Next week begins IDWeek 2022, and UNMC will have a strong showing at the conference! Want to support UNMC ID at this event? Follow us on Twitter @UNMC_ID throughout the conference.
Below, we have gathered info on all oral presentations, panel participation, and other involvement, so read on!
Tuesday, October 18th, 2022
All Day – Andrea Zimmer, MD – Moderator of “Vincent T. Andriole ID Board Review Course (Virtual)”
Wednesday, October 19th, 2022
9:45-10:45am – Nada Fadul, MD – Panelist on “Putting Quality into Practice
10:45-12:00pm – Trevor Van Schooneveld, MD – Speaking on “Careers in Antimicrobial Stewardship” as part of Fellows’ Day Workshop
7:30-9:30pm – Kimberly Scarsi, PharmD – Speaking as part of “State of the Science in HIV: Clinical Applications Across the Care Continuum”
Thursday, October 20th, 2022
12:15-1:00pm – Trevor Van Schooneveld, MD – Speaking on “Pneumonia Panel Implementation Lessons”
1:45-3:00pm – David Brett-Major, MD, MPH – Panelist on “Unforgettable Cases in Tropical Medicine”
2:10-2:35pm – Kimberly Scarsi, PharmD – Speaking on “New Drugs and Delivery Systems”
3:15-3:50pm – Sara Bares, MD – Speaking on “LA ART: Ready for Use in High-Risk Populations? Pro/Con
Friday, October 21st, 2022
7:30-9:00am – Jasmine Marcelin, MD – Panelist on ” Women in ID”
10:30-11:45am – Sara Bares, MD – Panelist on “Challenging HIV Clinical Cases”
3:15-3:40pm – Scott Bergman, PharmD – Speaking on “Influential Publications in Antimicrobial Stewardship From the Past Year”
10:30-11:45am – Erica Stohs, MD, MPH – Panelist on ” Challenging Cases in Transplant Infectious Diseases”
12:15-12:45pm – Riley Ostdiek, Medical Student – Rapid Fire presenter on “A Highly Effective ID Physician and Infection Preventionist-led Interactive Webinar Series for Infection Prevention and Control Training Among Frontline Healthcare Workers”
3:15-3:30pm – Jonathan Ryder, MD, and Clayton Mowrer, DO, MBA – Speaking on “Adoption and Utilization of Social Media among Adult and Pediatric Infectious Diseases Divisions and Fellowship Programs in the United States and Canada
4:05-4:30pm – M. Salman Ashraf, MBBS – Speaking on “Antibiotic Stewardship in Long-Term Care Facilities – We’re Doing It!
Sunday, October 23rd, 2022
8:30-9:00am – Nada Fadul, MD – Speaking on “Disparities of Post/Long COVID-19 Syndrome in Women and Young Adults”
Next week begins IDWeek 2022, and UNMC will have a strong showing at the conference! Want to support UNMC ID at this event? Follow us on Twitter @UNMC_ID throughout the conference.
Below, we have gathered info on all poster presentations given by UNMC members. Be sure to stop by these posters and show your support. Tomorrow, we will also post all oral presentations, panel participation, and other involvement, so stay tuned!
Posters Presented at IDWeek 2022:
Thursday, October 20th, 2022; 12:15pm-1:30pm
Erica Stohs, MD, MPH – Biofire pneumonia panel use in severe pneumonia and antibiotic treatment in COVID-19 patients
Casey Zelus, MD – BioFire FilmArray Pneumonia Panel Implementation: Examining Appropriate Usage and Opportunities for Diagnostic Stewardship
Friday, October 21st, 2022; 12:15pm – 1:30pm
Bryan Alexander, PharmD – Clinical Outcomes and Cost Savings of Dalbavancin Use in OPAT: Focus on Complicated Staphylococcus aureus Infections
Anum Abbas, MD – Cerebrospinal Fluid Findings of Solid Organ Transplant Recipients with West Nile Virus Infections
Nikki Regan, APRN – Telehealth Utilization and 2-year Outcomes among People with HIV at a Midwestern Clinic
Ryan Boyland, Medical Student – Curbsiding Twitter: Potential Value and Patient Confidentiality Implications of Infectious Diseases Clinician Peer Consultations via Social Media
Riley Ostdiek, Medical Student – A Highly Effective ID Physician and Infection Preventionist-led Interactive Webinar Series for Infection Prevention and Control Training Among Frontline Healthcare Workers
Titilola Labisi, MHA, MPH – Telehealth Utilization and 2-year Outcomes among People with HIV at a Midwestern Clinic
Josh Havens, PharmD – Patient perspectives on pharmacy experiences for antiretroviral refills
Timothy McElroy, MD – Local Antibiogram for Mycobacterium abscessus Shows Variability from Previously Published Susceptibility Data
Josh Havens, PharmD – B/F/TAF in HIV-Infected Adults with Substance Use Disorders: BASE Week 48 Results
Jeremy Tigh, PharmD – Acute Kidney Injury Rates Before and After Implementation of Integrated Bayesian Software for Vancomycin Dosing
Saturday, October 22nd, 2022; 12:15pm-1:30pm
Shawnalyn Sunagawa, PharmD – Sexually Transmitted Infection (STI) Therapy Compliance Pre and Post Centers for Disease Control and Prevention (CDC) STI Treatment Guideline Update
Jon Freese, Medical Student – Perceptions of the COVID-19 Vaccine within the Sudanese American Community
Salman Ashraf, MBBS – A Highly Effective ID Physician and Infection Preventionist-led Interactive Webinar Series for Infection Prevention and Control Training Among Frontline Healthcare Workers
Laura Fischer, MPH – Impact of Asymptomatic Upper Respiratory Viral Shedding in Pediatric Cardiothoracic Surgical Patients
Mackenzie Keintz, MD – Outcomes in Intravenous to Oral Antimicrobial Therapy in Beta-Streptococcus Species
Oliva Paetz, Medical Student – Missed Opportunities for Confirmatory HIV Testing at a Midwestern Medical Center
The following content was largely provided by Dr. Abbas to spread awareness about the new clinical trial starting soon at UNMC. To aid in participant recruitment, please share this with those who may be interested in the work.
What is a clinical trial?
While much of medicine is practiced within guidelines and evidence-based practices, getting the evidence for these practices is no small endeavor. This is achieved through the use of clinical trials, or research studies on treatments with good evidence for their potential use which need to be confirmed to work in the patient population. These foundational components of academic medical research pave the way for new treatments and future guidelines, ensuring that medical practice keeps pace with biomedical research.
What is HSV?
HSV (or herpes simplex virus) is a human viral pathogen which infects a large proportion of the population. Colloquially considered a sexually-transmitted infection, HSV comes in two types. HSV-1 is more common throughout the world and generally spread orally, causing cold sores or remaining asymptomatic. HSV-2 is less prevalent and is the type transmitted sexually.
Purpose of the UNMC PRIOH-1 Study:
The purpose of the PRIOH-1 study is to compare the effectiveness of the study drug pritelivir to the drug foscarnet in subjects with compromised immune systems who also have herpes simplex virus (HSV) lesions that have not responded to acyclovir treatment.
What is pritelivir?
The study drug is an investigational medication called pritelivir that you swallow as a tablet. Pritelivir is designed to protect uninfected cells from HSV infection. It is considered “investigational” because it has not been approved by any regulatory agency for treating acyclovir-resistant HSV skin lesions in subjects with compromised immune systems. The other drug in this study, foscarnet, is already approved and is administered through the vein (IV). This study is seeking an alternative to foscarnet that is more effective, safe, and convenient.
Do you have herpes lesions that keep coming back?
You may be eligible for the PRIOH-1 clinical research study. The PRIOH-1 study is for people with weakened immune systems (because of conditions such as HIV infection, organ transplantation, certain cancers, or long-term steroid use) and lesions caused by herpes simplex virus (HSV).
Study participants receive at no cost:
Possible access to a new study medication called pritelivir
Some participants may receive foscarnet, an approved treatment for HSV lesions
Study support and monitoring by a healthcare team
The opportunity to help advance HSV research
Who can participate?
You may be able to participate in the PRIOH-1 study if you are 16 years of age or older with a weakened immune system and an acyclovir-resistant HSV infection (skin lesions), requiring a switch to foscarnet treatment. Other criteria will apply.
About the study:
If you agree to participate and meet all eligibility criteria for Part C, you will be randomly assigned to receive either the study drug pritelivir or foscarnet. You have an even chance of receiving the study drug or approved drug. Those taking pritelivir will take an initial dose of 4 tablets, and then you will take one tablet each day. Those taking foscarnet will receive an hour-long IV infusion from study staff two or three times each day. You will visit the clinic weekly during the treatment period, so the study team can assess your lesions.
Study length:
Your participation in this study may last up to 152 days, depending on how long your treatment period lasts and when your lesion heals. The treatment period will continue until complete healing of all lesions or up to 28 days, whichever occurs first. If your lesions have not healed after 28 days, there will be up to 14 additional treatment days.
The battle between human and pathogen is one as old as time, shaping our evolution as well as culture. However, with the relatively recent invention of modern medicine and the germ theory of disease, it is often difficult to peer back into time and assess which pathogens ancient civilization may have dealt with. The historical records are spotty, ambiguous, and written through the lens of a different understanding of disease. But every once in a while, we get lucky. That is exactly what has recently happened with a 1400 year old Chinese treatise recently translated into English which, among other things, describes an illness suspiciously similar to what we call pertussis (or whooping cough). Read on for a quick digest of a fascinating article published in Open Forum Infectious Diseases describing a historical aspect of ID.
A page from Zhubing Yuanhou Lun (Treatise on the Origin and Symptoms of Diseases)
Chao Yuanfang, imperial physician of the Sui Dynasty was by all accounts a revered medical scholar and physician to the emperor in the early 600s CE. He is one possible author of the preeminent medical text of the time and region, Zhubing yuanhou lun (Treatise on the Origin and Symptoms of Diseases). This Treatise is composed of 50 scrolls detailing over 1700 medical illnesses, each categorized into 71 categories spanning all ages and organ systems.
The details of this work are incredibly interesting and discussed further in the article, but one illness description stood out- the loosely translated “cough of 100 days”. This disease was noted in the text to be a serious ailment most often found in children. It was said that “[If] it is not cured within 1 month and there is a cough within 100 days, only 1 or 2 of 10 will recover”. Some think this may be the earliest description of pertussis ever recorded.
To modern medicine, pertussis is a highly contagious bacterial disease caused by Bordetella pertussis. Before the dissemination of a vaccine in the 1940s, 200,000 children contracted this illness annually in the United States, causing mortality in 9,000 of those cases. Luckily, successful vaccination efforts dramatically reduced the harm of this infection, with current annual pertussis incidence between 10,000 and 40,000 with few deaths.
The article, titled Chao Yuanfang: Imperial Physician of the Sui Dynasty and an Early Pertussis Observer?, expands upon this idea, and shares additional details about these newly translated medical texts (link here). If truly describing pertussis, or some other ancient predecessor to this modern illness, these revelations further illustrate not only the rich history of medicine, but also the shared struggles that modern civilization may share with antiquity.
A #PharmToExamTable question about adverse vancomycin reactions, answered by Quynh Tran, PharmD, a Graduate of UNMC College of Pharmacy.
(Reviewed by Andrew Watkins, PharmD)
Vancomycin is a glycopeptide antibiotic frequently utilized to treat infections caused by resistant gram-positive organisms such as methicillin resistant Staphylococcusaureus (MRSA).1 Due to widespread vancomycin use, resistant organisms such as vancomycin-resistant Enterococcus (VRE) and vancomycin-resistant Staphylococcusaureus (VRSA) have been a growing problem within healthcare facilities. Thus, the glycopeptide family of antibiotics has since expanded to help overcome these resistances and offer alternate treatment options. New lipoglycopeptides antibiotics such as telavancin, oritavancin, and dalbavancin have been utilized for the treatment of resistant gram-positive organisms, particularly MRSA and Enterococcusfaecium. Clinical cross-reactivity between glycopeptides remains controversial, with varied reports suggesting possible immunological cross-reactivity. This review will focus on potential cross-reactivities between vancomycin and lipoglycopeptides.
What are Glycopeptide Antibiotics?
Glycopeptides are bactericidal cyclic non-ribosomal peptides produced by various filamentous actinomycetes. They facilitate inhibition of cell wall synthesis by impeding transglycosylation & transpeptidation.2 Vancomycin was one of the first glycopeptides discovered, and it can be used intravenously as a treatment for complicated skin infections, bloodstream infections, endocarditis, bone and joint infections, and meningitis caused by most gram-positive organisms. Due to an increase in resistance to vancomycin, lipoglycopeptides (a class of antibiotics that have lipophilic side chains linked to glycopeptides) were developed. The three antibiotics in this class approved by the FDA are telavancin, dalbavancin, and oritavancin. All three antibiotics are approved for skin/soft tissue infections, and they can be used for gram-positive bacteria that are resistant to vancomycin. Another benefit of these antibiotics is their prolonged duration of action, allowing less frequent administration. While telavancin typically requires administration every 24 hours, dalbavancin can be administered as a once weekly injection for 1-2 doses depending on the infection.3 In theory, telavancin is most at risk of possible cross-reactivity as its glycopeptide core is vancomycin.4 Due to their benefit, the lipoglycopeptides have been used more frequently in clinical settings, but because of their structural similarities to vancomycin, it is important to understand their cross-reactivity with vancomycin to assist in safe use of these medications in patients with vancomycin allergy.
Adverse Vancomycin Reactions
Adverse drug reactions with vancomycin include both non-immune mediated reactions such as nephrotoxicity and non-immunoglobulin E (IgE) mediated mast cell reactions (i.e., red man syndrome) as well as immune-mediated reactions such as T-cell mediated severe cutaneous adverse reactions (i.e., drug reaction with eosinophilia and systemic symptoms (DRESS)).
Non-IgE mediated vancomycin hypersensitivity – red man syndrome – is typically characterized by a pruritic, erythematous rash that predominantly affects the face, neck, and trunk and is caused by mast cell degranulation.5 It is usually related to intravenous doses greater than 1000 mg with rapid administration under 60 minutes. Recurrence of red man syndrome can usually be managed by reducing the rate of infusion of vancomycin and/or premedication with antihistamines. A potential mechanism for this reaction is direct mast cell degranulation via the MAS-related G-protein coupled receptor X2 (MPGPRX2).6
On the other hand, patients might experience immune mediated hypersensitivity with vancomycin such as IgE mediated reactivity (true anaphylaxis) and DRESS. There is no clear way to distinguish red man syndrome from IgE mediated reactions in patients receiving vancomycin; thus, IgE mediated hypersensitivity should be suspected in patients who have severe multiorgan involvement suggesting anaphylaxis or who fail red man protocols for intravenous administration.7 DRESS most frequently occurs during vancomycin therapy with a median of 18 days after start of therapy. Its clinical presentation includes widespread rash, fever, facial edema, increase in white blood cells, and involvement of internal organs. Konvinse et al. reviewed a cohort study of 23 patients with vancomycin DRESS and showed that over 80% of these patients carried the HLA-A*32:-01 allele compared to the 0 in 46 vancomycin tolerant controls.8
What About Lipoglycopeptide Cross-reactivity?
A recent study by Nakkam et al. looking at DRESS cross-reactivity among vancomycin, teicoplanin, dalbavancin, telavancin showed that patients with a history of previous vancomycin-induced DRESS had potential risk of cross-reactivity between vancomycin, teicoplanin, and telavancin, but lower risk of cross-reactivity with dalbavancin. This result aids in decision making in the future and reassures the use of dalbavancin in vancomycin-allergic patients.9
In conclusion…
Telavancin has higher potential cross-reactivity with vancomycin compared to dalbavancin and oritavancin due to its similarity in the core structure with vancomycin. However, further studies are needed to understand more about the cross-reactivity mechanism. Future studies on an association of vancomycin-induced DRESS with HLA-A*32:-01 could be important in understanding cross-reactivity for immune mediated reactions.
Zhanel GG, Calic D, Schweizer F, et al. New lipoglycopeptides: a comparative review of dalbavancin, oritavancin, and telavancin. Drugs 2010; 70: 859-886.
Kahne D, Leimkuhler C, Lu W, Walsh C. Glycopeptide and Lipoglycopeptide antibiotics. Chemical Reviews 2005; 105: 425-448.
Gelfand MS, Cleveland KO, Memon KA. Detection of vancomycin levels in patients receiving telavancin but not vancomycin. J Antimicrobial Chemotherapy 2012; 67: 508-509.
Sivagnanam S, Deleu D. Red man syndrome. Critical Care 2003; 7:119.
Azimi E, Reddy VB, Lerner EA. Brief communication: MRGPRX2, atopic dermatitis and red man syndrome. Itch (Phila) 2017; 2:e5.
Minhas JS, Wickner PG, Long AA, et al. Immune-mediated reactions to vancomycin. Ann Allergy, Asthma Immunol 2016; 116:544-553.
Konvinse KC, Trubiano JA, Pavlos R, et al. HLA-A*32:01 is strongly associated with vancomycin-induced drug reaction with eosinophilia and systemic symptoms. J Allergy Clin Immunol 2019; 144:183-192.
Nakkam N, Gibson A, Mouhtouris E, Konvinse KC, et al. Cross-reactivity between vancomycin, teicoplanin, and telavancin in patients with HLA-A*32:01 positive vancomycin induced DRESS sharing an HLA class Ii haplotype. Journal of Allergy and Clinical Immunology 2020.
As September comes to a close, we would like to take a moment and recognize the women physicians in medicine who make UNMC ID the fantastic division it is. Each year during the month of September the American Medical Association honors physicians who have offered their time, wisdom and support to advance women with careers in medicine. At UNMC ID, we are lucky to have a truly impressive roster of medical professionals who satisfy those requirements…and then some.
From top left: Dr. Andrea Zimmer, Dr. Elizabeth Schnaubelt, Dr. Jasmine Marcelin, Dr. Andrea Green Hines, Dr. Nada Fadul, Dr. Susan Swindells, Dr. Kimberly Scarsi, Dr. Subhadra Mandadi, Dr. Alison Freifeld, Dr. Kelly Cawcutt, Dr. Erica Stohs, Dr. Kari Neemann, Dr. Angela Hewlett, Dr. Diana Florescu, Dr. Natalia Castillo Almeida, Dr. Anum Abbas, and Dr. Sara Hurtado Bares, Dr. Catherine Cichon, Dr. Mackenzie Keintz
Above, we feature UNMC ID’s Women in Medicine. You will no doubt recognize many of these photos from numerous recent features on the blog highlighting achievements and ideas from the Division of Infectious Diseases. Additionally, many of these physicians play an active role in advocacy. Underscoring this, Dr. Cawcutt recently spoke at a women in health care conference last Friday, September 16. Dr. Marcelin will also be speaking at a women in healthcare leadership conference next Thursday, September 29. We celebrate all women in healthcare; thank you all for your work, commitment, and expertise!
(Check out the UNMC ID faculty page for bios and more information)
Rounding out the introductions to our recent ID faculty additions, we welcome Dr. Subhadra Mandadi to UNMC. Dr. Mandadi completed her residency training in Internal Medicine at Hurley Medical Center and fellowship in ID at the University of Buffalo. She joins us as an assistant professor working on the Community ID service line. Read on to learn more about Dr. Mandadi!
Dr. Subhadra Mandadi, ID physician who joins UNMC ID as an assistant professor.
Tell us a little about your background.
I am from India. After graduating from medical school, I worked as a physician for a few years before embarking on my journey to the United States. I completed residency training in 2015 and then graduated as a fellow in Infectious diseases in 2017. Wicked problems, from climate crises to global pandemics to antimicrobial resistance among many, surround us, and there is much need for ‘wicked’ scientists to address such issues. I am pursuing MSHS in Clinical and Translational Research at George Washington University to hone my abilities as an independent physician investigator to help address complex problems in Infectious diseases affecting the community.
Why did you choose UNMC?
UNMC is a well-reputed Infectious disease program for its commitment to empathetic patient care, clinical and translational research, academic education, and its perfect amalgamation. My career goals align with the mission of UNMC, and I wish to be a part of its tremendous contribution to the field of medicine. UNMC is widely known for promoting a collegial environment by incorporating psychological safety and establishing an avenue for professional growth and development. I believe UNMC can be a perfect platform to give wings to my aspiration of becoming a physician investigator.
What about ID makes you excited?
Dr. Bartlett wrote about ID, “It would be difficult to find another discipline in medicine with such extraordinary diversity, surprises, value in patient care, and clinical relevance for both domestic and international applications.” I strongly believe in this quote. ID is the most sensible field of medicine to which other disciplines reach out when faced with any perplexing and complex medical situation, even if it is non-ID related. Solving a puzzle and adopting a scholarly approach to patient care challenges makes ID exciting and rewarding.
Tell us something interesting about yourself unrelated to medicine.
I have two beautiful children, my other world, and together with my husband, they are my life coaches. I am training in Indian classical dance. I am an avid lover of cooking, traveling, and watching investigative crime series in my free time, and my favorite one so far is ‘Unforgotten.’ I am currently watching ‘Delhi crimes.’
In a previous post, we explored recent work conducted by UNMC ID faculty on untangling the pathogenesis of COVID-19. Medically speaking, that is only half of the story. In the effort to translate these observations about how SARS-CoV-2 makes us sick into treatments or vaccines, UNMC ID has been no less dedicated. Underscoring this point, read on for a research digest of three recent publications authored by UNMC ID faculty exploring COVID-19 treatment strategies.
Dr. Hewlett, co-author of a recent COVID-19 research article.
In response to another viral outbreak, the Ebola epidemic of 2014-2016, the Centers for Disease Control and Prevention (CDC) designated 56 US hospitals as bona fide treatment centers for Ebola infections. UNMC was one of these sites. Now, with the COVID-19 pandemic, these centers have shifted their efforts to help treat patients with severe presentations of this infection. A recent study, co-authored by Dr. Angela Hewlett, looked at these Ebola treatment centers and how they responded to the current pandemic. They found that nearly 90% of the original facilities were still in operation and almost all of these sites were reported to positively affect the COVID-19 response in their regions. Read the full article here for the details including challenges that these vital centers face for continued operation.
Dr. Castillo Almeida who, along with Dr. Kalil, authored this editorial in the New England Journal of Medicine.
In a research editorial authored by Dr. Natalia Castillo Almeida and Dr. Andre Kalil, the evidence for COVID-19 treatment with the antiviral medication molnupivavir was summarized. Specifically, this article analyzed results from two clinical trials which used this medication in patients with COVID-19. The article concluded that both studies found molnupivavir to be effective at preventing death from this illness, especially when used early in infection and in patients older than 60 years of age. These studies added molnupavir to the growing list of medications with some documented benefit in the effort to fight this pandemic. Read here for the full editorial, including the caveats and detailed benefits to molnupavir treatment.
(Note that knowledge surrounding COVID-19 treatments is rapidly growing, and data surrounding molnupivavir may have been refined since this article’s publication in December 2021)
Dr. Andre Kalil, co-author of a recent article identifying a shift in available clinical trial participants.
Lastly, Dr. Kalil also recently co-authored another publication sounding the alarm on decreasing recruitment of patients into the randomized controlled trials which are the necessary for vaccine and treatment development. The article suggests that this could be due to a multitude of factors, including the observation that, in the time since vaccinations have become widespread, most of those with severe disease are unvaccinated and more likely to be hesitant of clinical trials. This article explores the various reasons cited for hesitancy in certain patient populations as well as expands on how to combat this hesitancy to ensure we can still develop the necessary treatments as the virus continues to shift. Read more here for the full analysis.
A few weeks ago, we introduced three great new additions to the UNMC ID team. Among them, was Dr. Jonathan Ryder, a recent UNMC ID Fellowship graduate who joins UNMC ID faculty as an instructor working on the General ID service line. He is also completing a 3rd year fellowship in Antimicrobial Stewardship. Read on to get to know more about Dr. Ryder!
Tell us a little about your background.
I was born and raised in central Missouri, near Jefferson City. I studied biology and history at Truman State University in Kirksville, Missouri. During college, I attended UNMC’s Summer Undergraduate Research Program. I subsequently attended medical school at UNMC, graduating in 2017. I left UNMC for Indiana University School of Medicine for internal medicine residency, then returned to UNMC for infectious diseases fellowship, which I finished in June 2022.
Why did you choose UNMC?
Dr. Jonathan Ryder, a new addition to UNMC ID faculty.
UNMC has provided me ample opportunities for personal and professional growth, for which I am quite appreciative. When looking for a career in infectious disease, I was always interested in pursuing academia, as I love the teaching/learning environment, the pursuit of new knowledge through research, and providing clinical expertise at a referral hospital. An important part of success in academia is having a supportive environment, which I have found at UNMC. I have found multiple mentors to help me grow in my areas of interest: antimicrobial stewardship, medical education, and infection control. Essential to this supportive environment is the talented faculty. Lastly, Omaha remains a key reason for staying at UNMC, as it is close to family and continues to provide convenient living with plenty of entertainment and adventure.
What about ID makes you excited?
I continue to be excited about ID because of the breadth and depth of the field and the many ways we can contribute to improving patient care. Antimicrobial stewardship increasingly is essential to protecting our available antimicrobials and reducing antimicrobial resistance. Similarly, the field of infection control protects our patients and contributes expertise when novel pathogens arise. The widespread use of antibiotics puts ID at the forefront of medical education, as nearly every specialty uses these treatments. There remains a large need for clinical research in these areas and pursuing new knowledge keeps me interested and excited for the future!
Tell us something interesting about yourself unrelated to medicine.
I greatly enjoy reading history, especially history of science, medicine, and late 19th/early 20th century of US and Europe. However, I have recently started reading more fiction as well, in particular the Dune and Lord of the Rings series, given the recent theatrical productions of these books.
A #PharmToExamTable question about fluconazole dosing, answered by Brady Caverzagie, PharmD, a Graduate of UNMC College of Pharmacy.
(Reviewed by Andrew Watkins, PharmD)
Cryptococcus spp. are fungal pathogens found in the soil and pigeon droppings. Usually, Cryptococcus spp.do not cause severe or life-threatening symptoms in immunocompetent patients; however, in immunocompromised patients, cryptococcal infections can cause serious complications. Patients who are HIV positive with high viral loads and low CD4 cell counts are especially susceptible to infection with cryptococcal species, which can disseminate throughout the body, including the central nervous system (CNS). Once in the CNS, patients often have a classic meningitis-like presentation including headache, stiff neck, fever, and photophobia. Standard treatment for cryptococcal meningitis in the setting of HIV includes long courses of antifungals, relief of intracranial pressure, and supportive care.1
Antifungal treatment includes three different phases: induction, consolidation, and maintenance. The 2010 Infectious Disease Society of America (IDSA) guidelines for cryptococcal meningitis for HIV-infected individuals recommends induction therapy with liposomal amphotericin at a dose of 3-4 mg/kg intravenously per day along with flucytosine 100 mg/kg orally per day in four divided doses for at least two weeks. Induction therapy continues for two weeks or until clearance of Cryptococcus from the cerebrospinal fluid, whichever comes last. Consolidation therapy follows the induction period and consists of 400 mg per day of fluconazole by mouth for a minimum of eight weeks. The last phase is maintenance therapy which is generally 200 mg per day of fluconazole by mouth for 6-12 months.2
There is not an established fluconazole breakpoint for Cryptococcus spp., from the Clinical and Laboratory Standards Institute (CLSI), making it difficult to determine if the recommended treatment is optimal in the setting of elevated minimum inhibitory concentrations (MIC).3,4 Although the most common fluconazole MIC for Cryptococcus spp. Is 4 mg/L, a systematic review showed the median increase from 4 µg/mL in 2000-2012 to 8 µg/mL in 2014-2018.5 Additionally, worse patient outcomes and treatment failures have been observed in patients with cryptococcal isolates that have higher fluconazole MICs.6 The recent decrease in susceptibility to fluconazole in cryptococcal species is forcing a reevaluation of the appropriateness of 400mg per day of fluconazole in consolidation therapy for cryptococcal meningitis.4,5
Fluconazole works by inhibiting the fungal CYP P450 dependent enzyme lanosterol 14-α-demethylase, which converts lanosterol to ergosterol. Without ergosterol, the fungal cell membrane cannot function properly. Oral bioavailability of fluconazole is excellent at over 90%, making it a good option for long term outpatient therapy. While fluconazole distributes well to the urine and skin, with levels ~10x those seen in plasma, it distributes less well to the cerebrospinal fluid with levels 50-90% of those seen in plasma. The inhibition of human CYP enzymes (primarily CYP 3A4) leads to numerous drug interactions and careful monitoring of these interactions is important during therapy, especially in long courses of fluconazole used in cryptococcal meningitis.7
In the face of increasing MICs and an infection in an area of the body with lower drug penetration, the question becomes what dose will work for consolidation therapy in a patient with cryptococcal meningitis once they have completed induction therapy? Based on a model created to investigate fluconazole use for all phases of cryptococcal therapy, 400 mg daily would reach therapeutic levels of >100 AUC:MIC for 53% of isolates, 800 mg daily would reach therapeutic levels for 74% of isolates and 1200 mg would be effective for 83% of isolates.5 The data from the model can be reconfigured to demonstrate what dose can reasonably be expected to treat a particular isolate based on MIC (Table 1). The guideline driven 400 mg per day dose of fluconazole for consolidation may only be consistently effective for highly susceptible pathogens, leaving the rising incidence of resistant organisms to grow unchecked.
Table 1: Probability of achieving >100 AUC:MIC based on MIC and dose
MIC
DOSE
PROBABILITY
≤2 ΜG/ML
400 mg
>91%
4 ΜG/ML
800 mg
91%
8 ΜG/ML
1200 mg
85%
16 ΜG/ML
1600 mg
68%
Cryptococcal meningitis is a serious infection that needs to be adequately treated, and the MIC of cryptococcal isolates should be taken into consideration, particularly in immunocompromised patients. The guideline dosing for fluconazole consolidation treatment of 400mg daily is likely sufficient for cryptococcal isolates with an MIC of 2 mg/L, however fluconazole MICs among cryptococcal species have been increasing over the past two decades. To adequately reach therapeutic levels in patients with less susceptible organisms, doses of 800-1200mg per day could be necessary. Patients should be monitored carefully because tolerability of fluconazole may become a clinical issue at higher doses. Although limited evidence exists in these situations, an alternative agent may be necessary if MICs exceed 16 mg/L or patients become intolerant to fluconazole therapy.
References:
Dipiro JT, et al. Pharmacotherapy A Pathophysiological Approach. 11th ed. McGraw-Hill 2019.
Perfect JR, et al. Clinical Practice Guidelines for the Management of Cryptococcal Disease: 2010 Update by the Infectious Diseases Society of America, Clinical Infectious Diseases, Volume 50, Issue 3, 1 February 2010, Pages 291–322.
Clinical and Laboratory Standards Institute (CLSI). Performance Standards for Antifungal Susceptibility Testing of Yeasts. 1st ed. CLSI supplement M60. Wayne, PA: CLSI; 2017.
Bongomin F, et al. A systematic review of fluconazole resistance in clinical isolates of Cryptococcus species. Mycoses. 2018;61(5):290-297.
Chesdachai S, et al., Minimum Inhibitory Concentration Distribution of Fluconazole Against CryptococcusSpecies and the Fluconazole Exposure Prediction Model, Open Forum Infectious Diseases, Volume 6, Issue 10, October 2019.
Sai Cheon JW, McCormack J. Fluconazole resistance in cryptococcal disease: emerging or intrinsic?, Medical Mycology, Volume 51, Issue 3, April 2013, Pages 261–269.
Diflucan (fluconazole) [package insert] New York, NY: Pfizer Inc; September 2020.
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