C3671023 Substudy A (NCT05842967)(MONeT Study) is a phase 3, randomized, double-blind, placebo-controlled trial assessing the safety and immunogenicity of Pfizer’s RSVpreF vaccine in high-risk adults aged 18-59 with chronic medical conditions, such as pulmonary, cardiovascular, hepatic, renal, and metabolic disorders, including diabetes mellitus.

The study aims to show that the immune response in this younger high-risk group is non-inferior to that of adults aged 60 and older, as established in the pivotal phase 3 C3671013 study that demonstrated the vaccine’s efficacy against RSV Lower Respiratory Tract Illness (LRTI).

At IDWeek 2024, Elliot DeHaan, MD, director in vaccines clinical research and development at Pfizer, Inc, and lead clinician on this study, highlighted the significant findings, “What we found in this trial was that in adults 18 to 59 years of age with comorbid conditions such as chronic pulmonary conditions such as asthma, COPD, cardiovascular disease, and diabetes, these individuals had similar immune responses to adults 60 and older who were enrolled in the Renoir trial in which we demonstrated efficacy of that vaccine. This technique is called immuno-bridging, and what we can confer from that immuno-bridging result is that we expect the immune response to be the same in these individuals.”

Participants were randomized in a 2:1 ratio to receive either one dose of RSVpreF (453 participants) or a placebo (225 participants). Serum samples were collected before and one month after vaccination and tested alongside samples from approximately 400 RSVpreF recipients in the C3671013 study. Reactogenicity events were monitored for seven days post-vaccination, while adverse events (AEs) were tracked for one month. Adverse events of special interest (AESIs), newly diagnosed chronic medical conditions (NDCMCs), and serious AEs were recorded throughout the study. Non-inferiority would be confirmed if the lower bounds of the 95% confidence interval (CI) for the adjusted Geometric Mean Ratio (GMR) of neutralizing titers (NTs) exceeded 0.667, and the lower bounds of the 95% CI for seroresponse rate differences exceeded -10% for RSV A and B.

DeHaan discussed the safety profile of the vaccine observed in the trial, particularly for the high-risk population, “the most common solicited local reaction in our sub-study A was pain at the injection site, reported by around 35% of vaccine recipients. The two most common systemic solicited events were fatigue and headache. These results were very similar to those in other trials, indicating consistent tolerability and safety.”

Proportions of participants experiencing local reactions were higher in the RSVpreF group, while systemic events were similar across both groups. Rates of participants reporting any AEs were comparable between the RSVpreF and placebo groups during the month following vaccination and throughout the study.

One month after vaccination, neutralizing titers (NTs) for RSV A and B in high-risk adults aged 18-59 were non-inferior to those in adults aged 60 and older, meeting the criteria for non-inferiority in seroresponse rates. RSVpreF was well-tolerated with no significant safety concerns and demonstrated immunobridging to efficacy in the younger high-risk group compared to older adults. These findings support the use of RSVpreF for preventing RSV lower respiratory tract illness (LRTI) in adults aged 18-59 with high-risk conditions.

DeHaan discussed the implications of these results for future RSV vaccination efforts, especially considering the rising burden of RSV in adults, “we are aiming for approval in adults aged 18 to 59 with comorbid conditions. If granted, this would be the broadest indication for an RSV vaccine in this population. We’re hopeful for this and expect a decision in the fourth quarter of this year.”

Reference

DeHaan, Davis M, Towner W, et, al. Immunobridging Demonstrating Effectiveness of the Bivalent Respiratory Syncytial Virus (RSV) Prefusion F Subunit Vaccine in Adults 18-59 Years of Age at High Risk of Severe RSV Disease in a Phase 3 Trial: The C3671023 MONeT Study Results. Poster #596 was presented at IDWeek 2024. October 16-19, 2024. Los Angeles, CA.

Neonates are greatly susceptible to contracting RSV and developing severe disease in the earliest stages of life.

“They get bronchiolitis, they get pneumonia, and they’re hospitalized when they have trouble breathing and they need oxygen support,” said Helen Chu, MD, MPH, professor of Medicine, Epidemiology, and Global Health at the University of Washington. “For the last several decades, the number 1 cause of hospitalizations of infants in the United States was RSV infection. So it is a significant burden, both on the parents and the caregivers of these infants, and also on the healthcare system.”

At ID Week 2024, Chu participated in a symposium, A Whole New World? Respiratory Syncytial Virus in the Vaccine and Monoclonal Antibody Era. Later that same day, she sat down with Contagion to discuss some of the nuances between the maternal vaccine and monoclonal antibody.

In the last few years, there has been significant development in this area. And currently, there is 1 monoclonal antibody (nirsevimab-alip (Beyfortus), Sanofi/Astra Zeneca) and 1 maternal RSV vaccine (Abrysvo, Pfizer) that are both FDA approved to prevent lower respiratory tract disease in neonates.

“Both the maternal vaccine and the monoclonal antibody are designed to protect the infant in the first few months of life, specifically protecting against severe disease that requires hospitalization, and they are both highly effective in doing that,” Chu said. “In the clinical trials of the maternal vaccine, the efficacy against RSV hospitalization was around 60% to 70%. That number was very similar for the monoclonal antibody that’s given at birth to infants, also 60 to 70%, in the clinical trials. We now actually have more data from this first season, because both products are out, and it seems as though the monoclonal antibody is still looking like that out in the community. In studies from Europe, the effectiveness of the monoclonal antibody is 70% against hospitalization. So, if you think about that, it’s really the number of hospitalizations of infants in Europe has gone down dramatically because of receipt of nirsevimab.“

While there is great protection afforded both immunizations, she points out to some of the nuances between the 2 for delivery.

“The maternal vaccine is given during pregnancy. Right now, the recommendation in the United States is to give it between 32 and 36 weeks gestation, and the idea is then it protects the baby through antibody that’s transferred across the placenta, and then the antibody stays in the baby system for the first 4 to 6 months after birth,” Chu said. “This is different from the monoclonal antibody, nirsevimab, which is given when the baby is born, and then directly administered to the baby, and it also lasts 4 to 6 months.”

“In terms of logistics, I think there’s a couple of things that are challenging. First of all, the maternal vaccine has to be given during this very narrow gestational window—32 to 36 weeks in your OB’s office. So that is hard to do. Uptake was quite low—below 20% for nirsivimab. There have also been a lot of challenges, mostly related to the fact that you really need to give it very early in life to protect the infant, because they get very sick at a very young age, and being able to get it during the birth of the infant before they get discharged would be the best way to do that, but it’s a very expensive product, and right now, the reimbursement isn’t worked out.”

To learn more about RSV vaccines and monoclonal antibodies, check out our roundtable on the subject.

The distribution and prevalence of tick-borne diseases (TBDs) are influenced by climate factors, especially temperature and humidity, which play a significant role in tick survival and activity. Understanding the impact of these climate factors on TBDs is essential for public health preparedness. This study examined trends in TBDs in New Jersey over the past two decades.

At IDWeek 2024, Evelyn Wu, MD, resident at Stanford Health Care, shares insights into the background that influenced their study: “According to the CDC, the tick season runs from April through September, and the reason why there’s a tick season in the first place is because tick survival and host seeking activity are heavily dependent on climate. Generally speaking, ticks prefer warmer and wetter conditions. So some of the common tick-borne diseases in New Jersey include Lyme disease, babesiosis, anaplasmosis, Ehrlichiosis, and Rickettsial diseases. And if any of these cases are identified, they have to be reported to the New Jersey Department of Health.

The study found that diseases transmitted by Ixodes scapularis saw a significant increase during the off-season. In contrast, diseases spread by Amblyomma americanum and Dermacentor variabilis did not show significant increases during this period. During the in-season, case counts for all reportable tick-borne diseases, as well as those transmitted by Ixodes scapularis and Dermacentor variabilis, remained stable. However, diseases transmitted by Amblyomma americanum did experience a significant increase in the in-season.

Overall, cases of tick-borne diseases have significantly increased over the study period, particularly during the off-season (October to March; p < .01). Conversely, no significant increase was noted during the in-season period (April to September; p > .05).

Wu discussed the most significant findings from the research on climate variability and tick-borne diseases in New Jersey: “If I were to sum it up in one sentence, I would say that we’re seeing increases in tick-borne diseases, and the season for ticks seems to be expanding as well, and these trends do seem to be correlated with warmer and wetter conditions.”

A sub-analysis by vector showed significant increases in diseases transmitted by Ixodes scapularis (Deer Tick), including babesiosis, Lyme disease, and anaplasmosis, especially during the off-season (p < .01). In contrast, diseases transmitted by Amblyomma americanum (Lone Star Tick), such as Ehrlichiosis, significantly increased during the in-season (p < .001). There was no significant increase in diseases transmitted by Dermacentor variabilis (American Dog Tick), which includes Spotted Fever Group Rickettsiosis (p > .05). Additionally, univariate Poisson regression analysis indicated a positive correlation between all tick-borne diseases and both average temperature and total precipitation.

Wu discussed how the findings impact public health strategies in NJ and potentially in other regions facing similar climate challenges, “Since we are seeing the tick season expanding, I think one effective way to do this is just by increasing awareness of this issue, and one good way to do that is through education. In fact, New Jersey, just last year, passed a bill that mandated the development and implementation of a curriculum in all public schools around ticks and tick safety.”

The study gathered case counts for reportable tick-borne diseases (TBDs) from the New Jersey Department of Health from 2003 to 2022, amounting to 85,905 cases. We also collected climate data from the publicly available nClimDiv dataset.

The findings indicated that total case counts of reportable tick-borne diseases, as well as cases of diseases transmitted by Ixodes scapularis (Lyme disease, Babesiosis, Anaplasmosis), Amblyomma americanum (Ehrlichiosis), and Dermacentor variabilis (Spotted Fever Group Rickettsiosis), showed a significant positive correlation with both average temperature and total precipitation in univariate analysis. In the multivariate analysis, only diseases transmitted by the American Dog Tick were positively correlated with both climate factors. In contrast, diseases transmitted by Ixodes scapularis and the Lone Star Tick were positively correlated only with average temperature

Wu emphasized the importance of prevention, “I think prevention will be key. And by prevention, I don’t mean to stay inside and never step foot outdoors again, but it’s just making sure that we’re following tick safety precautions as much as we can. This means making tick checks a part of your routine after going outside, and it includes checking your pets if you brought them with you, wearing lighter clothing, and wearing long pants when you can to prevent ticks from sticking to you. And then just making sure you don’t let your guard down in the winter months. If we really want to get down to the heart of the issue, though, it is to do your part to slow down and prevent climate change, whatever that might look like in your own personal life.”

The findings indicate a rising trend in tick-borne diseases in New Jersey, correlated with average temperature and precipitation. The sub-analysis reveals vector-specific patterns, showing that diseases transmitted by Ixodes scapularis predominantly increase during the off-season, while those transmitted by Amblyomma americanum rise during the in-season period. These results emphasize the importance of remaining vigilant for TBDs during traditionally low-risk months and highlight the need for proactive strategies to address the impact of climate factors on TBD transmission.

Wu concluded with recommendations for communities to mitigate the risks of tick-borne diseases as climate patterns change: “I think this study highlights the importance of multidisciplinary collaboration when it comes to something as complex and multifactorial as tick-borne or vector-borne diseases. I think we really relied on the insights of our public health colleagues who provided insights on the type of data that they had available. Our climatologists taught us so much about the nuances of the climate parameters they had. They taught us that total precipitation isn’t the most ideal proxy for humidity because of its variability in geographical and temporal aspects.”

Reference

Wu E, et, al. There’s an uptick!: Increasing Cases of Tick-Borne Diseases Transmitted by Ixodes scapularis in New Jersey. Poster 1283 presented at IDWeek 2024. October 16-19, 2024. Los Angeles, CA.

The ongoing PROVE retrospective chart review study aims to assess real-world outcomes of cefiderocol treatment in patients with serious Gram-negative bacterial infections. At IDWeek, Cornelius (Neil) Clancy, MD, a professor of medicine at the University of Pittsburgh, presented findings demonstrating that cefiderocol has proven to be both effective and well-tolerated in treating serious Gram-negative bacterial infections in real-world settings, particularly among patients with high rates of ICU admissions and the need for organ support.

“These are serious infections in very sick patients,” Clancy noted. “The PROVE study had two primary major findings. One is that overall, it was quite effective in treating these very difficult-to-treat infections, which were largely caused by priority pathogens identified by WHO, such as Pseudomonas and Acinetobacter. These pathogens are associated with high rates of resistance to other antibiotics. The clinical success rate in the study overall was 75%, which is extremely good, and clinical success was observed in various types of
Infections, respiratory tract infections, urinary tract infections, and bloodstream infections.”

The study involving 1,075 patients with carbapenem-resistant infections, cefiderocol emerged as a key treatment option, demonstrating a clinical cure rate of 64% and a response rate of 71.6% by the end of treatment (EOT). Notably, 90.1% of these patients had at least one risk factor for their infections, and 59.8% were hospitalized in ICUs, with 48.1% requiring organ support.

Clancy continued, “We have very encouraging real-world data regarding the types of infections that clinicians are treating in hospitals throughout the country and around the world. The second major finding was how well tolerated, and safe the drug appeared. In over 1,000 patients, there were a total of three serious adverse drug reactions and only 13 patients discontinued use of the drug. This combination of safety and efficacy for the most difficult-to-treat infections we have is quite promising and offers a strong complement to previously published randomized clinical trial data.”

Cefiderocol was administered as first-line therapy in 70.3% of cases, with a median treatment duration of 11 days. The most common site of infection was the respiratory tract, accounting for 54.1% of cases, with Pseudomonas aeruginosa (35.3%) and Acinetobacter baumannii (19.6%) identified as the most frequently occurring pathogens in monomicrobial infections.

The study revealed varied outcomes based on infection type: patients with respiratory tract infections (RTIs) exhibited clinical cure and response rates of 58% and 68%, respectively, while those with bloodstream infections (BSIs) achieved slightly better rates of 66.7% and 74.1%. In terms of mortality rates, 31% of RTI patients and 18.5% of BSI patients succumbed to their infections by day 30. Among those infected with Pseudomonas aeruginosa, 67% achieved clinical cure, yet 22.3% died within the same timeframe.

“I think the real-world data that are presented in the PROVE study are a complement to randomized clinical trial data, which were used to get approval and for regulatory reasons for the drug initially, and they reflect really more realistically how the drug is and will be used in real patients in real-world settings,” Clancy stated.

Regarding infection complexity, clinical cure rates were 63.6% for monomicrobial infections and 65% for polymicrobial infections. The all-cause mortality (ACM) rates at days 14 and 30 were 15.6% and 24.3%, respectively, with ACM rates at day 30 of 25.6% for monomicrobial and 20% for polymicrobial infections.
Clancy concluded, “With any new drug, as more experience is gathered with using cefiderocol across different types of infections, bacteria, and patient populations, we’ll continue to understand where it fits within the armamentarium. What the PROVE study shows is that when used appropriately for the correct types of infections, there is a role for cefiderocol in treatment that patients will tolerate it well and it’s safe.”

Reference

Clancy, Neil. Real-World Effectiveness and Safety of Cefiderocol in the Treatment of Patients with Serious Gram-negative Bacterial Infections: Results of the PROVE Chart Review Study. Poster 1475 presented at IDWeek 2024. October 16-19, 2024. Los Angeles, CA.

In this article an infectious diseases pharmacist discusses 5 examples where challenging antibiotic workflows can be an issue. 

Authored By: Timothy P. Gauthier, Pharm.D., BCPS, BCIDP

Article Posted October 2024, First Released in the October 2024 IDstewardship Newsletter

1. The time it takes to make a dose of Amphotericin B

Not giving Ambisome today but the order is active as if one is due? Discontinue that order, save a pharmacy tech 15 minutes of wasted time plus avoid tossing an unnecessary dose! Amphotericin products vary, but for example Ambisome comes in 50 mg vials so a 500 mg dose requires 10 vials. Each vial has to be reconstituted and then individually filtered as it goes into the IV bag. That means 10 filters for that one dose! It’s a real pain and a lot of manipulation for the tech. Amphotericin B is also reconstituted in D5W only so that creates workflow challenges as well for nurses who may need D5W for flushing the line before/after the dose. You can read about the preparation here. The final product looks like orange juice.

2. The short expiration date of IV Bactrim

Not only does IV SMX/TMP bring a large volume load of D5W and cause a fair amount of hyperkalemia, it also is a major pain to avoid having it expire. The expiry on a mixed bag depends on the concentration of the dose. Doses of 5 mL per 100 mL D5W should be used within 4 hours of preparation. Doses of 5 mL per 75 mL D5W should be used within just 2 hours of mixing! Remember SMX/TMP is dosed based on mg/kg of the trimethoprim component and should be given over 60-90 minutes. Also fun fact, IV SMX/TMP does not require refrigeration once mixed, so it gets a “DO NOT REFRIGERATE” sticker, at least that is more convenient. Read all about this in the product label here .

3. Special handling of IV ganciclovir

New ganciclovir order at 9 PM is no big deal right? Well, maybe not. Hazardous products such as chemo are prepared under more controlled conditions  than other agents to protect the person making the dose. Go figure a drug with the brand name Cytovene happens to be cytotoxic. Depending on how an IV room pharmacy is set up, certain equipment may have to be turned on, left to run for a time, cleaned, then a dose can be prepared. It’s not a fast process and may even require going to another section of the hospital to complete the work. More information on ganciclovir in the label here .

4. When antibiotic stability varies by product

The same drug at the same dose has the same expiration date all the time, right? Wrong! Products can impact stability. This can relate to premixed bag versus vial or when using certain vial adaptor products to connect a vial directly to a bag. One example is IV meropenem 1 gm duplex containers (like a premixed bag) that must be used within 1 hour once activated if stored at room temperature. Compare that to a 1 gm meropenem vial that once diluted has stability data for 3 hours at room temperature. These types of nuances can create workflow challenges if you are trying to do extended infusions, especially during product shortages.

5. Compounding sulbactam-durlobactam

Admittedly I have never compounded this one myself, but it just sounds like an error waiting to happen as well as a considerable time commitment. To prepare a dose of this product you have to use a kit that includes a clear single-dose of sulbactam 1 gm as well as 2 amber single-dose vials of durlobactam 0.5 gm. The process is detailed in the package insert here . For any site not using SUL/DUR frequently (which is probably many), expect some confusion and added time for the IV room when this order comes in.

Have another one? Put it on X and tag @IDstewardship!

Disclaimer: The views and opinions presented in this article represent those of the author and do not necessarily reflect the policy or position of any previous, current, or potential future employer.

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