The following content was provided by Valentina Orduna, a medical case manager at the Specialty Care Clinic. She joined the HIV/Infectious Diseases team in May 2017 after already working for Nebraska Medicine for 16 years. At Nebraska Medicine, she started as a Pharmacy Technician for 10 years, three years as a Pharmacy Financial Counselor, and three years at the Peggy Cowdery Clinic as a New Patient Coordinator. Valentina is bilingual in Spanish and English. She is devoted and passionate about assisting in the medical field and helping the community.
Earlier this month, UNMC ID’s Specialty Care Clinic participated in the annual Cinco De Mayo festivities, using this opportunity to spread awareness and education about HIV. Read on for Valentina’s report from this great community outreach event.
“Earlier this month we celebrated Cinco De Mayo in South Omaha. Brief information about Cinco De Mayo: this event is NOT Mexican Independence Day. Cinco de Mayo celebrates the date of the Mexican army’s May 5th, 1862 victory over France at the Battle of Puebla during the Franco-Mexican War. Although this event is not celebrated much in Mexico (except in Puebla), in the United States, Cinco de Mayo is a big celebration.
In Omaha, the event runs for three days and attracts about 200,000 people to South Omaha. Each year the Specialty Care Center (SCC) tries to participate in either the health fair or the parade. This year we participated in the parade to bring HIV awareness and education to the community. From my experience working with mainly Hispanic patients, there is still a lot of stigma about HIV and how it is transmitted. We wanted to bring basic information about how HIV is transmitted and how it is not transmitted. I’m thankful for the support of everyone at the SCC who helped me make the participation in this event a success and I’m looking forward to future participation in different events in the Hispanic community. “
– Valentina Orduna, bilingual medical case manager, Specialty Care Clinic – Nebraska Medicine
The third annual Infectious Diseases (ID) Pharmacists Day is today, Monday, May 22, 2023. This day recognizes the importance of ID pharmacists and the contributions they make to patient care. Here at UNMC ID, we are lucky to have a team of highly talented and dedicated ID pharmacists working to help patients and fight infectious diseases every day. In celebration of this day, read on below for a quick introduction to some of our fantastic ID pharmacists.
Bryan Alexander, PharmD, BCIDP, BCPS, AAHIVP
Clinical Pharmacist and Pharmacy Program Coordinator for Outpatient Parenteral Antimicrobial Therapy
Brief Biography: After having been raised in the suburbs outside Cleveland, my training and professional life have taken me to stops living in Chicago, Baltimore, Saint Louis, central Virginia, and now Omaha. My family is now happily settled here – my wife is a university professor and we have two elementary-age children.
I love being an ID Pharmacist because the profession is so wide-ranging in scope and impact, and pharmacotherapy remains central to the range of countermeasures that we employ. Also, infectious disease attracts the most collaborative, brilliant, and compassionate people, such that the teams I get to work with and the problems we work on are constantly edifying.
I love being an ID Pharmacist because ID is so complex and interesting; there is always a new problem to solve or a drug regimen to optimize to try to ensure the best care for patients. I work with the absolute best people who make my job so much fun.
Brief Biography: Grew up in rural Nebraska and attended the University of Nebraska-Lincoln (Go Huskers!) for undergrad prior to obtaining my PharmD from the University of Nebraska Medical Center. I then completed my PGY1 pharmacy residency and PGY2 ID pharmacy residency at Nebraska Medicine prior to accepting my current position.
Molly Miller, PharmD, BCIDP
Clinical Pharmacist Practitioner practicing in Infectious Diseases, Antimicrobial Stewardship, and Outpatient Parenteral Antimicrobial Therapy
Brief Biography: I am from a small town in Northern Nevada originally and went to undergrad and pharmacy school in Utah, where I graduated in 2020. I then came to NMC for residency, and stayed on for my career!
I love being an ID Pharmacist because… Too many reasons to just pick one. For starters, I love the impactful work that I get to do day in and day out. Making a positive impact on patients’ lives and public health is very rewarding and fulfilling. This area of medicine also appeals to my natural curiosity and need for life-long learning as the field is rapidly evolving with new drugs, pathogens, emerging infections, and evolving resistance patterns.
I love being an ID Pharmacist because it keeps me on my toes! There is always something new to learn and new ways to solve problems. The ID group at Nebraska Medicine is extraordinarily collaborative and knowledgeable and I am lucky to be able to work with them on a daily basis.
Brief Biography: I was born and raised in Omaha, received my PharmD from the University of Nebraska Medical Center in 2012, and started at Nebraska Medicine Bellevue. I became the Antimicrobial Stewardship Pharmacist at Nebraska Medicine Bellevue in 2017.
Daniel Schroeder, PharmD, BCPS
Clinical Pharmacist Practitioner and Antimicrobial Stewardship Pharmacist at Nebraska Medicine Bellevue and Nebraska Antimicrobial Stewardship Assessment and Promotion Program
Jenna Pruesker, PharmD, BCPS
Nebraska Antimicrobial Stewardship Assessment and Promotion Program Pharmacy Coordinator at Nebraska Medicine and Nebraska DHHS Pharmacist
Brief Biography: Doctor of Pharmacy; University of Nebraska Medical Center, College of Pharmacy 2013, PGY1. Residency: CHI Health Saint Elizabeth, Lincoln, Nebraska.
Before joining Nebraska Medicine in 2022, I spent 9 years at Faith Regional Health Services in Norfolk, Nebraska as the Antimicrobial Stewardship Program Director.
I love being an ID Pharmacist because it involves so much critical thinking and problem-solving. My work is primarily outreach to rural, resource-limited settings, so helping facilities solve antibiotic-related problems challenges me to think outside the box every day.
I love being an ID Pharmacist because the field is constantly evolving which provides plenty of challenging clinical situations to work through and endless research opportunities.
Brief Biography: I graduated from the University of Nebraska College of Pharmacy in 2007 and joined the HIV/Infectious Diseases group in 2015 and the Department of Pharmacy Practice in 2019. As a pharmacy clinician at the Specialty Care Center, I provide care for people living with HIV including antiretroviral therapy initiation and revision as well as various other management services together with primary care services.
Josh Havens, PharmD, BCPS
Specialty Care Center, HIV Program
Shawna Sunagawa, PharmD
PGY2 ID Resident
Brief Biography: I am originally from Hawaii but completed my undergrad and pharmacy degree at Creighton University, #RollJays! I matched for PGY1 residency at Nebraska Medicine and was fortunate enough to stay on for a PGY2 ID!
I love being an ID Pharmacist because of the interprofessional nature of the field! Not only am I working with phenomenal ID providers, pharmacists, microbiologists, and other healthcare professionals but I also get to “work with” some pretty cool bugs/drugs!
Brief Biography: I currently work as the Antimicrobial Stewardship Coordinator for Nebraska Medicine and as a Clinical Professor at the Department of Pharmacy Practice at the University of Nebraska Medical Center. I am also the Program Director for the PGY2 Infectious Diseases Pharmacy Residency and conduct research in infectious diseases pharmacotherapy. My group’s current project is optimizing anti-infective use inside and outside of hospitals.
Scott Bergman, PharmD, FCCP, FIDSA, BCIDP
Pharmacist Coordinator, Antimicrobial Stewardship Program (ASP) – Nebraska Medicine
In case you missed it, there is still time to register online for the 2023 Antimicrobial Stewardship Summit. Registration closes this upcoming Tuesday, May 23rd. Read below for information regarding this great opportunity!
The Nebraska Antimicrobial Stewardship Assessment and Promotion Program (ASAP) will be hosting its annual Nebraska Antimicrobial Stewardship Summit in person on Friday, June 2, 2023, at the Embassy Suites LaVista Hotel and Conference Center. There will be a combined morning session followed by afternoon breakout sessions with targeted presentations in long-term care and acute care/outpatient settings tracks. Registration for the Summit is $99 per attendee, which includes parking, food, and CE credits for physicians, nurses, pharmacists, and medical laboratory scientists. Read on below for more information and to register!
TARGET AUDIENCE This accredited continuing education activity is designed for:
– Post-acute and long-term facilities: Long-term care providers, medical directors, infection preventionists, nurses, consultant pharmacists, directors of nursing, quality program leaders, and other health care providers interested in improving the management of common infections through the incorporation of antimicrobial stewardship principles.
– Outpatient facilities and acute care hospitals: Family medicine providers, internal medicine providers, ambulatory care providers, pharmacists, nurses, medical directors, quality program leaders, and other health care providers interested in improving the management of common infections through the incorporation of antimicrobial stewardship principles.
SUMMIT LOCATION Embassy Suites by Hilton Omaha La Vista Hotel & Conference Center 12520 Westport Parkway, La Vista, NE 68128
This #PharmToExamTable post exploring the pathophysiology and approach to cefepime neurotoxicity was authored by Xiaotong Zhang and Kaycee Bartels, 2023 PharmD candidates at the University of Nebraska Medical Center (UNMC).
Fast Facts: – Cefepime-induced neurotoxicity (CIN) is relatively rare and can be difficult to identify but should be considered if a patient begins experiencing altered mental status changes during cefepime therapy, especially in the setting of impaired renal function.
– When CIN is identified, cessation of cefepime, use of anti-epileptic drugs, and hemodialysis are management options. A note of the adverse reaction should be documented in the patient chart to alert future providers that neurotoxicity occurred during cefepime therapy. Careful evaluation of renal function or potentially avoiding cefepime should be considered in the future.
– Beta-lactam therapeutic drug monitoring is being researched to reduce the likelihood of adverse effects such as CIN, but there are no currently published national guidelines for practitioners to widely implement this process.
What is cefepime-induced neurotoxicity?
Kaycee Bartels, UNMC PharmD candidate and co-author of this post.
Cefepime-induced neurotoxicity (CIN) was first noted in a patient with end-stage renal disease on hemodialysis in 1999. This patient presented with altered mental status, myoclonus, and experienced a tonic-clonic seizure, but recovered after urgent hemodialysis.[1] It is estimated that CIN occurs in 3% of patients and mean onset of CIN symptoms is 5 days after cefepime initiation.[2] Cefepime is a fourth-generation cephalosporin that was FDA approved in 1996.[3] It has activity against gram-negative bacilli such as Pseudomonasaeruginosa, Klebsiella pneumoniae, and Serratia, gram-positive cocci including methicillin-susceptible Staphylococcus aureus and Streptococcus pneumoniae, and is effective against AmpC beta-lactamase-producing Enterobacterales.[2, 4] Cefepime can be utilized for the treatment of pneumonia, febrile neutropenia, urinary tract infections, uncomplicated skin and soft tissue infections, and complicated intra-abdominal infections.[3] It is primarily excreted by the kidneys (85% unchanged) and has a warning for neurotoxicity listed in the package insert. During post-marketing surveillance, serious adverse reactions have been reported including life-threatening or fatal occurrences of encephalopathy (disturbance of consciousness including confusion, hallucinations, stupor, and coma), myoclonus, seizures, and nonconvulsive status epilepticus. [3, 5]
What is the mechanism of cefepime-induced neurotoxicity (CIN)?
The proposed mechanism of cefepime-induced neurotoxicity is not well understood; however, it is thought to be caused by GABA-A receptor inhibition.[2, 6] This inhibition of GABA-A prevents influx of chloride ions into the postsynaptic neuron and causes an increase in action potential.[7] This increase in cellular excitability leads to altered mental status and seizures.[2, 8]
All beta-lactam antibiotics have the potential to cause neurotoxicity; however, it has been shown that cefepime carries a higher risk. In a retrospective study of patients treated with either cefepime or meropenem, cefepime carried a ten times higher risk of convulsions than meropenem.[9] There are certain risk factors that can increase the likelihood of experiencing CIN, including hematological malignancy, critical illness, older age, and renal dysfunction, which all lead to increased drug exposure.[10, 11] While there are many risk factors, the primary risk factor associated with CIN is renal dysfunction, as excessive serum concentrations of cefepime (>20 mg/L) have been associated with neurotoxic adverse effects.[9, 10]
Xiaotong Zhang, UNMC PharmD candidate and co-author of this post.
A retrospective cohort study analyzed the frequency of cefepime-associated neurotoxicity in patients with varying degrees of renal dysfunction. Only 4% of patients with eGFR > 90 mL/min/1.73m2 experienced neurotoxic symptoms, while 54% of patients with eGFR < 30 mL/min/1.73m2 experienced neurotoxic symptoms.[10] This study demonstrated the potential increased risk for cefepime neurotoxicity in patients with renal dysfunction.
How can cefepime neurotoxicity be prevented?
As mentioned above, higher serum concentrations could put patients at increased risk for neurotoxicity. Therefore, appropriate renal dose adjustments are necessary to ensure patients do not accumulate cefepime.
In addition to renal dose adjustments, dosing strategies to optimize time above the minimal inhibitory concentration (MIC) while minimizing total daily drug exposure can be utilized since cefepime is a beta-lactam with time-dependent bactericidal activity. To ensure effectiveness of therapy, free drug concentration should remain above the minimum inhibitory concentration (fT>MIC) 70% of the time.[12] Extended infusions or continuous infusions of cefepime have been shown to optimize time above MIC. A systematic review found that at the same total daily dose, administering cefepime as prolonged intermittent infusions over 3 to 4 hours or continuous infusions (4 grams every 24 hours) consistently improves achievement of PK-PD targets compared with traditional intermittent infusions over 30 minutes every 12 hours.[13] If an intermittent dosing regimen with a short infusion time of 30 minutes is used, smaller doses given more frequently will improve fT>MIC. A retrospective cohort study of inpatients with documented Gram-negative bacteremia or pneumonia described an alternate dosing regimen that replaced doses of 2 grams every 12 hours with 1 gram every 6 hours. The cefepime dosing regimen of 1 gram every 6 hours led to a higher probability of target attainment (PTA) and a similar clinical outcome compared to traditional dosing of 2 grams every 12 hours.[14]
When cefepime neurotoxicity is suspected, how can symptoms be managed?
When CIN is suspected, further work-up for etiology should be performed including an electroencephalogram to assess neurological symptoms, if available.[15] Cefepime therapy should be discontinued, and alternative antibiotic therapy should be initiated. Resolution of CIN occurs a median of 2 to 3 days after the interventions.[2, 11] When CIN occurs, appropriate renal dose reduction, cessation of cefepime, and use of anti-epileptic drugs have been demonstrated to provide clinical improvement.[5, 8, 10, 16] Hemodialysis should be considered a treatment option in patients with severe encephalopathy to rapidly decrease the blood and cerebrospinal fluid cefepime levels and shorten the duration of central nervous system toxicity.[15]
What’s on the horizon for prevention of CIN?
Beta-lactam therapeutic drug monitoring (TDM) is being studied as a strategy to prevent CIN. The pharmacokinetics of cefepime are altered under certain pathophysiological conditions, which may increase total cefepime exposure. Therapeutic drug monitoring of cefepime may be beneficial in certain patients including those who are critically ill, have life-threatening infections, have acute or chronic renal failure, or are infected with more resistant pathogens.[12]
A retrospective cohort study conducted at the University Hospital of Bern, Switzerland included 319 patients from whom TDM was performed during cefepime therapy. Cefepime was given three times a day with dosing adjustment for an estimated glomerular filtration rate (eGFR) of ≤ 50 mL/min/1.73 m2 according to the manufacturer’s recommendations. Cefepime trough concentrations were obtained < 1 hour prior to the next dose and the highest cefepime plasma trough concentration was used to assess the association between the incidence of CIN and cefepime plasma trough concentration. Results from multivariable logistic regression showed for every increase of 1 mg/L in the trough the risk of neurotoxicity increased by 33% (OR 1.33 [95% CI 1.23—1.45], p <0.001). Based on a fitted logistic regression model, the study found that the probability of neurotoxicity was 25% for cefepime trough concentrations ≥ 12 mg/L, 50% for cefepime concentration ≥ 16 mg/L, and no individual developed neurotoxicity at trough level < 7.7 mg/L.[10] A systematic review found that serum or plasma cefepime trough levels of >20 mg/L are related to higher risk for developing cefepime-induced neurotoxicity (CIN), while the trough levels under around 7 mg/L would result in a low risk of CIN.[8] TDM is one method to evaluate the risk for CIN, but further research on the thresholds of neurotoxicity and efficacy are needed to direct our utilization of levels in daily practice.[12]
1. Lee, S.-J., Cefepime-induced neurotoxicity. Journal of Neurocritical Care, 2019. 12(2): p. 74-84.
2. Maan, G., et al., Cefepime-induced neurotoxicity: systematic review. J Antimicrob Chemother, 2022. 77(11): p. 2908-2921.
3. FDA, CEFEPIME injection, for intravenous use. 1996.
4. Angelescu, M. and A. Apostol, [Cefepime (maxipime), large spectrum 4th generation cephalosporin, resistant to beta-lactamases]. Chirurgia (Bucur), 2001. 96(6): p. 547-52.
5. Appa, A.A., et al., Characterizing Cefepime Neurotoxicity: A Systematic Review. Open Forum Infect Dis, 2017. 4(4): p. ofx170.
6. Amakhin, D.V., et al., Paradoxical Anticonvulsant Effect of Cefepime in the Pentylenetetrazole Model of Seizures in Rats. Pharmaceuticals (Basel), 2020. 13(5).
7. Mihic, S.J. and R.A. Harris, GABA and the GABAA receptor. Alcohol Health Res World, 1997. 21(2): p. 127-31.
8. Maan, G., et al., Cefepime-induced neurotoxicity: systematic review. Journal of Antimicrobial Chemotherapy, 2022. 77(11): p. 2908-2921.
9. Tanaka, A., et al., Comparison of the prevalence of convulsions associated with the use of cefepime and meropenem. Int J Clin Pharm, 2013. 35(5): p. 683-7.
10. Boschung-Pasquier, L., et al., Cefepime neurotoxicity: thresholds and risk factors. A retrospective cohort study. Clinical Microbiology and Infection, 2020. 26(3): p. 333-339.
11. Payne, L.E., et al., Cefepime-induced neurotoxicity: a systematic review. Crit Care, 2017. 21(1): p. 276.
12. Pais, G.M., et al., Clinical Pharmacokinetics and Pharmacodynamics of Cefepime. Clin Pharmacokinet, 2022. 61(7): p. 929-953.
13. Burgess, S.V., et al., Evaluating outcomes of alternative dosing strategies for cefepime: a qualitative systematic review. Ann Pharmacother, 2015. 49(3): p. 311-22.
14. Gould, A., et al., Clinical Evaluation of an Alternate Cefepime Dosing Protocol for Gram-Negative Bloodstream and Respiratory Infections. Open Forum Infectious Diseases, 2016. 3(suppl_1).
15. Lindsay, H., S. Gruner, and J. Brackett, Cefepime-Induced Neurotoxicity Despite Dose Adjustment for Renal Disease: A Brief Report and Review of the Literature. Journal of the Pediatric Infectious Diseases Society, 2016. 6(2): p. 199-201.
16. Li, H.T., et al., Clinical, Electroencephalographic Features and Prognostic Factors of Cefepime-Induced Neurotoxicity: A Retrospective Study. Neurocrit Care, 2019. 31(2): p. 329-337.
Research Digest is a periodic installment that recognizes the world-class clinical research performed right here at UNMC ID. This post is also the last in a series of posts recognizing STI awareness week/month with quick summaries of recent articles on monkeypox and HIV published by UNMC ID faculty. As always, check out the full articles linked in each digest.
Dr. Kalil, co-author of a recent publication exploring the best practices in the face of future epidemics/pandemics.
The first article, co-authored by Dr. Andre Kalil explores the lessons we have learned throughout the COVID-19 pandemic and applies them in a call for action in the ongoing Mpox (monkeypox) epidemic.
Published early this year in The Lancet- Infectious Diseases, Dr. Kalil draws on the medical community’s experience gained through the past decade of outbreaks as well as draws parallels between what techniques that would characterize an optimal COVID-19 response could offer current efforts to combat this new pathogen. With no proven therapies for Mpox, the authors call for funding and development of ethical and safe randomized controlled trials for pathogens of epidemic or pandemic concern, boosting our preparedness for future outbreaks. Read the full article here.
Dr. Swindells, co-author of two recent articles exploring treatment options for people with HIV.
The second article explores the promise of long-acting antiretroviral therapies in the treatment of HIV. Co-authored by Dr. Susan Swindells, the paper provides a 152-week update for the ATLAS-2M trial which is investigating long-acting IM Cabotegravir and Rilpivirine treatment for maintenance of HIV-1 virologic suppression. Designed as a non-inferiority trial, the study concludes that this regimen and dosing schedule is effective for up to 3 years (the current length of the study). Click here for the full article.
In the third paper, also co-authored by Dr. Swindells, the authors explore whether recent clinical findings supporting the non-inferiority of rifapentine-moxifloxacin over standard rifampin-ethambutol for treatment of tuberculosis (TB) hold true in the subpopulation of people with HIV. Eligible participants with CD4+ counts > 100 cells/uL who were receiving efavirenz antiretroviral therapy were enrolled and split between the two TB treatment options. The study concludes that this alternative regimen is indeed effective in this specific patient subpopulation, with a modestly reduced rate of reported adverse events. See the article in full here.
The Nebraska Antimicrobial Stewardship Assessment and Promotion Program (ASAP) will be hosting its annual Nebraska Antimicrobial Stewardship Summit in person on Friday, June 2, 2023, at the Embassy Suites LaVista Hotel and Conference Center. There will be a combined morning session followed by afternoon breakout sessions with targeted presentations in long-term care and acute care/outpatient settings tracks. Registration for the Summit is $99 per attendee, which includes parking, food, and CE credits for physicians, nurses, pharmacists, and medical laboratory scientists. Read on below for more information and to register!
TARGET AUDIENCE This accredited continuing education activity is designed for:
– Post-acute and long-term facilities: Long-term care providers, medical directors, infection preventionists, nurses, consultant pharmacists, directors of nursing, quality program leaders, and other health care providers interested in improving the management of common infections through the incorporation of antimicrobial stewardship principles.
– Outpatient facilities and acute care hospitals: Family medicine providers, internal medicine providers, ambulatory care providers, pharmacists, nurses, medical directors, quality program leaders, and other health care providers interested in improving the management of common infections through the incorporation of antimicrobial stewardship principles.
SUMMIT LOCATION Embassy Suites by Hilton Omaha La Vista Hotel & Conference Center 12520 Westport Parkway, La Vista, NE 68128
‘Bench to Bedside’ is a new recurring segment exploring the basic science research conducted in infectious diseases right here at UNMC. This week, in recognition of STI Awareness Month, we feature the Rucks laboratory which studies chlamydial biology through the lens of infection. Special thanks to Natalie Sturd (left) and Dr. Rucks (right) for providing this content and sharing their work.
What are some outstanding questions in the field of chlamydial biology and pathogenesis?
Until about a decade ago, C. trachomatis was a genetically intractable organism, meaning methods used by other researchers for studying bacteria were not available in our field. In basic science research, genetic manipulation is one of the major approaches we take when we want to study a pathogen. However, in the last 10 years, significant advances have been developed that allow transformation7-10. Though we are still playing “catch up” with research on organisms that have been genetically manipulated for several decades, advances in the chlamydial genetic toolbox have led to an explosion in our ability to interrogate the function of chlamydial proteins and effectors. Further, we can turn our attention to some questions in the field that have since remained unresolved. For example, it is not fully understood how C. trachomatis regulates alternating between its EB and RB forms.Also,with regards to the Inc proteins that were mentioned in this week’s Microbe Monday post, many of their individual functions haven’t been elucidated. Apart from their individual functions, Inc proteins have the potential to interact with each other, and their cooperative functions (and how this might expand their individual functions) aren’t currently appreciated. From the host perspective, how C. trachomatis can avoid detection and clearance by the host immune system during asymptomatic, chronic infections is also an active research topic.
What is our research focus in the Rucks lab? Any exciting new directions?
Broadly speaking, the focus of our lab is understanding the host-pathogen interactions of C. trachomatis, how these interactions are regulated, and identifying their impact on host signaling and/or trafficking pathways. As such, we must both examine 1) the microbiology of C. trachomatis and 2) what’s happening with the cell biology of the host cell. In the Rucks lab, there are several areas of active research, including 1) studying how Chlamydia manipulates host vesicle trafficking, 2) understanding proteomic turnover of Inc proteins, and 3) dissecting how Inc-host protein interactions change the interactomes and signaling pathways in host cells. Regarding that last point, a prior study in our lab used a proximity labeling system using APEX2 to identify host proteins found in the vicinity of the inclusion membrane11. This allowed us to cast a wide net to identify proteins recruited to the inclusion. Some of our exciting directions are following up on specific host proteins to investigate how Chlamydia might be recruiting them and altering host pathways.
One of these studies that we are particularly excited about involves follow-up studies designed to better understand the function of two host proteins, LRRF1 and Flightless 1 (FLII/FLI1), that were identified in the proximity labeling study. Both proteins have been shown to be involved in regulating the host’s immune response. LRRF1 has been shown to be involved in innate immune signaling and FLII is a prominent regulator of actin dynamics, fibrosis, and wound healing. Knowing how these biological functions might relate to the reproductive tract pathology of chlamydial infections, we are particularly enthusiastic about investigating the outcome of the localization of these proteins to the inclusion membrane. Additionally, there are increasingly sophisticated co-culture tissue culture models of chlamydial infection, which are designed to better replicate the microenvironment of chlamydial infection. We’re currently using a co-culture system in our lab, combining epithelial cells, fibroblasts, and different innate immune cells.
In a separate line of research, we’re particularly curious about the cooperative functions of Inc proteins and how these might be temporally controlled throughout the chlamydial developmental cycle. Currently, in the field, it is typical to examine a single Inc at a single timepoint post-infection. This approach is reflective of the difficulty in studying an obligate intracellular pathogen. Improved genetic tools are helping us ask questions that we feel are more relevant to Chlamydia pathogenesis, as a successful infection is not likely beholden to a single Inc at a single timepoint post-infection. To test this question, we’ve been developing a whole cadre of new chlamydial strains that allow for the simultaneous knockdown of multiple Incs and the complementation of all or single Inc proteins.
So, while we may not be the ones treating chlamydial infections in the clinic, we are no less dedicated to improving reproductive health outcomes—we are simply coming at it from a different (very molecular) perspective!
Microbe Monday is a monthly installment featuring a microbe of clinical or scientific importance. This month, in recognition of STI Awareness month, we discuss Chlamydia trachomatis. The following content was provided by Natalie Sturd and Dr. Elizabeth Rucks– experts in Chlamydial biology at UNMC.
Chlamydia trachomatiscauses the most common bacterial sexually transmitted disease in both developed and developing nations, and rates of C. trachomatis infections have been steadily rising since the CDC began data collection in 19841. In developing countries, it is also the causative agent of blinding trachoma, which is the leading cause of preventable blindness. In the United States, we spend almost $700 million in direct medical costs towards treating chlamydial infections, which is second only to what we spend treating HIV and HPV. While there are readily available and effective antibiotic treatments for chlamydial infections, the challenges we face in health care involve the asymptomatic nature of most infections, as well as the pathologic consequences of repeat and/or chronic infections.
Pap smear showing C. trachomatis (H&E stain).
Indeed, for genital infections, 70-80% of infections in women and 40-50% in men are asymptomatic2, which means these infections regularly go unnoticed and untreated. Both untreated and repeat infections increase the risk of developing more serious chronic sequelae1. In the female reproductive tract, this can present as pelvic inflammatory disease (PID) and fibrosis of the reproductive tract, leading to ectopic pregnancy and tubal infertility. Current treatment regimens for chlamydial infections include the use of broad-spectrum antibiotics like doxycycline and/or azithromycin3, which can lead to the development of bacterial vaginosis (BV)4,5. BV is marked by an imbalance of vaginal microbiota with an increase of Lactobacillus and/or Garderella species and is treated with metronidazole, which indiscriminately eliminates both undesirable and desirable members of the vaginal microbiome3. Thus, despite awareness and available treatment, chlamydial infections remain a significant source of patient morbidity and constitute a serious financial burden on our healthcare system.
Chlamydia trachomatis inclusion bodies (brown) in a McCoy cell culture.
During the 6 million years that C. trachomatis has evolved with its human host6, its genome underwent reductive evolution, meaning it lost many of the genes found in other prokaryotes and retained a much smaller genome (~1.04Mbp; ~895 open reading frames). As a result of genome reduction, C. trachomatis is an obligate intracellular pathogen, meaning it requires the host cell to complete its developmental cycle. Chlamydia has a distinct biphasic developmental cycle, alternating between two morphological forms: the infectious, non-replicative elementary body (EB) and the non-infectious, replicative reticulate body (RB). The developmental cycle begins with EB entry into the host cell, where it establishes an intracellular niche within a pathogen-specific vacuole, termed the inclusion. The EB rapidly differentiates into the RB, which continues to divide within the inclusion. During later stages of the developmental cycle, RBs asynchronously undergo secondary differentiation to create new EBs. Importantly, each stage of chlamydial development is marked by distinct patterns of gene transcription, as each stage has different nutritional, proteomic, and molecular requirements to continue to grow and avoid detection by the host. From within the inclusion, C. trachomatis must mediate specific host interactions and these interactions are critical for chlamydial pathogenesis. A family of chlamydial effector proteins known as inclusion membrane proteins (Incs) are the primary mediators of these kinds of interactions and are a primary focus in our lab. Inc-host protein interactions have been implicated in the modulation of cellular survival pathways, vesicular trafficking of exocytic vesicles, and inhibition of the host innate immune response, all of which are hypothesized to contribute to a successful infection and a limited host response.
Watch for our next post this week where we will feature the Rucks lab and dive into the research exploring this important pathogen conducted at UNMC.
Natalie Sturd (left) and Dr. Rucks (Right), C. trachomatis researchers at UNMC.
We in the Rucks lab hope to contribute towards improving prevention and infection outcomes from a basic science approach. Specifically, our work helps 1) understand how C. trachomatis establishes an infection in human tissues and 2) identify the outcome of infection in the host cells/tissues in regard to cell biology.
References
1. Centers for Disease Control and Prevention. Sexually Transmitted Disease Surveillance 2020. Atlanta: U.S. Department of Health and Human Services; 2022.
2. Shetty S, Kouskouti C, Schoen U, et al. Diagnosis of Chlamydia trachomatis genital infections in the era of genomic medicine. Brazilian Journal of Microbiology. 2021;52(3):1327-1339.
3. Workowski KA, Bachmann LH, Chan PA, et al. Sexually Transmitted Infections Treatment Guidelines, 2021. MMWR Recomm Rep. 2021;70(4):1-187.
4. Tamarelle J, Ma B, Gajer P, et al. Nonoptimal Vaginal Microbiota After Azithromycin Treatment for Chlamydia trachomatis Infection. J Infect Dis. 2020;221(4):627-635.
5. Unemo M, Bradshaw CS, Hocking JS, et al. Sexually transmitted infections: challenges ahead. Lancet Infect Dis. 2017;17(8):e235-e279.
6. Nunes A, Gomes JP. Evolution, phylogeny, and molecular epidemiology of Chlamydia. Infect Genet Evol. 2014;23:49-64.
Today marks the first day of SHEA 2023 and UNMC ID is presenting throughout the conference. See below for a guide to where to find us.
Tuesday, April 11th, 2023
At 4:15 pm, Jasmine Marcelin, MD is giving a presentation entitled, ‘Disrupting Health Inequities in Emerging Infections”. SHEA Spring 2023 Opening Plenary-(Addressing Inequities in Healthcare Epidemiology: Where We Are and Where We’re Headed)‘. Location: Columbia BCD
Wednesday, April 12th, 2023
From 12:00 – 1:30 pm in the Regency Ballroom, UNMC ID has three posters presented during the ‘Networking Lunch with Posters’ session:
Jonathan Ryder, MD; In-Depth Assessment of Critical Access Hospital Stewardship Program Adherence to CDC’s Core Elements in Iowa and Nebraska. Poster #651.
Jenna Preuske, PharmD; Pharmacist Interventions for Appropriate COVID-19 Antiviral Therapy in Long-Term Care Facilities: A Public Health Initiative. Poster #520.
Erica Stohs, MD, MPH; Pneumonia Panel Results and Antibiotic Prescribing in COVID-19 Patients in 2020 vs 2022 (645). Poster #645
Thursday, April 13th, 2023
At 10am, Jasmine Marcelin, MD is giving a presentation entitled, ‘Building Trust of COVID-19 (and other) vaccines in the BIPOC Community‘. Location: Columbia BCD
From 12:00 – 1:30 pm in the Regency Ballroom, UNMC ID has one poster presented during the ‘Networking Lunch with Posters’ session:
Mackenzie Keintz, MD; Evaluation of Indication in a Urinalysis Driven Reflex Urine Culture Protocol at an Academic Medical Center. Poster #603.
Friday, April 14th, 2023
From 12:00 – 1:30 pm in the Regency Ballroom, UNMC ID has one poster presented during the ‘Networking Lunch with Posters’ session:
Scott Bergman, PharmD; Perioperative Cefazolin Prescribing Rates Following Suppression of Alerts for non-IgE Mediated Penicillin Allergies. Poster #581.
April is Sexually Transmitted Infection (STI) awareness month. This second week of April in particular is set aside to educate and raise awareness about sexually transmitted infections, or STIs, and how they impact our lives. It is also a time to work towards reducing STI-related stigma, fear, and discrimination and a time to ensure people have the tools and knowledge for prevention, testing, and treatment.
The CDC estimates that about 20 percent of the U.S. population – one in five people – in the U.S. had an STI on any given day in 2018. Left undiagnosed or untreated, many STIs can lead to serious health problems and permanent damage, both in the short and long term. ID and primary care providers are on the frontlines of this crisis, and we would like to take this opportunity to recognize their work in identifying, diagnosing, and treating STIs- as early diagnosis and treatment is key to preventing associated complications.
UNMC ID is away this week at SHEA 2023, but watch our posts for the rest of April for a series on STI awareness month, including the microbes, research, and medicine involving STIs at UNMC.
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