Division of Infectious Diseases

#PharmToExamTable: What is cefiderocol, and when should I think about using it? 

A #PharmToExamTable question about cefiderocol and its clinical uses, answered by Aaron Hunsaker, PharmD, a previous PGY1 pharmacy resident at UNMC and current PGY2 pharmacy resident a the University of Utah Health.

(Reviewed by Andrew Watkins, PharmD)

In the area of increased gram-negative bacterial resistance, practitioners have longed for a horse with which they could ride into battle. Cefiderocol, or Fetroja, could possibly be that fix. The brand name even hints to its novel mechanism and their website pulls on this, showing Roman soldiers going into battle with their trojan horse. The goal of this review is to summarize the pharmacology, pharmacokinetics, and literature of cefiderocol and where it has the potential to be used. 

Pharmacology1

Mechanism of action: Cefiderocol is a cephalosporin that has activity against gram-negative aerobic bacteria. Like other beta lactam antibiotics, it enters the cell via passive diffusion through porin channels. It also functions as a siderophore and binds extracellular free iron. This allows cefiderocol to enter the cell via bacterial siderophore iron uptake, which allows the molecule to overcome porin channel deletions. 

Recommended Dosage: 2 grams every 8 hours infused over 3 hours 

Primary Literature Review: 

APEKS-cUTI by Portsmouth et al 2

This is a phase 2 clinical trial that compared cefiderocol to imipenem-cilastatin for the treatment of complicated urinary tract infections (cUTI) caused by gram-negative bacteria.  With a sample size of 371, Cefiderocol was a non-inferior treatment compared to imipenem in the treatment of cUTI.

APEKS-NP by Wunderink et al 3

This was a phase 3 clinical trial that compared cefiderocol to extended infusion meropenem for the treatment of gram-negative nosocomial pneumonia. The trial was able to recruit 251 participants, among which the most common pathogen was Klebsiella pneumoniae (32%) followed by Pseudomonas aeruginosa (16%). This was a relatively sick population with a majority of patients in the ICU at baseline (77%). Cefiderocol was also non-inferior to extended infusion meropenem in prevention of mortality from nosocomial pneumonia infections. The safety profile was similar between the two medication groups.

CREDIBLE-CR by Bassetti et al. 

This is a phase 3 descriptive trial that studies the efficacy and safety of cefiderocol to best available therapy for the treatment of serious infections caused by carbapenem-resistant gram-negative bacteria. Among the 150 recruited participants, the most common source of infection was nosocomial pneumonia (45% in both groups) followed by bloodstream infections (~30-35% in both groups). Acinetobacter baumannii and Klebsiella pneumoniae were the two most common carbapenem-resistant gram-negative pathogens. Clinical cure for nosocomial pneumonia occurred in 60% cefiderocol treated patients (24/40) and 63% in best available therapy treated patients (12/19). Clinical cure for bloodstream infections or sepsis occurred in 70% of cefiderocol treated patients (16/23) and 50% in best available therapy (7/14), but all-cause mortality was higher in the cefiderocol group when patients had an infection caused by Acinetobacter spp. or in pulmonary and bloodstream infections, but not with cUTIs.

Conclusion:

Cefiderocol is a novel cephalosporin that has a broad spectrum of activity against gram negative organisms. However, what do these differences in data mean for the future of cefiderocol? Well:

  • APEKS-cUTI and APEKS-NP showed that cefiderocol can be used in complicated urinary tract infections and pneumonia caused by multi drug resistant gram-negative organisms.
  • All three trials showed positive outcomes in infections caused by Klebsiella pneumoniae, Pseudomonas aeruginosa, and Escherichia coli. APEKS-NP also showed us the potential use of cefiderocol in a relatively sick patient population. 
  • However, the CREDIBLE-CR trial complicates the recommendation for the use of cefiderocol in patients with a pulmonary infection and bloodstream infection, especially infections caused by Acinetobacter spp. andStenotrophomonas. 

While the differences were likely significant, it is important to note that no statistical tests were run, the trial was an open labeled study, and the patient population was small, leaving us with a desire for more data to further support the use of cefiderocol in these types of infections. Therefore, the use of cefiderocol in pulmonary infections or bloodstream infections should be used with caution and if it is considered, it should be used as a last-ditch effort. Further studies with larger populations and statistical analyses are needed to fully make a recommendation. 

References:

  1. Cefiderocol Drug Information. https://online.lexi.com/lco/action/doc/retrieve/docid/patch_f/6884009?cesid=aEKKkaNZrPz&searchUrl=%2Flco%2Faction%2Fsearch%3Fq%3Dcefiderocol%26t%3Dname%26va%3Dcefiderocol. Accessed October 20th, 2020
  2. Simon Portsmouth et al. Cefiderocol versus imipenem-cilastatin for the treatment of complicated urinary tract infections caused by Gram-negative uropathogens: a phase 2, randomised, double-blind, non-inferiority trial. Lancet Infect Dis. 2018 Dec;18(12):1319-1328. doi: 10.1016/S1473-3099(18)30554-1.
  3. Richard G Wunderink et al. Cefiderocol versus high-dose, extended-infusion meropenem for the treatment of Gram-negative nosocomial pneumonia (APEKS-NP): a randomised, double-blind, phase 3, non-inferiority trial. Lancet Infect Dis. 2020 Oct 12;S1473-3099(20)30731-3. doi: 10.1016/S1473-3099(20)30731-3.
  4. Matteo Bassetti et al. Efficacy and safety of cefiderocol or best available therapy for the treatment of serious infections caused by carbapenem-resistant Gram-negative bacteria (CREDIBLE-CR): a randomised, open-label, multicentre, pathogen-focused, descriptive, phase 3 trial. Lancet Infect Dis. 2020 Oct 12;S1473-3099(20)30796-9. doi: 10.1016/S1473-3099(20)30796-9

Graduating Fellows’ Last Words – Dr. Laura Selby

The following content was provided by graduating UNMC ID fellow, Dr. Laura Selby (pictured left).

Dr. Selby will be transitioning to an infectious diseases faculty position in Bend, Oregon. Congratulations Laura!

If one word could sum up my clinical experience of the last two years of Infectious Diseases fellowship it would be “pandemic”. When I moved to Nebraska and started training at UNMC in July of 2020, the United States was only a few months into the COVID-19 pandemic. There was limited evidence for what treatments worked best, vaccines were not yet available, and PPE shortages continued to make news nationwide.

So much of my learning as an ID fellow happened through the lens of COVID. I learned how to treat multi-drug resistant secondary bacterial pneumonia from COVID patients. Differentiating viral vs bacterial infections was nearly every COVID consult. Hospital epidemiology and infection prevention lessons were learned through COVID outbreak investigations. I worked on my patient communication skills by explaining the importance of COVID vaccination to my HIV Clinic patients. My research projects pivoted to, you guessed it, COVID.

This is not to say that I wasn’t well trained in all areas of Infectious Diseases during my fellowship. With the notable exceptions of low influenza rates, and travel medicine consults, throughout the pandemic people still had bacteremias, prosthetic joint infections, neutropenic fevers, and newly diagnosed HIV requiring ID consultation and management. Patients still got cancer treatment and organ transplants, so my experience with immunocompromised hosts wasn’t compromised (no pun intended). Yet, for nearly every diagnostic mystery consult, COVID was added to my differential right next to syphilis, TB, and histoplasmosis.

Amid the stress, overwork, and death that the COVID-19 pandemic has brought, watching the faculty of the UNMC ID Division practice and model compassion for patients, evidence-based medicine, and conduct research, all while still finding time to give lectures and teach on rounds, has shaped me as a physician and a person. I could fill pages with all the lessons I have learned from each of the standout faculty at UNMC such as learning the intricacies of randomized controlled trials from Dr. Andre Kalil during journal club and rounds, training in high consequence pathogen preparedness and PPE with Drs. Elizabeth Schnaubelt, David Kline, and Angela Hewlett, lessons on travel medicine with Drs. James Lawler and David Brett-Major while rounding on patients who haven’t traveled (thanks COVID), diagnostic stewardship skills from Drs. Trevor Van Schooneveld and Kelly Cawcutt, how to conduct a hospital outbreak investigation from Dr. Mark Rupp, employee health management in a pandemic with Dr. Rick Starlin who was also a wonderful research mentor, how to practice evidence-based medicine when the evidence is questionable at best from Dr. Nicolas Cortes-Penfield, management of patients with HIV from Drs. Sara Bares, Nada Fadul, Sue Swindells, and Jasmine Marcelin, and all the other amazing faculty I have neglected to name.

As I prepare to leave fellowship and move onto the next stage of my career, I am grateful that I had the opportunity to train at such an amazing program. It has been a privilege to work with the UNMC Infectious Diseases Division.

– Dr. Laura Selby, Graduating UNMC ID Fellow, June 2022

Conference Recap: Annual HIV Update for Providers and Educators Returns

The UNMC Annual HIV Update for Providers and Educators returned on June 9, 2022. The conference was not hosted in 2020 and 2021 due to the COVID-19 pandemic. This year, the UNMC HIV team joined forces with the DHHS HIV PrEP Institute team to provide a day-long event focused on HIV TREATMENT and PREVENTION.

For the first time, the conference was hosted as a hybrid event with approximately 60 attendees in person, and over 100 attendees registered in the interactive virtual forum. 

Honored presenter Dr. Susan Swindells (second from the left) and other conference contributors

The morning was focused on What’s New in HIV Care with a fantastic summary of up to date treatment recommendations and review of clinical trials, with honored presenter Dr. Susan Swindells. A “hot topics” session covered STI Treatment Guidelines, Weight Gain on ART, and the intersection of COVID-19, HIV, and health disparities. The morning was rounded out with panel discussions related to team based approach to address psychosocial barriers to care, as well as long-acting ART.

Panel of speakers featured at the afternoon session focusing on PrEP and HIV prevention.

In the afternoon, we switched gears to focus on HIV prevention, particularly PrEP. The presenters highlighted PrEP in special populations including adolescents and Native Americans. We heard from a team that has initiated a new PrEP project to make this tool accessible to people across Nebraska, as well as a panel of patients familiar with PrEP. Finally, we heard about the importance of “Rebranding PrEP” to increase interest and uptake across populations. 

We would like to acknowledge the teams that made this hybrid conference and continuing education possible: UNMC/Nebraska Medicine, Nebraska AIDS Project, Omaha Childrens’ Hospital, Ponca Tribe Heath Services, UNO, DHHS, Midwest AIDS Training and Education Center Kansas/Nebraska, Washington University, KC Care Clinic, University of Cincinnati, St. Louis PTC, Entertainment LIVEstyle, and all of our speakers, moderators, panelists, organizers, vendors, and attendees. 

If you would like to learn more about the 2022 HIV Update and PreP Institute Conference, or want to get involved in future conferences, please contact nregan@nebraskamed.com.

Content and photos for this post were kindly provided by Nichole Regan, APRN-NP

In Case You Missed It: UNMC Clinic to Offer Walk-in Testing Tomorrow and Friday in Observance of National HIV Testing Day

In case you missed it, tomorrow (6/30) and Friday (7/1) from 1:00pm to 4:00pm the Specialty Care Clinic will be offering walk-in HIV testing, with no appointment needed.

Read on below for our previous post with details about this event.

The following content was provided by Kevin Borges, UNMC Specialty Care Clinic Manager. Graphic obtained from the CDC.

Thursday (6/30) and Friday (7/1) from 1:00pm to 4:00pm the Specialty Care Clinic will be offering walk-in HIV testing, with no appointment needed.

Each year, June 27th is observed as National HIV Testing Day (NHTD).  This year’s NHTD theme is “HIV Testing is Self Care.”  The act of getting tested is the first step in either treatment or prevention that leads to individuals being empowered to live long and healthy lives.  

The Nebraska Medicine/UNMC Specialty Care Clinic specializes in the prevention and treatment of HIV.  Our clinic is staffed with doctors, nurse practitioners, pharmacists, nurses, social workers, and more!  We are all here to provide the highest level of care in a judgement-free atmosphere.  There is a wide range of prevention and treatment options available and we would be happy to review your best options with you.  If you or someone you know could potentially benefit from HIV testing, we invite you to our clinic.  On the afternoons of Thursday 6/30 and Friday 7/1 from the hours of 1:00pm to 4:00pm we are opening our doors to walk in HIV testing, with no appointment needed.  Our clinic is located at 804 South 52nd Street Omaha, NE 68106.  We can also be reached at 402-559-2666.  We look forward to serving you.

Graduating Fellows’ Last Words – Dr. Jonathan Ryder

The following content was provided by graduating UNMC ID fellow, Dr. Jonathan Ryder (pictured left).

Dr. Ryder will be transitioning to an instructor faculty position at UNMC. Congratulations Jonathan!

“As the seasons change, sometimes they blur together, nearly indistinguishable from each other. Yet, some seasons have such stark contrast, it’s hard to miss the transition. As I approach another transition in my life, the end of infectious diseases fellowship and the start of a career, I imagine the transition will be simultaneously smooth and jolting.

The first day as an unsupervised attending physician, questioning my own decision-making. The first research project as the primary mentor, looking for the next steps. Learning new leadership roles. Being seen as an expert. Managing meetings and lectures with clinical duties and projects. These new roles and duties may be a bit jolting at first.

While these parts of the future feel daunting, I’m re-assured by the superb training I’ve received, which gives me confidence the transition will be quite smooth. I have already been afforded opportunities to act as the attending. I have worked with invaluable mentors who have paved the way for me to conduct further research as part of a team. Further, I know I have many mentors I can fall back on with questions, as truly the journey has just begun. I’ve already been juggling multiple responsibilities for the past several years. Ultimately, as I will be staying at UNMC, I already am familiar with many of the processes and the environment.

So, what does my future hold? I will be transitioning to an instructor faculty position at UNMC. This position affords me the opportunity to focus on research endeavors within my interests of antimicrobial stewardship, infection control, and medical education. Clinically, I will serve in the realm of general infectious diseases in both the inpatient and outpatient settings. I’m greatly looking forward to this wonderful opportunity to build my clinical, educational, and research toolboxes.

As I reflect on the past 2 years, I am grateful to have trained in the UNMC ID fellowship program. I am appreciative of the many patients who have taught me so many lessons through their own difficulties and successes. Additionally, it is hard to say enough about the faculty who have trained me. I’m lucky to continue my journey at UNMC and continue to be around people I respect and trust, as I am certain to face difficult situations in the future for which I will need their help. Lastly, my co-fellows have been supportive, inspirational, and a joy; I’m honored to be their colleague and look forward to seeing what they are able to accomplish in the future.“

– Dr. Jonathan Ryder, Graduating UNMC ID Fellow, June 2022

In Case You Missed It: UNMC ID Physician Pens Both Prescriptions and Children’s Books

Dr. Nicolas Cortes-Penfield, UNMC ID Physician and recent author of an infectious disease themed children’s book

It seems that clinical ID knowledge may also be useful outside of the clinic. In case you missed it, UNMC ID’s Dr. Nicolas Cortes-Penfield was recently featured in Nebraska Medicine’s public-facing blog for his infectious disease themed children’s book titled “A is for Anisakis: An Infantile Introduction to Infectious Diseases.” With carefully selected ID entries for each letter of the alphabet, the book was a hit with his two daughters, Elise and Celeste, and has garnered quite a bit of interest from the ID field at large. It is in the process of revision for illustrated publication. Congratulations on a creative and fantastic infectious disease publication (and the opportunity to feature it here)!

For a peek inside the book and some additional content, check out the original blog post here.

UNMC Clinic to Offer Walk-in Testing for National HIV Testing Day

The following content was provided by Kevin Borges, UNMC Specialty Care Clinic Manager. Graphic obtained from the CDC.

Thursday (6/30) and Friday (7/1) from 1:00pm to 4:00pm The Specialty Care Clinic will be offering walk in HIV testing, with no appointment needed.

Each year, June 27th is observed as National HIV Testing Day (NHTD).  This year’s NHTD theme is “HIV Testing is Self Care.”  The act of getting tested is the first step in either treatment or prevention that leads to individuals being empowered to live long and healthy lives.  

The Nebraska Medicine/UNMC Specialty Care Clinic specializes in the prevention and treatment of HIV.  Our clinic is staffed with doctors, nurse practitioners, pharmacists, nurses, social workers, and more!  We are all here to provide the highest level of care in a judgement-free atmosphere.  There is a wide range of prevention and treatment options available and we would be happy to review your best options with you.  If you or someone you know could potentially benefit from HIV testing, we invite you to our clinic.  On the afternoons of Thursday 6/30 and Friday 7/1 from the hours of 1:00pm to 4:00pm we are opening our doors to walk in HIV testing, with no appointment needed.  Our clinic is located at 804 South 52nd Street Omaha, NE 68106.  We can also be reached at 402-559-2666.  We look forward to serving you.

t eVylIuMrgK

UNMC ID to Investigate New RSV Vaccine Candidate

The following was adapted from content provided by Dr. Diana Florescu, one of the UNMC ID faculty members working on investigating this new vaccine.

What is RSV?

RSV, or respiratory syncytial virus, is a highly infectious virus transmitted primarily by contact with infected respiratory secretions or contaminated objects. Seasonal epidemics occur annually in autumn/winter in temperate climates Typically, the primary infection begins with fever, runny nose and cough, lasting 10 to 14 days. In more severe infections, the disease spreads from the upper to the lower respiratory tract and results in inflammation of the lower airways  and airway obstruction with associated increased breathing rate, shortness of breath and wheezing, sometimes requiring oxygen support to avoid progression to pneumonia with respiratory failure. 

Who is at risk of an RSV infection?

RSV has been recognized as a significant cause of respiratory illness in all age groups and an estimated 90% of the population experience their first RSV infection within the first 2 years of life. While the burden of RSV is highly recognized in the pediatric population, particularly in the very young and in those with cardio-respiratory disease, RSV infections are also a serious health concern in the elderly and in immunocompromised individuals. Approximately 170,000 hospitalizations and 10,000 deaths occur annually in people over the age of 65 years old with increasing hospitalization and death rate by increasing age. 

Wait, if 90% of the population has had RSV, why do we need a vaccine? What about natural acquired immunity?

In the case of RSV, natural acquired immunity is not durable. Immune responses after primary infection in young infants are usually weak and short-lived. Re-infections with RSV are common at all ages, although of decreasing severity, since with recurrent infection the disease becomes more limited to the upper respiratory tract. Morbidity and disease severity increases again in people >50 years old, most likely due to decreasing immune responsiveness associated with advancing age. 

How does this new vaccine candidate work?

This RSV vaccine candidate aims to protect against both circulating RSV subtypes (A and B).  The vaccine is designed to protect against acute respiratory tract infections and more severe lower respiratory tract disease (e.g. RSV bronchiolitis, pneumonia) in adults ≥60 years of age.  

For more information regarding this study, contact florescuresearchteam@unmc.edu or call (402) 836-9265

Research Digest: COVID-19 Pathologies Explored by UNMC ID Faculty (Part 1)

At the beginning of the COVID-19 pandemic, there seemed to be many more questions than answers. How is this virus spreading? What is the best way to protect our communities? Which organ systems are at risk of damage from infection? To answer these questions, the medical community at large turned to research- and UNMC ID was no exception. Read below for synopses of three recent publications authored by UNMC ID faculty which each explore different aspects of COVID-19.

Dr. Jasmine Marcelin, UNMC Infectious Disease Physician and co-author of a recent COVID-19 review article.

One thing was clear from the start, COVID-19 is a complex disease with widely variable clinical symptoms, ranging from asymptomatic or a loss of smell to multiorgan failure. In a recent review article co-authored by Dr. Jasmine Marcelin, current COVID-19 knowledge is synthesized, from the physical characteristics of the SARS-CoV-2 virus to infection stages, immune responses, clinical presentations, and postacute sequelae of COVID-19 (long COVID). For a detailed, up-to-date, and digestible brief on all things COVID-19, find the article here.

Dr. Daniel Brailita, UNMC Infectious Disease physician and corresponding author on a recent publication on COVID-19 detection.

Another recent publication co-authored by Dr. Angela Hewlett, Dr. Mark Rupp, and Dr. Daniel Brailita, among various other UNMC researchers, assessed SARS-CoV-2 viral shedding in critically ill patients and how best to determine if a patient is still infectious. The study found that nasopharyngeal swab (one of the standard SARS-CoV-2 detection techniques) does not alway agree with detection of viral shedding in lower respiratory sputum samples. That is, critically ill patients who test negative by nasal swab may still have sufficient viral shedding in their lungs. This is critical information as it could help inform the level of protection medical professionals must take when performing aerosolizing procedures, even on supposedly COVID-negative patients. Read the full study here.

Dr. Nicolas Cortes-Penfield, UNMC Infectious Disease physician and co-author on a recent report on COVID-19 vaccination complications.

Finally, a recent article co-authored by Dr. Nicolas Cortes-Penfield reported outcomes of rare complications from COVID-19 vaccination. Specifically, the paper outlines 4 cases of acute and chronic demyelinating neuropathies following COVID-19 vaccination seen at UNMC in 2021. Among these patients, there was no clear predilection for a specific vaccine brand. While all of these cases presented between 2 and 21 days post-vaccination, there was not enough information to make a clear causative link between vaccination and these cases of demyelinating neuropathies. However, the study notes that continued identification and reporting of these side effects are crucial to making this determination. Find the paper here.

Wj w lymemqo WSm dfiTYM

Research Digest: UNMC ID Faculty Lead New HIV Publications

Since the beginning of the HIV pandemic, UNMC ID has provided expert clinical care to people with HIV (PWH) through the University of Nebraska Medical Center HIV Program and Clinic. Underscoring the great providers and researchers who work as a part of this team, many of our faculty members routinely publish their work in leading ID journals. See below for a quick synopsis of three recent publications from UNMC ID faculty exploring and reporting on HIV.

Dr. Sara Bares recently co-authored a publication which investigates the prevalence of functional impairment in PWH and its relation to cardiometabolic disease, a spectrum of conditions from insulin resistance to heart disease and diabetes, across different patient populations. They found that over 1 in 3 middle-aged and older PWH reported living with a functional impairment, globally. This rate was elevated in certain demographics as well as with certain treatment regimens and correlated with increased risk of cardiometabolic risk. Importantly, this work may help physicians better recognize and treat cardiometabolic disease in PWH. Read more here!

Dr. Suzan Swindells, along with many other UNMC researchers, also recently co-authored a publication assessing treatment strategies for HIV-associated tuberculosis. A four-month regimen of rifapentine and moxifloxacin has been reported to be successful in clearing tuberculosis infections, but how this treatment interfered with HIV medications, specifically efavirenz, was not previously known. The paper concludes that rifapentine is not only effective for HIV-associated tuberculosis treatments, but no dose adjustment of efavirenz is needed. See the details here!

Lastly, Dr. Nada Fadul, along with UNMC co-authors Nichole Regan and Laura Krajewski, recently published an article examining the effect of a shift to telehealth visits during the COVID-19 pandemic on medical care for PWH. After analyzing 2298 HIV clinic visits from May 2020 through April 2021, they concluded that utilization of telehealth visits were similar across measured patient demographics and did not lead to reduced treatment success rates in PWH. This adds to the growing evidence of the utility of telehealth when conditions require it. See the full article here.

Subscribe

Work at UNMC
Get Directions
Apply