

Chiotos said audit and feedback reports were generated monthly using a previously validated algorithm to both identify patients with CAP and discuss the antibiotic use.

“We delivered the reports both by email as well as during a monthly quality improvement meeting with our hospital medicine clinicians, which allowed for discussion around the report and recommendations for optimal management of CAP,” Chiotos said in an interview with 

The intervention showed increased improvement in clinician adherence to antibiotic recommendations. “Preintervention, 213 of 413 (52%) encounters received the appropriate antibiotic choice and duration, which increased to 308 of 387 (80%) postintervention,” the investigators wrote.

The investigators’ analysis demonstrated an 18% increase in adherence without any significant changes over time. Although there were no differences in the length of stay or hospital revisits, Chiotos points out the importance of the overall study.

"We showed that there was no difference in the rate of revisits or readmissions and that there was a slightly shorter length of stay during the post-intervention period, when antibiotic durations were shorter,” Chiotos said. “While not better outcomes per se, the fact that kids do just as well with a shorter duration and are at less risk of side effects is an important finding and a win for our patients.”

The investigators conducted a “quasi-experimental study” between December 2021 and November 2023 within CHOP. They used an “interrupted time series analysis (ITSA) to estimate the immediate change and change over time in the proportion of CAP encounters adherent to validated metrics of antibiotic choice and duration, then used Poisson regression to estimate intervention effect as a rate ratio (RR).” 

The investigators determined the specific antibiotic and duration using only data from the electronic health record (EHR). "Appropriate antibiotic choice was defined as administration of amoxicillin or ampicillin within the first 48 hours. If the patient was admitted to the PICU or had a concurrent diagnosis code for empyema or lung abscess, ceftriaxone was also considered appropriate. If the patient had a history of methicillin-resistant 

 (MRSA) infection or colonization within the preceding one year, any anti-MRSA antibiotic was also considered appropriate. For patients with reported beta-lactam allergy or beta-lactam antibiotic use within the preceding 28 days, any antibiotic was considered appropriate," the investigators wrote.

In addition to determining the right antibiotic and duration, Chiotos believes this novel application could be utilized further. “Because we were able to derive definitions for CAP as well as for appropriate antibiotic use using only data from the electronic health record—as opposed to manually reviewing charts—utilizing feedback reports such as these may be more feasible for stewardship programs.”

References
1. Katz SE, Williams DJ. Pediatric Community-Acquired Pneumonia in the United States: Changing Epidemiology, Diagnostic and Therapeutic Challenges, and Areas for Future Research. 

. 2018;32(1):47-63. doi:10.1016/j.idc.2017.11.002
2. Chiotos K, Dutcher L, Grundmeier RW, et al. Impact of clinician feedback reports on antibiotic use in children hospitalized with community-acquired pneumonia. 

. Published online December 3, 2024. doi:10.1093/cid/ciae593



Data detailing antibiotic choice and duration derived from electronic health records improved appropriate therapy use for community-acquired pneumonia. 

Clinician Feedback Reports on Antibiotics Shape Usage in Pediatric Inpatients With Pneumonia 

Exploring the challenges and strategies for combating MDR Pseudomonas aeruginosa infections, as discussed with Jason Pogue, PharmD, BCPS, BCIDP

Emerging Resistance in Pseudomonas Treatment: Key Insights from the CACTUS Study

, compared the effectiveness of ceftolozane-tazobactam (CT) and ceftazidime-avibactam (CZA) in treating multidrug-resistant (

 infections. The study found that both treatments had similar clinical outcomes. Of the 234 patients treated with CT, 

, compared to 55% for those treated with CZA. The 30-day mortality rates were also similar: 20% for CT and 19% for CZA.

In the final part of our interview with Jason M Pogue, PharmD, BCPS, BCIDP, clinical professor at the University of Michigan and investigator of the study, we discussed the high rates of emergent resistance observed in Pseudomonas treatments. Resistance developed in 1 in 5 patients, regardless of the treatment arm. Pogue noted that 

 resistance is driven by upregulated chromosomal mechanisms, rather than by transferable beta-lactamases. This type of resistance is more common in clinical settings where traditional agents like cefepime, meropenem, and piperacillin-tazobactam (piptazo) are not used, as these drugs often contribute to elevated resistance levels.

When asked about the high rates of resistance observed, Pogue emphasized the nature of 

 as a particularly challenging pathogen. He explained that the resistance seen with newer agents like CT and CZA is not unexpected, given the bacteria's ability to upregulate chromosomal resistance mechanisms.

“When we sat and looked at these results, when we first got them, we started thinking through them. This is what jumped out to us first: Regardless of what treatment arm you were in, you're giving this novel, or I guess at least novel-ish, since they're like, 10 years old now, novel agents for resistant 

, and one out of every five times in both arms, you're seeing resistance development.”

 is a jerk. I don't know how else to say this—it's kind of the nature of 

He further explained the biological mechanisms behind this resistance, "What's unique about 

 is a lot of the beta-lactam resistance that we see is driven by upregulation of chromosomal mechanisms of resistance. So, rather than passing beta-lactamases from one to another, the resistance is in the chromosome of the organism. And in the presence of certain things, notably antibiotics, you can see upregulation of these resistance mechanisms.”

Building on this, he clarified why resistance development should be viewed in the context of treatment settings, "It’s not shocking that this happens because, when you're using these drugs, you're already in a situation where resistance is present in the background. You’re just kind of taking it to the next level with these agents. And I think it’s important for us to think about the fact that this happens 1 out of 5 times. That’s kind of the nature of Pseudomonas.”

MICHAEL KENT, PHARMD

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