Dr. Jennifer Davis joins UNMC ID as an assistant professor following her ID fellowship at Massachusetts General Hospital/Brigham and Women’s Hospital. She is an expert in HIV care and will practice in the HIV clinic, but will also see a broad range of other patients on the ID consult service. Read on to learn more about our superb new ID physician. Congratulations, Jennifer!
Tell us a little about your background in medicine.
I was born in Maine and raised in Andover, Massachusetts. I did my undergraduate work at Middlebury college in Vermont where I was a double language and culture major in Japanese and Mandarin Chinese. I lived in Japan for a few years after college where I taught English in public elementary and junior high school in rural Okinawa. I then attended Emory University School of Medicine in Atlanta where I fell in love with ID and HIV in particular. I completed residency in Internal Medicine at the University of California San Francisco and then Infectious Diseases fellowship at the Massachusetts General Hospital/Brigham and Women’s Hospital (BWH) combined fellowship program. In my second year of fellowship, I was the HIV Clinician Educator Fellow at BWH under Dr. Paul Sax and was also a scholar in the Harvard Macy Program for Educators in Health Professions. Moving to Omaha will be the first time I have lived in the Midwest, and I’m looking forward to the new adventure.
Tell us about your new position.
I’m joining the Infectious Diseases Division as an Assistant Professor of Medicine in mid August. My clinical practice will primarily be devoted to seeing patients in the HIV clinic. I will also see patients on the General Infectious Diseases consult service which cares for patients with a wide range of infections and symptoms suggestive of infection.
Why did you want to work at UNMC?
When I started looking for post-fellowship jobs, I knew that I wanted to stay in academic medicine with a focus on HIV and medical education. A co-scholar in the Harvard Macy Program (the amazing Dr. Jasmine Marcelin) introduced me to UNMC and I was very impressed both by the HIV team and the general atmosphere and culture of the ID division as a whole. It was clear to me when I interviewed that this is a place where I would be valued and given ample support and opportunity to grow.
What about ID makes you excited?
Chocolate cupcakes with chocolate and vanilla buttercream frosting made by Dr. Davis for a co-fellow’s birthday a few months ago.
Everything! I love thinking about itty bitty bugs and the drugs that do battle with them. I love being able to spend time with patients to learn their stories because you never know when the smallest detail about an afternoon spent with a grandson’s pet bearded dragon will explain the source of a Salmonella bacteremia. It is a privilege to get to know our patients so intimately, and often times in ID (though not always) our patients improve to the point where they seem like different people at their follow-ups a few months later.
Tell us something interesting about yourself unrelated to medicine.
I love to read and bake. My book tally at the end of the year is often embarrassingly high. I’m very much looking forward to experimenting in my new kitchen and feeding my new colleagues with the results of those experiments.
Part 1 of this #PharmToExamTable post explores treatment options for uncomplicated ESBL UTIs and was authored by Anna Rehberg, 2024 UNMC College of Pharmacy PharmD Candidate
(Content reviewed by: Jenna Preusker, PharmD, BCPS, BCIDP, Scott Bergman, PharmD, BCIDP, and Nicholson Perkins, PharmD)
Fast Facts about ESBL UTI treatment:
People who have more healthcare exposure are more likely to get ESBL infections, but it can also be community-acquired.
ESBL-producing organisms cannot be treated with oral beta-lactam antibiotics.
Guidelines recommend uncomplicated cystitis caused by an ESBL-producing organism be treated with oral SMX-TMP or nitrofurantoin if they are susceptible.
Guidelines recommend ESBL cUTIs and pyelonephritis be treated with oral SMX-TMP, fluoroquinolones, or IV carbapenems.
Introduction to ESBLs
ESBLs, or Extended Spectrum Beta Lactamases, are enzymes produced by Gram-negative bacteria that inactivate most penicillins, cephalosporins, and aztreonam while remaining susceptible to carbapenems in the absence of other resistance mechanisms.1 ESBLs do not inactivate non-beta lactam antibiotics such as levofloxacin, sulfamethoxazole-trimethoprim, fosfomycin, or gentamicin.1 However, organisms harboring ESBLs often contain additional mechanisms of resistance that could render these antibiotics ineffective. ESBLs can be found in any gram-negative organism but are most prevalent in Escherichia coli, Klebsiella pneumoniae, Klebsiella oxytoca, and Proteus mirabilis.2 In the United States, the CTX-M enzyme is the most common type of ESBL present, accounting for approximately 80% of all ESBL infections nationally.1
ESBL infections occur most frequently in those with high healthcare exposure, particularly those requiring prolonged hospital stays, residents of skilled nursing homes, or residents of long-term acute care facilities, but they can also cause community-acquired infections in otherwise healthy people who have taken antibiotics before.3 Bacteria with ESBL enzymes can spread from person to person in healthcare settings or through contaminated food or water, just like other bacteria and microbes.3
IDSA guidelines do not provide recommended durations of therapy for ESBL infections, but expert clinicians advise the duration of therapy should not differ for infections caused by organisms with resistant phenotypes compared to infections caused by more susceptible phenotypes.1 Also, oral antibiotics can be an equally efficacious step-down therapy option when the patient meets the following criteria:1
Hemodynamic stability
Source control
Susceptible to an appropriate, non-beta lactam, oral agent
No concerns for insufficient intestinal absorption
What are preferred antibiotics for the treatment of uncomplicated cystitis caused by ESBL-producing organisms?
Nitrofurantoin and sulfamethoxazole–trimethoprim (SMX-TMP) are the preferred agents for the treatment of uncomplicated cystitis caused by ESBL-producing organisms.1 In an open-label non-inferiority study, five days of nitrofurantoin therapy was compared to three days of double-strength SMX-TMP for the treatment of uncomplicated cystitis.4 A total of 338 women, aged 18 – 45 years old, enrolled in this trial with the primary outcome of clinical cure at 30 days after therapy completion with secondary outcomes including cure rates at 5 to 9 days. Clinical cure was achieved in 79% of patients in the SMX-TMP group and 84% of patients in the nitrofurantoin group. Clinical and microbiological cure rates at first follow-up visit were equivalent between groups. Though this study did not exclusively evaluate ESBL cystitis, the authors concluded that a five-day course of nitrofurantoin is equivalent clinically and microbiologically to a three-day course of SMX-TMP and should be considered an effective fluoroquinolone-sparing alternative for the treatment of uncomplicated cystitis in women.4
Fluoroquinolones and carbapenems are also effective agents for treatment of uncomplicated cystitis caused by ESBL-producing organisms, but their use is discouraged in this disease state.1 Limiting the use of these agents reduces the risk of antibiotic adverse events and benefits patients in the future by preserving antimicrobial activity.1 In a randomized, single-blinded study done in 2005, a three-day course of amoxicillin-clavulanate and ciprofloxacin were compared for the treatment of uncomplicated cystitis.5 There was a total of 370 women enrolled, aged 18 – 45 years old, who were then randomized 1:1 into two groups. The results demonstrated the three-day regimen of amoxicillin-clavulanate was not as effective as ciprofloxacin for the treatment of acute uncomplicated cystitis, even in women infected with susceptible strains. Inferiority of amoxicillin-clavulanate was partially due to not fully eradicating E. coli from the vaginal area. This outcome can be explained by the increasing resistance to amoxicillin along with the length of time amoxicillin and clavulanate are in the serum (1.3 hours and 1 hour, respectively) compared to ciprofloxacin (4 hours). This study did not monitor side effects of fluoroquinolones, but general side effects for all medications mentioned can be seen in Table 1.5
Fosfomycin is also an option for the treatment of uncomplicated ESBL cystitis.1 However, infections caused by K. pneumoniae, Serratia marcescens, Enterobacter spp. and P. aeruginosa are resistant to fosfomycin due the presence of FosA genes.6 However, this gene is often absent in ESBL E. coli, so fosfomycin can be used as treatment in those cases.6 But in a study done comparing a five – day course of nitrofurantoin to a single dose of fosfomycin for uncomplicated cystitis clinical cure, fosfomycin only had a 58% cure rate compared to 70% in the nitrofurantoin group.7
To be continued next week…
References:
Pranita D Tamma and others, Infectious Diseases Society of America 2023 Guidance on the Treatment of Antimicrobial Resistant Gram-Negative Infections, Clinical Infectious Diseases, 2023;, ciad428, https://doi.org/10.1093/cid/ciad428
Tamma PD, Smith TT, Adebayo A, et al. Prevalence of bla CTX-M Genes in Gram-Negative Bloodstream Isolates across 66 Hospitals in the United States. J Clin Microbiol 2021; 59(6).
Gupta K, Hooton TM, Roberts PL, Stamm WE. Short-course nitrofurantoin for the treatment of acute uncomplicated cystitis in women. Arch Intern Med. 2007;167(20):2207-2212. doi:10.1001/archinte.167.20.2207
Hooton TM, Scholes D, Gupta K, Stapleton AE, Roberts PL, Stamm WE. Amoxicillin-clavulanate vs ciprofloxacin for the treatment of uncomplicated cystitis in women: a randomized trial. JAMA. 2005;293(8):949-955. doi:10.1001/jama.293.8.949
Ito R, Mustapha MM, Tomich AD, et al. Widespread Fosfomycin Resistance in Gram-Negative Bacteria Attributable to the Chromosomal fosA Gene. mBio. 2017;8(4):e00749-17. Published 2017 Aug 29. doi:10.1128/mBio.00749-17
Huttner A, Kowalczyk A, Turjeman A, et al. Effect of 5-Day Nitrofurantoin vs Single-Dose Fosfomycin on Clinical Resolution of Uncomplicated Lower Urinary Tract Infection in Women: A Randomized Clinical Trial. JAMA. 2018;319(17):1781–1789. doi:10.1001/jama.2018.3627
Dr. Sias Scherger completed his ID fellowship at the University of Colorado, where he stayed on as faculty for a few years. He now joins us at UNMC ID, where he will focus on the treatment of immunocompromised patients. A Nebraska native and graduate of UNMC’s College of Medicine, we welcome him back! Read on to learn more about our great new addition to the UNMC ID faculty. Congratulations Sias!
Tell us a little about your background in medicine.
I was born in Lincoln, NE, and have also lived in North Platte and Omaha. I did my undergraduate education at the University of Nebraska-Lincoln, medical school at the University of Nebraska Medical Center, and Internal Medicine Residency at Wake Forest Baptist Health in Winston-Salem, NC. I completed an Infectious Diseases Fellowship at the University of Colorado, where I stayed as faculty for 3 years before returning to UNMC.
Tell us about your new position.
I started at UNMC on July 1st, 2023. My main area of focus is infections in immunocompromised hosts, including solid organ transplant and hematopoietic stem cell transplant recipients, but also patients with malignancies, immunosuppressive medications, or congenital/acquired immune deficiencies. I am also working toward developing a research career to investigate some of the challenges that patients with impaired immune systems face.
Why did you want to work at UNMC?
I like the balance between clinical patient care, research and scholarly pursuits, and education that an academic medical center like UNMC provides. As a referral hospital, we also see some of the sickest and most challenging patients and are able to work with experts from all disciplines. The Infectious Diseases division is robust, productive, and provides excellent support for junior faculty. Lastly, I think the friendliness and sense of community in Nebraska is unique.
What about ID makes you excited?
I love several things about Infectious Diseases. To me, the interplay between the host immune system and infectious pathogens is the most fascinating concept in medicine. ID also has a unique role in treating not only the individual but also public health at large, which we have seen throughout the COVID-19 pandemic. I also love the variety; I see patients with infections in all organ systems, including both medical and surgical patients.
Tell us something interesting about yourself unrelated to medicine.
Outside of work, I mostly spend time with my wife and children. I try to read (something non-medical), do something outside when the weather permits, and enjoy practicing Brazilian Jiu Jitsu.
Dr. Juan Teran joins UNMC ID as an assistant professor and the medical director of the Nebraska Infection Control Assessment and Promotion Program (ICAP). He recently completed an ID fellowship at Boston University. Read on to learn more about this great new addition to the UNMC ID team. Congratulations Juan!
Tell us a little about your background in medicine.
I was born and raised in Quito, Ecuador and completed my medical education at Universidad Internacional del Ecuador. After obtaining my degree, I did a year of community medicine as a general practitioner in outskirts of Quito. That was my first exposure to ID by caring for diseases ranging from your bread-and-butter pathology like community-acquired pneumonia to more unique infections such as leishmaniasis and tuberculosis. With an enlivened interest for clinical medicine and ID, I moved to Florida where I completed my Internal Medicine Residency at the University of Miami/JFK Hospital in West Palm Beach. After three years in South Florida, I made my way northeast to Boston where I completed my fellowship in Infectious Diseases with a strong emphasis in Antimicrobial Stewardship.
One defining step in my career was completing an additional year of training in Infection Control and Hospital Epidemiology at the Boston VA Healthcare System. That year provided a great introduction to the inner workings of a hospital and all the work that goes behind the scenes to control and prevent health care-associated infections.
Tell us about your new position.
I’m joining UNMC as an Assistant Professor of Medicine in the Division of Infectious Diseases. Most of my work is dedicated to working with Nebraska ICAP as their new medical director. ICAP provides infection control and antimicrobial stewardship expertise to many healthcare settings, such as hospitals, dental offices, and dialysis centers, but also no non-healthcare settings, such as schools and daycares. I will also care for patients both in the inpatient and clinic settings.
Why did you want to work at UNMC?
I enjoy working in an academic setting where I get to learn from colleagues who are renowned experts in their fields. In addition, I really enjoy teaching medical students, residents, and fellows. Moreover, it is an honor to work at ICAP with an outstanding team that has provided such a positive impact on the state of Nebraska.
What about ID makes you excited?
I might be biased, but I love ID! I really enjoy the fact that I don’t have to focus on a single organ or system but rather, I can take a holistic view of my patients. Within ID, not only do I have to understand my patient, but also track down the microbe involved. I really enjoy that detective work.
Tell us something interesting about yourself unrelated to medicine.
I come from a family of musicians and artists. In 2022 they awarded my family with the Guinness world record for Most Family Members in a Musical (sadly, I was not able to join them in Ecuador for that show). I always have music on in the background, and I enjoy playing the guitar in my free time.
Research Digest is a periodic installment that recognizes the world-class clinical research performed right here at UNMC ID.This week, we feature two articles exploring the pharmaceutical treatment of two different infectious diseases with wide-reaching implications. As always, be sure to check out the linked full articles for more details.
The first article, co-authored by Dr. Fadul (left) and Dr. Bares (right; among others at UNMC and other institutions), details work conducted to assess the readiness of clinics providing care for people with HIV to implement a new generation of antiretroviral therapies (ARTs): long-acting injectables (LAIs). This new class of drugs repurposes current ART treatments in a form that can be taken once every 1-2 months instead of daily, improving patient compliance and viral suppression. Sparked by FDA approval of the first of these therapies in January 2021, the authors set out to determine the readiness of clinics to shift to this new ART platform. Among a wealth of detailed conclusions, the article found that the overwhelming majority of clinics surveyed (+90%) welcomed the implementation of LAIs and declared that the treatment was applicable, fitting, and suitable to their clinics. However, there was considerable variability in the current readiness of clinics to administer this new form of treatment, with clinics citing patient non-adherence to monthly visits and cost as primary concerns. The authors conclude that new approaches to increase patient compliance with regular visits are needed to optimize the roll-out of current and future LAI ARTs. Read the full story here.
The second article, authored by Dr. Sunagawa (right) and many others from the UNMC ID community, reports a new effort at UNMC to adequately address and document patient-reported penicillin allergy and graded challenges used for test doses in patients. Penicillin allergy is reported by 7-10% of patients, although more than 90% of these patients have been subsequently found to not be allergic to the antibiotic class. Lingering incorrect reports of allergy is a major factor driving providers to prescribe antibiotic agents with broader spectrums, higher adverse effect risk profiles, and increased antibiotic resistance. Furthermore, patient charts from those undergoing graded challenges to improve tolerability to these drugs may still falsely report allergy following testing. Assessing the clinical landscape of graded challenges and the magnitude of this problem was one of the primary goals of this study. The authors found that both oral and IV graded challenges with beta-lactam antibiotics were implemented successfully in a hospital setting without inpatient allergy consult and with a low rate of adverse events (1-4%), none severe. Additionally, 92% of EHR charts were updated following desensitization. Read the full article here.
Dr. Shawna Sunagawa is not new to UNMC ID, having completed her pharmacy residency here at Nebraska Medicine/UNMC. She is, however, transitioning to a new role within the division, and we are very excited to have her stay on! Read on to learn more about this fantastic new addition to the UNMC ID faculty. Congratulations, Shawna!
What is your background in medicine? How did you get to this point in your career?
I’m originally from Hawaii but completed my undergraduate and pharmacy degrees at Creighton University. I was fortunate enough to complete my PGY1 and PGY2 ID pharmacy residencies here at UNMC/Nebraska Medicine. And as much as I miss the year-round warm weather, I am so excited to continue to work with and learn from the phenomenal ID Division and College of Pharmacy faculty/staff!
Tell us a little about your new position.
I initially matched and started my PGY1 pharmacy residency here in 2021; however, I have just transitioned into my new Clinical Instructor role in July 2023. My main practice site will be supporting patients at the ID Specialty Care Center while participating in research and teaching activities within the College of Pharmacy.
Why did you want to stay at UNMC?
100% – the people! I get to work with some of the top infectious diseases clinicians/researchers in the nation, who are not only exceptional clinicians/researchers but are also fantastic people! They are clearly super supportive of new faculty’s career development/pursuits – education, research, clinical services, etc! Plus, with my practice site being the ID Specialty Care Center, I have the opportunity to continue to support and care for a diverse patient population.
What about ID makes you excited?
There are constantly evolving new concerns and issues within the realm of infectious diseases (pandemics, new anti-infective therapies, multi-drug resistant organisms, etc.), and I am excited to be able to play a role in helping solve many of these therapeutic puzzles/challenging cases. There’s always something new to learn!
Tell us something interesting about yourself unrelated to medicine.
I love attending sporting events, playing tennis, trying new restaurants, and hanging out with my husband and two pups! My husband and I have a lifelong goal of trying to watch an MLB game in every stadium. Now that we are coming out of the pandemic, we are excited to make it to a few more stadiums this upcoming year!
The following content was provided by Dr. Abbas (R) and Dr. Van Schooneveld (L), UNMC ID fellowship program directors. Read on to learn about our great program and please share with those who may be interested!
Fellowship application season is open, and as the leaders of our ID fellowship, we wanted to highlight some of the exciting aspects of our program. Our program and our division are growing. We began in 2011 with 2 fellows, grew to 4 in 2017, 5 in 2020, and our full complement now includes 6 fellows. Our faculty also continues to grow, as we now have 32 physician faculty and 4 full-time ID pharmacists with diverse expertise. Dr. Trevor Van Schooneveld is the Program Director and Director of the Antimicrobial Stewardship program and Dr. Anum Abbas is the Associate Program Director. This year we are looking forward to meeting you on our remote interviews via Zoom!
Dr. Casey Zelus teaching medical students about blood cultures
Fellows at UNMC enjoy a robust clinical experience that includes not only the typically complex patients seen at a tertiary referral center, but also includes extensive experience caring for immunosuppressed patients. In addition to our General ID service, where our fellows gain experience in teaching medical students and Internal Medicine residents, we have two separate immunocompromised services that care for oncology and solid organ transplant patients. We also have an orthopedic infectious diseases rotation where fellows gain experience managing these complex patients and work with faculty who have extensive experience in this area. We have expanded our ambulatory offerings with the creation of a non-tuberculous mycobacteria (NTM) clinic and a travel clinic. Fellows have the opportunity to spend time in the microbiology laboratory, as well as learn infection control and antimicrobial stewardship. The faculty at UNMC are nationally recognized experts in their field, and are also very approachable and devoted to the education and success of trainees. They have created extensive educational opportunities, covering topics from opportunistic infections in solid organ and hematopoietic stem recipients to emerging global pathogens and biopreparedness. Fellows gain knowledge in HIV/AIDS management working in our multidisciplinary HIV clinic which cares for over 1200 people with HIV. In addition to having access to world class ID expert antimicrobial stewardship, OPAT, and HIV pharmacists, our division also includes an ID pharmacy residency program and opportunities for research collaboration and rounding with pharmacy students, residents and faculty.
As new career opportunities develop for ID physicians, we have worked to provide our fellows with the skills to engage in these fields. UNMC ID fellows receive extensive experience in the area of infection control and antimicrobial stewardship as well as dedicated biocontainment training. UNMC also offers the opportunity to stay for an optional third year to further develop a research portfolio or pursue additional clinical expertise in subspecialty areas.
Graduate Dr. Raj Karnatak presenting his research
An important part of fellowship is developing skills in interpreting and performing research, and we provide our fellows with six months of mentored research experience centered on their career goals. A research committee assists fellows in mentor identification and project development. Fellows also participate in a week-long UNMC sponsored research training program, and typically present their work at national conferences like IDWeek and SHEA.
Our goal as program directors is to provide fellows with an educational experience that provides them with skills and knowledge to make them successful in whatever career path they choose. The opportunities available to ID physicians continue to expand and we hope you will consider UNMC ID. If you are interested in more information, please feel free to visit our website where you can check out a video to learn more about us. You can also contact us at the following:
Dr. Trevor Van Schooneveld Program Director, Infectious Diseases Fellowship Medical Director, Antimicrobial Stewardship Program University of Nebraska Medical Center 985400 Nebraska Medical Center Omaha, NE 68198-9400 Email: tvanscho@unmc.edu
Dr. Anum Abbas Associate Program Director, Infectious Diseases Fellowship Assistant Professor, Division of Infectious Diseases 985400 Nebraska Medical Center Omaha, NE 68198-9400 Email: anum.abbas@unmc.edu
It is August, and fellowship application season is upon us once again. Watch the UNMC ID blog in the coming weeks for fellowship application content. We begin with a practical guide to fellowship interviews. If you know someone gearing up for this important step, please share this post. A refresher on these skills can always be useful!
Multiple ID faculty contributed to this list and thus the credit goes to the entire UNMC Division.
As faculty, we have the amazing opportunity to both mentor and interview residents applying for fellowship in Infectious Diseases, and we have seen it all. From the great, well-prepared interviewee to the one who had the institutional information completely incorrect. We wish we could mentor every resident in person, but since that is not possible, we decided to do the next best thing and offer our tips and tricks to acing the ID (or any other) interview! Tips and tricks are in no particular order.
Be yourself and relax.
Articulate why you are interested in this fellowship program, what your ID interests are and where you think you would like your career to go (even if you acknowledge that might change or be a little vague at this time).
Have an idea of how the program works and ask specific questions to help deepen that knowledge regarding the education you will receive. What are the strengths, weakness and unique aspects of the program you want to know more about?
Remember that you are interviewing the fellowship program as much as they are interviewing you. Do your research and come prepared with questions about everything from how the fellowship will prepare you for your career as an ID physician to where you will park.
Need suggestions on how to curate your list of questions?
Look up the program and Division on their website.
It is helpful to know a little about the faculty you are interviewing with, so if you get a schedule ahead of time find out what their clinical/research interests are and ask them about it – you can check out their publications on PubMed or Google Scholar to focus questions on specific topics. If you don’t get a schedule ahead of time, ask them what their interests are or what their role is during your interview.
Formulate questions important to you about the program, the institution and the local area regarding resources, lifestyle and more.
Be prepared to talk about your successes and the challenges you have encountered. For example, if you have an unexpected break in training, use that as example to illustrate what you learned from that experience. We do not expect perfection, but value honesty and clarity.
If you have something on your application that might be viewed negatively (academic difficulties, etc.) take the initiative and explain how you have overcome it and why you are a good candidate now before we have to ask you about it.
Consider a “highlight” reel handout for faculty on an updates to your CV since you submitted your application in ERAS. This can be incredibly beneficial if you have had a new publication, presentation or other activities demonstrating your interest in ID and future potential as a fellow.
Be friendly and treat everyone, including program coordinators and other office personnel kindly and with respect. Your interview starts from the moment some first meets you (a current fellow, administrative assistant or staff) and ends when you say goodbye to the last person. ALL opinions count. If you are rude to anyone, trust us, we will find out.
Be truthful and be yourself. Don’t answer questions with what you think the interviewer wants to hear (e.g. don’t say you want to do academic medicine if you are interested in private practice). This is the only way for both you and the program to determine whether or not you are truly a good fit.
Tell us something interesting about yourself, even if it doesn’t relate to ID. It is important to be well-rounded, and hearing about hobbies, experiences and interests helps keep the interview conversation fun and flowing.
Thank the faculty for their time; the emails and cards with a personal comment regarding a specific detail of the interview are both appreciated and noticed.
This #PharmToExamTable post exploring the use of Rifampin in infective endocarditis was authored by Josh Meyer. Josh is a P4 Pharmacy student here at UNMC.
Take Home Points:
Rifampin should not be used to treat S. aureus native valve endocarditis.
There is currently low-quality evidence that suggests potential benefit for using rifampin to treat prosthetic valve endocarditis caused by S. aureus and only limited reports of outcomes from infections with commonly used bioprosthetic valves. The need for improved therapy in this serious infection is great.
Safety concerns warrant further investigation to adequately weigh the risks versus benefits and optimal dosing of using adjunctive rifampin for treatment of prosthetic valve endocarditis caused by S. aureus.
Background
Staphylococcus aureus is now considered to be the most common causative organism of infective endocarditis (IE).1 Every patient with a S. aureus bloodstream infection is at high risk of IE because the organism harnesses the ability to form structured biofilm matrices on indwelling medical devices and host tissue, which allows it to evade immune system defense mechanisms and impede penetration of antimicrobial drugs.2 This is just one mechanism that contributes to the significant virulence of S. aureus.
Findings from several in vitro and in vivo studies have provided a strong theoretical framework regarding rifampin’s unique pharmacokinetic and pharmacodynamic profile and its clinical utility for treating S. aureus infections.3 Rifampin’s high volume of distribution, ability to penetrate biofilms, and bactericidal activity against staphylococci make it a seemingly advantageous choice for treating S. aureus IE.4 However, resistance develops rapidly to rifampin when used alone so it should always be in combination with other antimicrobials. Recommendations for the treatment of staphylococcal IE depend on whether prosthetic material is involved, and rifampin is only recommended in select circumstances.
Guidelines for Staphylococcal Native Valve Endocarditis (NVE)
For the treatment of staphylococcal NVE, the most current guidelines from the American Heart Association & Infectious Diseases Society of America (AHA/IDSA) recommend against the routine use of rifampin for staphylococcal NVE. Instead, 6 weeks of intravenous (IV) anti-staphylococcal penicillins (nafcillin/oxacillin) or cefazolin for oxacillin-susceptible strains and IV vancomycin or daptomycin monotherapy for oxacillin-resistant strains.1
Why Isn’t Rifampin Recommended for S. aureus NVE?
The utilization of rifampin as adjunctive therapy for NVE caused by S. aureus has been shown to lead to increased rates of hepatotoxicity and overall mortality.1 Riedel and colleagues conducted a retrospective, matched-cohort study to compare clinical outcomes between 42 patients who had received adjunctive rifampin and 42 patients who received standard therapy for treatment of S. aureus NVE. They found that patients treated with rifampin had decreased survival at 30 days or hospital discharge (79% versus 95%; P = 0.048), increased median length of hospital stay (21.3 days versus 14.7 days; P = 0.09), and increased median length of bacteremia (5.2 days versus 2.1 days; P < 0.001). In addition, patients that received rifampin were more prone to have elevated hepatic transaminases (9 cases versus 1 case; P = 0.014). Although, the authors of this article note that these elevations were only observed in patients with underlying hepatitis C virus (HCV) infection who had baseline levels exceeding the upper limit of normal.5
Guidelines for Staphylococcal Prosthetic Valve Endocarditis (PVE)
PVE due to S.aureus has been estimated to have a mortality rate of >45%.6 Due to the significant mortality and morbidity that is associated with PVE caused by S. aureus, combination antimicrobial therapy including rifampin is advised per AHA/IDSA guidelines.1 They recommend IV anti-staphylococcal penicillins or cefazolin for oxacillin-susceptible strains and IV vancomycin for oxacillin-resistant strains, in combination with IV gentamicin during the first 2 weeks and IV or by mouth (PO) rifampin for the total duration of 6 weeks.1,7 The European Society of Cardiology (ESC) guidelines have very similar recommendations for the treatment of staphylococcal PVE; however, they suggest a daily dose of rifampin 900-1200 mg IV or PO in 2 or 3 divided doses. They also note that some experts recommend delaying the initiation of rifampin after 3-5 days until bacteremia has cleared.6 This is because of the risk of resistance developing during the stage of infection when bacteria are dividing in the bloodstream.
Why is Rifampin Recommended for S. aureus PVE?
The AHA/IDSA guideline recommendation to use rifampin is based on its activity against S. aureus and animal models. In the animal models, rats received subcutaneous implants to mimic prosthetic hardware and were subsequently inoculated with bloodstream isolates of methicillin-resistant S.aureus (MRSA). The findings of this study suggest that combination antimicrobial regimens containing rifampin are superior to single-drug regimens for sterilization of indwelling hardware infected with MRSA.8 However, the appropriateness of extrapolating this data to the treatment of IE in humans is somewhat debated.
Uncertainties Surrounding the Use of Rifampin
Timing of rifampin initiation
The reasoning for ESC’s recommendation to delay initiation of rifampin until clearance of bacteremia is due to in vitro observations of antagonistic effects against replicating bacteria and synergistic effects on dormant bacteria when combining rifampin with oxacillin.6,9 An additional in vitro study conducted by Zinner et al. showed that rifampin had synergistic effects on low concentrations of oxacillin, but antagonistic effects on high concentrations of oxacillin.10
Rifampin dosing
AHA/IDSA guidelines note that their recommended dose of 300 mg three times daily is not supported by any pharmacokinetic studies.1 In a 2020 survey of 557 infectious diseases physicians in the United States and Canada, 91% reported using rifampin to treat staphylococcal PVE; however, the majority (55%) of respondents reported that they had used a dose of 300 mg twice daily.11 Inconsistencies regarding dosing of rifampin and various in vitro studies showing its highly variable pharmacokinetic and pharmacodynamic profile highlight the need for additional studies.
Is Rifampin Use Associated with Better Outcomes for the Treatment of S. aureus PVE?
A retrospective analysis performed by Drinkovic and colleagues showed that the rate of valve sterilization was not significantly different in patients with S. aureus PVE who were treated with rifampin versus those that were not (67% versus 63%).12 More recently, Le Bot et al. conducted a multicenter observational retrospective cohort study to assess the impact of using rifampin for treatment of staphylococcal PVE. Baseline characteristics were similar between the group that received rifampin and the group that did not receive rifampin. However, MRSA was more prevalent in patients treated with rifampin (21.9% versus 6.0%; P = 0.04). After multivariate analysis, they found only 3 variables that were independently associated with 1-year mortality: cerebral emboli, definite IE based on the modified Duke criteria, and MRSA. Of the 180 patients enrolled in this study, 114 of them had PVE due to S. aureus. They found no significant difference in in-hospital, six-month, and one-year mortalities and no significant difference in relapse rate between the 64 patients who received rifampin-based combination treatment and the 50 patients who did not receive rifampin. However, they did show that patients treated with rifampin had a significantly longer length of hospital stay than those that did not receive rifampin (42.8 + 20.1 days versus 30.7 + 14.7 days; P = 0.0006). The authors of this study also point out that a substantial proportion (43.9%) of patients with staphylococcal PVE did not receive rifampin.7 This may reflect an evolving clinical approach to treating IE in which rifampin-based combination therapy is seemingly falling out of favor; however, due to the limited sample size and large period (2000-2018) in which data were collected for this retrospective analysis, it is difficult to make this presumption. Moreover, data in this study were obtained from 3 referral centers located in western France. Thus, their findings may not be representative of practice patterns in other European countries or the United States.
Rifampin: Warnings & Precautions
A key concern with rifampin is its potent cytochrome P-450 (CYP) system-inducing effects. It has its most potent inducing effects on CYP3A4, but it has also been shown to induce CYP2C9, CYP2C19, CYP1A2, UDP-glucuronyltransferase (UGT), and P-glycoprotein (P-gp).13 Consequently, rifampin is a common perpetrator of drug-drug interactions. Below is a table of major relevant drug-drug interactions.13-15 Significant interactions exist with a long list of other drugs that are not shown.
Table 1: Rifampin drug-drug interactions and effects
Mechanical heart valves place patients at high risk for valvular thrombosis and therefore necessitate lifelong anticoagulation with warfarin. Bioprosthetic heart valves are less durable than mechanical valves; however, they are less thrombogenic and only require 3 months of anticoagulation following placement.16 Direct oral anticoagulants (DOACs) such as rivaroxaban and apixaban are sometimes used off-label for patients with bioprosthetic heart valves.17Nonetheless, drug-drug interactions become a concern when rifampin is used to treat PVE in the setting of oral anticoagulation due to its tendency to decrease exposure of warfarin and DOACs, subsequently reducing their efficacy. This risk can be more readily mitigated in patients taking warfarin by routinely monitoring international normalized ratio (INR) and adjusting its dose accordingly. The interaction between DOACs and rifampin is more challenging to manage due to the limited ability to monitor. In addition to anticoagulants, the use of rifampin is contraindicated with several antiretrovirals and antifungals. This makes rifampin a much less appealing agent for any indication in patients with HIV and/or certain fungal infections.
Discoloration of bodily fluids is a common yet benign side effect of rifampin. Despite having a relatively mild side effect profile, the use of rifampin has been associated with serious adverse effects such as hepatotoxicity and interstitial nephritis.14 This, along with its effects on CYP450 enzymes, should be taken into consideration when determining if rifampin can be safely used to treat patients with PVE caused by S. aureus.
Conclusions
The European and American guidelines that were both published in 2015 strongly recommend the use of adjunctive rifampin for treatment of staphylococcal PVE. Despite the extensive uptake of this practice, it has not yet been shown to be effective. Additional clinical trials will be needed to better elucidate the clinical utility of rifampin in staphylococcal PVE. Furthermore, drug-drug interactions and patient-specific factors such as renal and hepatic function should be heavily considered when determining if rifampin can be safely used for staphylococcal PVE in individual patients.
References:
Baddour LM, Wilson WR, Bayer AS, et al. Infective endocarditis in adults: Diagnosis, antimicrobial therapy, and management of complications. Circulation. 2015;132(15):1435-1486. doi:10.1161/cir.0000000000000296
Vor L, Rooijakkers SH, Strijp JA. Staphylococci evade the innate immune response by disarming neutrophils and forming biofilms. FEBS Letters. 2020;594(16):2556-2569.doi:10.1002/1873-3468.13767
Perlroth J, Kuo M, Tan J, Bayer AS, Miller LG. Adjunctive use of rifampin for the treatment of Staphylococcus aureus infections. Archives of Internal Medicine. 2008;168(8):805. doi:10.1001/archinte.168.8.805
Adema JL, Ahiskali A, Fida M, Mediwala Hornback K, Stevens RW, Rivera CG. Heartbreaking Decisions: The Dogma and Uncertainties of Antimicrobial Therapy in Infective Endocarditis. Pathogens. 2023; 12(5):703. https://doi.org/10.3390/pathogens12050703
Riedel DJ, Weekes E, Forrest GN. Addition of rifampin to standard therapy for treatment of native valve infective endocarditis caused by staphylococcus aureus. Antimicrobial Agents and Chemotherapy. 2008;52(7):2463-2467. doi:10.1128/aac.00300-08
Habib G, Lancellotti P, Iung B. 2015 ESC guidelines on the management of infective endocarditis: A big step forward for an old disease. Heart. 2016;102(13):992-994. doi:10.1136/heartjnl-2015-308791
Le Bot A, Lecomte R, Gazeau P, Benezit F, Arvieux C, Ansart S, Boutoille D, Le Berre R, Chabanne C, Lesouhaitier M, Dejoies L, Flecher E, Chapplain JM, Tattevin P, Revest M. Is Rifampin Use Associated With Better Outcome in Staphylococcal Prosthetic Valve Endocarditis? A Multicenter Retrospective Study. Clin Infect Dis. 2021 May 4;72(9):e249-e255. doi: 10.1093/cid/ciaa1040. PMID: 32706879.
Lucet JC, Herrmann M, Rohner P, Auckenthaler R, Waldvogel FA, Lew DP. Treatment of experimental foreign body infection caused by methicillin-resistant Staphylococcus aureus. Antimicrob Agents Chemother. 1990 Dec;34(12):2312-7. doi: 10.1128/AAC.34.12.2312. PMID: 2128441; PMCID: PMC172053.
Van der Auwera P, Klastersky J. In vitro study of the combination of rifampin with oxacillin against Staphylococcus aureus. Rev Infect Dis. 1983 Jul-Aug;5 Suppl 3:S509-14. doi: 10.1093/clinids/5.supplement_3.s509. PMID: 6635442.
Zinner SH, Lagast H, Klastersky J. Antistaphylococcal activity of rifampin with other antibiotics. J Infect Dis. 1981 Oct;144(4):365-71. doi: 10.1093/infdis/144.4.365. PMID: 6270215.
Huang G, Gupta S, Davis KA, Barnes EW, Beekmann SE, Polgreen PM, Peacock JE Jr. Infective Endocarditis Guidelines: The Challenges of Adherence-A Survey of Infectious Diseases Clinicians. Open Forum Infect Dis. 2020 Aug 24;7(9):ofaa342. doi: 10.1093/ofid/ofaa342. PMID: 32964063; PMCID: PMC7489528.
Drinkovic D, Morris AJ, Pottumarthy S, MacCulloch D, West T. Bacteriological outcome of combination versus single-agent treatment for staphylococcal endocarditis. Journal of Antimicrobial Chemotherapy. 2003;52(5):820-825. doi:10.1093/jac/dkg440
Rifampin. In: Clinical Pharmacology [database on the Internet]. Tampa (FL): Elsevier; 2023 [cited 2023 Jun 3]. Available from: www.clinicalpharmacology.com. Subscription required to view.
Forrest GN, Tamura K. Rifampin combination therapy for nonmycobacterial infections.Clinical Microbiology Reviews. 2010;23(1):14-34. doi:10.1128/cmr.00034-09
Pai MP, Momary KM, Rodvold KA. Antibiotic drug interactions. Medical Clinics ofNorth America. 2006;90(6):1223-1255. doi:10.1016/j.mcna.2006.06.008
Otto CM, Nishimura RA, Bonow RO, et al. 2020 ACC/AHA guideline for the management of patients with valvular heart disease: A report of the american college of cardiology/american heart association joint committee on clinical practice guidelines. Circulation. 2021;143(5). doi:10.1161/cir.0000000000000923
Kalra A, Raza S, Jafry BH, et al. Off-label Use of Direct Oral Anticoagulants in Patients Receiving Surgical Mechanical and Bioprosthetic Heart Valves. JAMA Netw Open. 2021;4(3):e211259. doi:10.1001/jamanetworkopen.2021.1259
At UNMC ID, we are always proud of our leaders who strive to improve patient care daily. A few months ago, we featured Nichole Regan in a post detailing her work with the national Training-of-Trainers (TOT) Program presented by the HRSA Ryan White HIV/AIDS Program Center for Quality Improvement & Innovation (CQII). CQII celebrates its 20-year anniversary this year; nearly 2,000 individuals have graduated from its advanced trainings across the country, including our own Nichole Regan! The TOT is an advanced capacity-building training program for individuals with experience in clinical quality management who wish to refine their skills in training others on quality improvement principles and practice.
Last month, as part of this program, team members at Nebraska Medicine attended a mini-training led by Nichole focusing on the utility of process mapping and flow charts in improving the quality of patient care. Participants were taught how these tools are used in medical practice with real-world examples. Following this, they got to have some fun with the topic, using what they learned to develop a flow chart- not for medical processes, but instead for how to make a pizza! Takeaways from this exercise included:
It can be hard to find a good starting point. It often helps to work backward if you are stumped!
Each team had the same task but ended up with very different flow charts.
Flowcharts can be basic/high level or very detailed with processes inside of processes.
Flow charts can and should be modifiable for the specific task at hand.
Process mapping helps us understand, visualize and appreciate our processes— and also helps us know where improvement can happen.
Thanks, Nichole! Both for sharing the utility of these tools and for your continued commitment to quality improvement!
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