Research Digest is a periodic installment that recognizes the world-class clinical research performed right here at UNMC ID.Today, we review three articles covering the infectious complications of organ transplants. As always, check out the linked full articles for more details.
Dr. Zimmer, co-author of this review on GVHD-related bacterial pneumonia.
In the first article featured, co-authored by Dr. Andrea Zimmer, the post-organ transplant causes of bacterial pneumonia are outlined, particularly in regard to the chronic graft-versus-host disease (GVHD) population. GVHD is a systemic inflammatory response to organ transplantation where immune cells in the transplanted organ begin to attack the host. A severe complication of transplantation, treatment often necessitates long-term immunosuppression, which opens the door for opportunistic pathogens to cause disease. This review covers chronic GVHD and bacterial pneumonia pathophysiology and a host of specific causative pathogens including Mycobacterium tuberculosis, Legionnaires’ Disease, Nocardia, and Pseudomonas aeruginosa as well as preventative and treatment considerations. Read more here for the full details on this devastating transplant complication.
Dr. Abbas, the lead author of this article on WNv infections in transplant patients.
The second article, authored by Dr. Anum Abbas as well as Adia Sikyta, Dr. Diana Fluoresce, and others from the UNMC community, explores West Nile virus (WNv) infections following solid organ transplant. While WNv infection in immunocompetent individuals is typically asymptomatic or results in a mild fever, infection in immunocompromized solid organ transplant recipients can be much more severe, leading to neurological damage in some cases. Further, this patient population is at increased risk, with higher rates of infection than the general population. This study examined the medical records of solid organ transplant recipients at UNMC between 2010 and 2018, finding 8 patients with documented WNv infection. The majority of these patients previously received a kidney transplant and all presented with either meningitis, encephalitis, or both. The article explores the treatment, recovery, and outcome of these patients and compares this to the existing literature. Read on here for more information.
Dr. Stohs, lead author of this paper outline the utility of antimicrobial stewardship in the post-transplant patient population.
Lastly, Dr. Erica Stohs recently authored an article outlining the importance of antimicrobial stewardship in the care of solid organ transplant recipients. The article explains that antimicrobial stewardship is needed to combat rising antimicrobial resistance and associated adverse events (such as C. difficile infection) in this patient population. The paper explores, in great detail, exactly what can be done to combat these infectious transplant comorbidities, how to monitor progress, what works, and what likely doesn’t. The major take-aways were:
Clinicians can target C. difficile infections in transplant recipients through diagnostic testing stewardship and comparative trials of therapeutic and prophylactic agents.
Renal transplant recipients do not benefit from treatment of asymptomatic bacteriuria when greater than 2 months from transplant.
Solid organ transplant recipients benefit from antibiotic allergy delabeling, allowing receipt of narrowed, targeted antibiotics.
Research Digest is a periodic installment that recognizes the world-class clinical research performed right here at UNMC ID. Last time, we reviewed two articles covering advances in antibiotic and antimicrobial medications. This week, we feature three more articles from UNMC exploring the pharmaceutical treatment of different infectious diseases with wide-reaching implications. As always, check out the linked full articles for more details.
Dr. Kimberly Scarsi, one of the co-authors of this article
The first article, titled Pharmacogenetic interactions of efavirenz or rifampin and isoniazid with levonorgestrel emergency contraception during treatment of HIV or tuberculosis and co-authored by UNMC College of Pharmacy’s Michelle Pham, Anthony Podany, and Kimberly Scarsi, explores the interaction of isoniazid, rifampin, and efavirenz on the effectiveness of levonorgestrel as an emergency contraceptive. Some of these drugs alter the activity of detoxifying enzymes in the liver, potentially reducing the plasma concentrations of hormonal contraceptives. While this effect is avoided by administering higher levonorgestrel dosages, certain genetic mutations common in the general population also affect these enzymes and may further complicate compensatory treatment regimens. Indeed, this study found that individuals who possess CYP2B6 poor metabolizer genotypes displayed exacerbated efavirenz-levonorgestrel interactions, making this effect more difficult to overcome. In contrast, NAT2 slow acetylator genotypes reduced the interaction, underscoring that genetic variability can profoundly alter the efficacy and effective treatment dosages of many medications. Read the full story here.
Dr. Molly Miller, lead author of this article in Open Forum Infectious Diseases
The second article, co-authored by many members of UNMC ID and Pharmacy, including Molly Miller, Trevor Van Schooneveld, Erica Stohs, Jasmine Marcelin, Bryan Alexander, Andrew Watkins, Hannah Creager, and Scott Bergman, aimed to assess whether the implementation of multiplex PCR panels for pneumonia diagnosis impacted antibiotic de-escalation. This is crucial as earlier identification of causative organisms could result in a more rapid adjustment to the narrowest effective antibiotic regimen, potentially limiting the generation of antibiotic resistance to broad-spectrum antimicrobials. Conversely, the increased sensitivity of this technique to detect organisms could have the opposite effect, as clinicians treat PCR results which may not end up clinically significant. The group did not detect a difference in antibiotic use before or after implementation of the PCR pneumonia panel in this pilot study; however, this work lays the groundwork to further evaluate a significant real-world impact on antibiotic de-escalation in ICU patients treated for pneumonia. Read the article here.
Dr. Andre Kalil, author of this comment piece on antiviral therapy
The last article, written by Dr. Andre Kalil and published in The Lancet: Respiratory Medicine, reviews the effectiveness of Remdesivir in the treatment of patients hospitalized for COVID-19. Remdesivir is a viral RNA polymerase inhibitor with a complicated recommended treatment history throughout the pandemic. Kalil reviews the wealth of data supporting the use of this drug in hospitalized COVID patients, namely a faster time to recovery, shorter length of hospital stay, decreased progression to mechanical ventilation, and lower mortality. Nonetheless, many published guidelines over the past few years showed little agreement with each other, and none recommended expanded use of this treatment, a trend aided by shortages of drug production as well as research decisions that favored analysis of many different patient situations over a generalized analysis of efficacy among hospitalized patients, limiting the power of these studies. Dr. Kalil explores the history of Remdesivir use over the past few years, the potential missteps along the way, and lessons we can learn for future treatment of viral illnesses with life-saving antiviral medications. Read the whole story here.
Dr. Susan Swindells, clinician, researcher, and recipient of the 2023 Alexander Fleming Award for Lifetime Achievement
Last week was IDWeek, which brought many members of UNMC ID to Boston, Massachusetts, to learn and share all things ID. In addition, select individuals are honored by the Infectious Diseases Society of America (IDSA) for outstanding contributions to the field. This year, Dr. Swindells was recognized for her significant contributions to ID research, service, and clinical practice with the Alexander Fleming Award for Lifetime Achievement.
In giving this award, the IDSA president, Dr. Carlos del Rio, commented, “Dr. Swindells’ tireless efforts and leadership have led to clinical research successes that truly make a difference in the lives of persons living with HIV globally. We applaud her decades of mentorship and contributions to the field…”
Dr. Rupp also praised the news, saying, “Dr. Swindells is a skilled and compassionate clinician, a gifted scientist and a generous mentor and educator. Not only has Dr. Swindells been a local leader for HIV care, but she is also internationally recognized for her work in the treatment of tuberculosis and opportunistic infections associated with HIV/AIDS. Furthermore, Dr. Swindells served admirably during the COVID-19 pandemic and helped to craft the US national guidelines regarding evaluation and treatment of infection due to SARS CoV-2. The UNMC ID Division could not be more pleased or proud.”
Congratulations, Dr. Swindells! This award is a huge achievement and much deserved. Your contribution to UNMC and the ID field at large has been nothing short of extraordinary. Thank you for all you do!
We are excited to welcome Dr. Stephen Cooper as a new fellow in our Infectious Diseases program! Dr. Cooper joins us following the completion of an internal medicine residency in Omaha at Creighton University.Read on to learn a little more about him.
Tell us about the position you are starting.
I am excited to undergo a fellowship in infectious diseases at the University of Nebraska Medical Center. I look forward to learning more about the world of infectious diseases, everything from microorganism resistance mechanisms to politely asking primary teams to remove central lines.
Why did you choose to come to work at UNMC?
I realized during my M3 year as I was writing another patient biography that I belonged with the infectious disease doctors of the world. I’ve always wanted to see and learn as much as possible and was excited by the opportunities present at UNMC. We have a phenomenal ID team here with world-renowned physicians and expert teams in subspecialty areas of ID like orthopedics, transplant, and hematology/oncology ID.
What makes you excited about working in ID?
There isn’t really a good way to say I like infectious diseases without sounding like a weird bacteriaphile. It doesn’t help that our ears perk up when a patient’s cultures grow an organism that the primary team can’t pronounce. I find infectious diseases fascinating but mainly derive satisfaction from ridding people of the effects that come from harboring said mutinous organisms. The field of ID is so broad because any organ can have an infection in it. I love that I get to keep wearing my internal medicine hat when thinking about patients and yet have the sole job of eradicating infections. As physicians, we deal with a lot of chronic issues, and it is really rewarding to be able to cure someone of an infectious process.
Tell us something about yourself that is unrelated to medicine
I am a husband and father of two of the most wonderful children on the planet, unbiased opinion. I enjoy pretty much every sport known to mankind from your classics like basketball and football to your backyard games like Bareither Ball and Can Jam. I was a decathlete in college and have always enjoyed being active, much to the chagrin of my sinew. On a typical day off you can find me throwing some disc at Seymour park or biking around Omaha.
We are excited to welcome Dr. Tyler Rosengren as a new fellow in our Infectious Diseases program! Dr. Rosengren joins us following the completion of an internal medicine residency in Mason City, Iowa at MercyOne North Iowa.Read on to learn a little more about him.
Tell us about the position you are starting.
Here at UNMC, I am starting an Infectious Disease fellowship to continue following an interest I have had in microbes that I have had since early in my career.
Why did you choose to come to work at UNMC?
Growing up outside of Omaha, UNMC is where I have had a lot of my personal medical care in the past. As I progressed through my education, this hospital system became one that I looked at in a different light and wanted to become a part of. The added benefit of having family not far from the city is a bonus, but the UNMC Infectious Disease program itself is not only fantastic on its own, but it has some national recognition for things such as its antimicrobial stewardship guidelines and its role in the Ebola cases some years back.
What makes you excited about working in ID?
ID is an interesting field of medicine where not only are you treating the patient, but their disease process itself. There is another organism(s) that you are actually trying to treat that is causing all of the patient’s problems. This means that as new microbes and viruses are found, we have new organisms to treat. This, coupled with the difficulty in treating ever-evolving organisms, leads to a field that is constantly having to shift and adjust its thought process and standard of care. This constant evolution is what makes me interested in the field as a whole.
Tell us something about yourself that is unrelated to medicine
Outside of medicine, I have my wife and son whom I spend most of my time. We do have a pet rabbit as well. I have an odd conglomeration of hobbies from video games and reading fantasy stories to going on trips, trying new restaurants, and starting home projects. My attention span for any one project/hobby can be fairly limited by the amount of free time I have, so sometimes I end up bouncing between things not infrequently trying to do multiple things all at once.
The UNMC Infectious Diseases Division recognizes the talented and dedicated group of Advanced Practice Providers (APPs) that deliver excellent and compassionate clinical care for our patients. We are appreciative and feel privileged to work with you. Thank you for all that you do – every day!
Here at UNMC ID, we have 5 service lines that rely on these crucial team members (pictured above in order from left to right):
Community ID:
Amber Klaasmeyer, APRN-NP; Michelle Rude, APRN-NP
HIV/SCC:
Dan Cramer, APRN-NP; Ann Fitzgerald, APRN-NP; Nikki Regan, APRN-NP; Christine Tran, APRN-NP
Oncology ID:
Whitney Knuth, APRN-NP; Sarah Schober, PA-C; Jolene Tijerina, APRN-NP
Orthopedic ID:
Sarah Maher, APRN-NP; Kimberly Rhodes, APRN-NP
Solid Organ Transplant ID:
Cassandra Day, PA-C; Jen Hrbek, APRN-NP; Adia Sikyta, APRN-NP
Dr. Mackenzie Keintz is no stranger to UNMC ID as a third-year ID fellow, but she is joining UNMC ID faculty as a clinical instructor. She is also the associate medical director of Nebraska ICAP’s Project First Line, which enhances the ID training of frontline healthcare workers. Read on to learn more about Dr. Keintz. Congratulations, Mackenzie!
Tell us a little about your background in medicine.
I was born in a small town in northern Wisconsin. I went to the University of Wisconsin-Madison for my undergraduate degree. The major I had chosen my freshman year at UW-Madison was discontinued leading me to select Medical Microbiology and Immunology, which ended up being very fortunate as it led me to my decision to become an infectious disease physician. I went to St. George’s University in Grenada, West Indies for medical school. I lived in Grenada for two years before moving to Atlanta, GA for my clinical rotations. I came to UNMC in 2018 for my internal medicine residency and completed my training in infectious disease here as well!
Tell us about your new position.
I am joining the Division of Infectious Disease faculty as a clinical instructor and third-year fellow. I am also the associate medical director of Project First Line through our Nebraska ICAP program and associate medical director of the Nebraska ASAP program. I will see patients on the General Infectious Disease service both at main campus and at Bellevue. I will also take care of patients living with HIV in clinic.
I am pursuing a third year of fellowship to further my training in antimicrobial stewardship or using antibiotics wisely. I am particularly interested in antibiotic prescribing in the outpatient setting. Over the next year, I will be working with UNMC providers in the outpatient setting to improve antibiotic prescribing. In my role in Nebraska ASAP, I will utilize those skills to improve outpatient antibiotic prescribing across the entire state of Nebraska! I also am very interested in medical education. Through my role with Project First Line, I have been working on educating frontline healthcare workers, including CNAs, RNs, and environmental service workers, in infection control practices. These trainings help keep all our of colleagues safe while they provide care for our patients.
Why did you want to work at UNMC?
I was drawn to UNMC during residency interviews due to the friendly collegial culture. I knew that I wanted to return to the Midwest after living abroad and in the southern US for a couple of years. UNMC has a nationally recognized division of infectious diseases. Even as an internal medicine resident, I was welcomed into the ID division, leading to excellent mentorship experiences throughout training. After finishing training, I knew I wanted to stay at an academic medical center. UNMC has everything I was looking for in terms of clinical, stewardship, and medical educational opportunities.
What about ID makes you excited?
Clinically, the thing I like most about ID is the puzzle. Sometimes, that is in the form of a diagnostic mystery, while other times, it comes in the form of management strategy. I like being able to piece together what is the most efficient and effective antibiotic combination I can create for a given infection. I also enjoy that I get to learn really interesting things about my patients. I get to hear about their travel, pets, and passions, which not only helps me to understand their infection risk but also them on a deeper level.
I am also very excited about antimicrobial stewardship. I love being able to help my colleagues in other areas of medicine take care of patients better. Antimicrobial resistance is a problem that continues to grow so it is very important to utilize our antibiotics thoughtfully to preserve their function in the future.
Tell us something interesting about yourself unrelated to medicine.
In addition to my interest in microbes, I have an interest in growing rare plants. The prize of my collection right now is a Monstera Albo (pictured right)!
Part 2 of this #PharmToExamTable post explores treatment options for complicated ESBL UTIs, offers patient case examples, 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.
What are preferred antibiotics for the treatment of complicated cystitis and pyelonephritis caused by ESBL-producing organisms?
Treatment for complicated cystitis (cUTI) and pyelonephritis differ in terms of preferred antibiotics and duration compared to uncomplicated cystitis. Nitrofurantoin and fosfomycin cannot be used because they do not achieve adequate concentrations in the renal parenchyma.8,9
Preferred options to treat complicated cystitis and pyelonephritis include SMX-TMP, fluoroquinolones, and carbapenems.1 One study compared cure rates with ciprofloxacin 500 mg twice daily for 7 days to SMX-TMP 800-160 mg twice daily for 14 days.10 There were 255 premenopausal women analyzed in the study, with half in each antibiotic arm. Ciprofloxacin had cure rates of 99%, while SMX-TMP cured 89%. Of note, 24% of patients had side effects from ciprofloxacin, and 33% had side effects from SMX-TMP.10 Specific side effects and drug information can be seen in Table 2.
Another study compared IV levofloxacin 750 mg daily for 5 days versus IV levofloxacin 500 mg until clinical symptoms subside then transition to oral (PO) levofloxacin 500 mg daily for 7-14 days for the treatment of complicated UTIs and pyelonephritis.11 The five-day course of IV levofloxacin 750 mg daily had an 89.87% clinical effectiveness rate, and the 7 – day course of IV then PO had an 89.31% effectiveness rate, with both microbiological rates also being similar. These courses were deemed non-inferior, meaning the short course therapy of IV levofloxacin 750 mg daily can be utilized for treatment, meanwhile mitigating resistance.11 Of note, levofloxacin 750 mg and 500 mg has been proven to have 99% bioavailability in its oral tablet formulations compared to the IV option.12 With this study showing IV levofloxacin 500 mg for 5 days treats cUTI and pyelonephritis successfully, it can be extrapolated based on the bioavailability studies that oral levofloxacin can be used in place of IV. As most patients are initiated on IV antibiotics when admitted into the hospital, it would seem reasonable after the diagnosis of complicated UTI or pyelonephritis to switch patients to oral levofloxacin for the remainder of treatment, given the patient can take and absorb oral medications. However, these two studies did not include ESBL-producing organisms but are included in the ESBL-producing organisms treatment guidelines.1
Lastly, if the patient is critically ill, has a history of ESBL, or has resistance to fluoroquinolones and SMX-TMP, carbapenems can be used for treatment.1 However, time on carbapenems should be limited to save bacterial activity for future use by the patient.1
Patient Case Examples:
A 74-year-old female (weight: 90 kg) who lives in a nursing home, reports to her nurse that she is having new burning urination, nausea, incontinence, and lethargy. Her past medical history (PMH) includes COPD, CKD stage 3, osteoporosis, and a hysterectomy. Her urinalysis (UA) shows the urine is positive for nitrites and leukocyte esterase. The urine culture demonstrates ESBL Klebsiella oxytoca which has never been in her urine before. The patient reports unilateral lower back pain and has developed intermittent temperatures peaking at 38°C while receiving acetaminophen 1000 mg Q8H. The diagnosis for pyelonephritis is made by the medical team when the resident is asked for. No reported drug allergies or past use of antibiotics. What is the best antibiotic choice and duration for her?
Levofloxacin 750 mg PO daily for 5 days (preferred pyelonephritis treatment)
Nitrofurantoin 100 mg BID for 3 days (Beers Criteria)
Ertapenem 1g q24 hours for 5 days (Too broad spectrum & increased cost/burden of administration)
Ciprofloxacin 250 mg BID for 3 days (uncomplicated UTI treatment)
A 33-year-old female at the clinic reports she just got back from her vacation in the Maldives this weekend and reports burning urination, nausea, vomiting, and subjective fever. Her PMH only includes type 1 diabetes, with an A1c below 7% for many years. Her UA is positive for nitrites and leukocyte esterase. Her urine culture resulted as ESBL E. coli. No reports of back pain at the time. She said she’s never had a UTI before and hasn’t taken antibiotics for many years, but mentioned she is allergic to Sulfa drugs (reaction: difficulty breathing). What is the best antibiotic choice and duration for her?
Nitrofurantoin 100 mg BID for 5 days (Preferred uncomplicated UTI treatment)
Ertapenem 1g q24 hours for 5 days (Too broad spectrum & increased cost/burden of administration)
Levofloxacin 750 mg QD for 3 days (Not first line per ESBL guidelines & risky side effect profile)
Sulfamethoxazole-trimethoprim 800 -160 mg BID for 3 days (Allergic)
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
Agwuh KN, MacGowan A. Pharmacokinetics and pharmacodynamics of the tetracyclines including glycylcyclines. J Antimicrob Chemother. 2006;58(2):256-265. doi:10.1093/jac/dkl224
Ten Doesschate T, Kuiper S, van Nieuwkoop C, et al. Fosfomycin Vs Ciprofloxacin as Oral Step-Down Treatment for Escherichia coli Febrile Urinary Tract Infections in Women: A Randomized, Placebo-Controlled, Double-Blind, Multicenter Trial. Clin Infect Dis. 2022;75(2):221-229. doi:10.1093/cid/ciab934
Talan DA, Stamm WE, Hooton TM, et al. Comparison of ciprofloxacin (7 days) and trimethoprim-sulfamethoxazole (14 days) for acute uncomplicated pyelonephritis pyelonephritis in women: a randomized trial. JAMA. 2000;283(12):1583-1590. doi:10.1001/jama.283.12.1583
Ren H, Li X, Ni ZH, et al. Treatment of complicated urinary tract infection and acute pyelonephritis by short-course intravenous levofloxacin (750 mg/day) or conventional intravenous/oral levofloxacin (500 mg/day): prospective, open-label, randomized, controlled, multicenter, non-inferiority clinical trial. Int Urol Nephrol. 2017;49(3):499-507. doi:10.1007/s11255-017-1507-0
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
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