The following was adapted from content provided by Dr. Diana Florescu, one of the UNMC ID faculty members working on investigating this new vaccine.
What is RSV?
RSV, or respiratory syncytial virus, is a highly infectious virus transmitted primarily by contact with infected respiratory secretions or contaminated objects. Seasonal epidemics occur annually in autumn/winter in temperate climates Typically, the primary infection begins with fever, runny nose and cough, lasting 10 to 14 days. In more severe infections, the disease spreads from the upper to the lower respiratory tract and results in inflammation of the lower airways and airway obstruction with associated increased breathing rate, shortness of breath and wheezing, sometimes requiring oxygen support to avoid progression to pneumonia with respiratory failure.
Who is at risk of an RSV infection?
RSV has been recognized as a significant cause of respiratory illness in all age groups and an estimated 90% of the population experience their first RSV infection within the first 2 years of life. While the burden of RSV is highly recognized in the pediatric population, particularly in the very young and in those with cardio-respiratory disease, RSV infections are also a serious health concern in the elderly and in immunocompromised individuals. Approximately 170,000 hospitalizations and 10,000 deaths occur annually in people over the age of 65 years old with increasing hospitalization and death rate by increasing age.
Wait, if 90% of the population has had RSV, why do we need a vaccine?What about natural acquired immunity?
In the case of RSV, natural acquired immunity is not durable. Immune responses after primary infection in young infants are usually weak and short-lived. Re-infections with RSV are common at all ages, although of decreasing severity, since with recurrent infection the disease becomes more limited to the upper respiratory tract. Morbidity and disease severity increases again in people >50 years old, most likely due to decreasing immune responsiveness associated with advancing age.
How does this new vaccine candidate work?
This RSV vaccine candidate aims to protect against both circulating RSV subtypes (A and B). The vaccine is designed to protect against acute respiratory tract infections and more severe lower respiratory tract disease (e.g. RSV bronchiolitis, pneumonia) in adults ≥60 years of age.
At the beginning of the COVID-19 pandemic, there seemed to be many more questions than answers. How is this virus spreading? What is the best way to protect our communities? Which organ systems are at risk of damage from infection? To answer these questions, the medical community at large turned to research- and UNMC ID was no exception. Read below for synopses of three recent publications authored by UNMC ID faculty which each explore different aspects of COVID-19.
Dr. Jasmine Marcelin, UNMC Infectious Disease Physician and co-author of a recent COVID-19 review article.
One thing was clear from the start, COVID-19 is a complex disease with widely variable clinical symptoms, ranging from asymptomatic or a loss of smell to multiorgan failure. In a recent review article co-authored by Dr. Jasmine Marcelin, current COVID-19 knowledge is synthesized, from the physical characteristics of the SARS-CoV-2 virus to infection stages, immune responses, clinical presentations, and postacute sequelae of COVID-19 (long COVID). For a detailed, up-to-date, and digestible brief on all things COVID-19, find the article here.
Dr. Daniel Brailita, UNMC Infectious Disease physician and corresponding author on a recent publication on COVID-19 detection.
Another recent publication co-authored by Dr. Angela Hewlett, Dr. Mark Rupp, and Dr. Daniel Brailita, among various other UNMC researchers, assessed SARS-CoV-2 viral shedding in critically ill patients and how best to determine if a patient is still infectious. The study found that nasopharyngeal swab (one of the standard SARS-CoV-2 detection techniques) does not alway agree with detection of viral shedding in lower respiratory sputum samples. That is, critically ill patients who test negative by nasal swab may still have sufficient viral shedding in their lungs. This is critical information as it could help inform the level of protection medical professionals must take when performing aerosolizing procedures, even on supposedly COVID-negative patients. Read the full study here.
Dr. Nicolas Cortes-Penfield, UNMC Infectious Disease physician and co-author on a recent report on COVID-19 vaccination complications.
Finally, a recent article co-authored by Dr. Nicolas Cortes-Penfield reported outcomes of rare complications from COVID-19 vaccination. Specifically, the paper outlines 4 cases of acute and chronic demyelinating neuropathies following COVID-19 vaccination seen at UNMC in 2021. Among these patients, there was no clear predilection for a specific vaccine brand. While all of these cases presented between 2 and 21 days post-vaccination, there was not enough information to make a clear causative link between vaccination and these cases of demyelinating neuropathies. However, the study notes that continued identification and reporting of these side effects are crucial to making this determination. Find the paper here.
Since the beginning of the HIV pandemic, UNMC ID has provided expert clinical care to people with HIV (PWH) through the University of Nebraska Medical Center HIV Program and Clinic. Underscoring the great providers and researchers who work as a part of this team, many of our faculty members routinely publish their work in leading ID journals. See below for a quick synopsis of three recent publications from UNMC ID faculty exploring and reporting on HIV.
Dr. Sara Bares recently co-authored a publication which investigates the prevalence of functional impairment in PWH and its relation to cardiometabolic disease, a spectrum of conditions from insulin resistance to heart disease and diabetes, across different patient populations. They found that over 1 in 3 middle-aged and older PWH reported living with a functional impairment, globally. This rate was elevated in certain demographics as well as with certain treatment regimens and correlated with increased risk of cardiometabolic risk. Importantly, this work may help physicians better recognize and treat cardiometabolic disease in PWH. Read more here!
Dr. Suzan Swindells, along with many other UNMC researchers, also recently co-authored a publication assessing treatment strategies for HIV-associated tuberculosis. A four-month regimen of rifapentine and moxifloxacin has been reported to be successful in clearing tuberculosis infections, but how this treatment interfered with HIV medications, specifically efavirenz, was not previously known. The paper concludes that rifapentine is not only effective for HIV-associated tuberculosis treatments, but no dose adjustment of efavirenz is needed. See the details here!
Lastly, Dr. Nada Fadul, along with UNMC co-authors Nichole Regan and Laura Krajewski, recently published an article examining the effect of a shift to telehealth visits during the COVID-19 pandemic on medical care for PWH. After analyzing 2298 HIV clinic visits from May 2020 through April 2021, they concluded that utilization of telehealth visits were similar across measured patient demographics and did not lead to reduced treatment success rates in PWH. This adds to the growing evidence of the utility of telehealth when conditions require it. See the full article here.
A #PharmToExamTable question about Infective Endocarditis treatment, answered byAmanda Vanderwerf, PharmD, a 2021 Graduate of UNMC College of Pharmacy who is now an Emergency Medicine Pharmacy Resident at UNMC.
(Reviewed by Andrew Watkins, PharmD)
MSSA Infective Endocarditis
Infective endocarditis (IE) carries significant rates of morbidity and mortality and is now the third or fourth most common life-threatening infection syndrome.2 Historically, viridans streptococci were the most common cause of IE, but today Staphylococcus aureus has become the leading cause of IE in many regions of the world, accounting for 15-40% of all IE cases.1 Due to the particularly virulent nature of S. aureus, IE with this bacteria is generally associated with in-hospital mortality of 20-30%. The need for aggressive IV anti-staphylococcal antibiotics is imperative and methicillin susceptible S. aureus (MSSA) make up the majority of cases.1,5 In the 2015 Guidelines for Infective Endocarditis in Adults, anti-staphylococcal penicillins (ASP), such as Oxacillin or Nafcillin, are recommended for MSSA IE, with cefazolin listed as an appropriate alternative for patients with a history of non-anaphylactoid reactions to penicillins.2 However, many experts regularly use cefazolin for MSSA IE instead of ASP due to drug tolerability. Several studies have shown significantly higher rates of adverse drug events (ADE) with ASP such as nephrotoxicity and hepatotoxicity, and premature antibiotic discontinuation in both hospitalized patients and in the outpatient setting when compared to cefazolin.3,4,9 The lower rates of ADEs, reduced cost, and longer half-life make cefazolin an ideal agent for outpatient parenteral antibiotic therapy (OPAT) specifically. But is cefazolin really just as effective as ASP for the treatment of MSSA IE? This question has been debated due to the theoretical “inoculum effect” of cefazolin and documented treatment failures while using this agent. In an effort to find answers, there is a large amount of literature being published to clarify the risk, if any, of using cefazolin as a first line MSSA IE treatment.
What is the inoculum effect?
The cephalosporin inoculum effect is defined as a prominent rise in the antibiotic minimum inhibitory concentration (MIC) ≥16 ug/mL when in the presence of an inoculum higher than the standard bacterial inoculum recommended for in vitro testing (~107 CFU/mL vs ~105 CFU/mL). For reference, the MIC susceptibility breakpoint for cefazolin against MSSA is 2 mcg/ml.9 Therefore, when treating infections with a high bacteria burden, such as endocarditis, this inoculum effect may become more of a concern. Since the beginning of its use, it has been noted that several penicillinase-producing MSSA strains have been able to readily hydrolyze cefazolin. Subsequently, in the 1970s, cases of S. aureusendocarditis failing cefazolin therapy were described, with one of these cases showing the MSSA strain exhibiting high MICs of cefazolin when a large inoculum was used (cefazolin inoculum effect [CzIE]). The primary enzymes responsible have been further identified as Type A and Type C BlaZ.6
Review of literature
The most recent systematic literature review published in 2019 aimed to evaluate 90-day mortality for patients with MSSA bacteremia who were treated with ASP compared to cefazolin. For the primary endpoint of 90-day all-cause mortality, data from 7 studies comprising of 4391 patients showed 25.1% in the ASP group and 18.2% in the cefazolin group, resulting in a RR of 0.71, 95% CI (0.50, 1.02). Therefore, cefazolin may not be associated with increased 90-day mortality for MSSA bacteremia of any source. The relevant subgroup analysis of patients with high-inoculum infection identified 3 studies reporting on 90-day all-cause mortality (42 patients with endocarditis, 46 patients with abscesses) and 6 studies reporting on 30-day all-cause mortality (652 patients with endocarditis, 273 patients with abscesses). The authors found no association of treatments with 90-day all-cause mortality (endocarditis: RR 0.71 (0.12, 4.05); abscesses: RR of 1.17 (0.30, 4.63)) or for 30-day all-cause mortality (endocarditis: RR of 0.71 (0.37, 1.34); abscesses: RR 0.76 (0.35, 2.28)).8
However, when looking at the most recent prospective studies, there are more concerning results. Lee et al. performed the first prospective observational cohort study in 2018 comparing outcomes of cefazolin versus nafcillin for MSSA bacteremia amongst 10 Korean hospitals, aimed to specifically evaluate the clinical impact of CzIE on treatment outcomes. Overall, results of this study showed patients who received cefazolin were less likely to experience treatment failure than those receiving nafcillin (p 0.017) as well as decreased risk of 90-day mortality compared to nafcillin (p 0.008). However, when comparing the outcomes in the CzIE(+) group with those of the CzIE(-) group that received cefazolin, results showed that the treatment failure rate (p 0.049), rate of switching antibiotics because of clinical failure (p 0.036), and rate of 1-month mortality (p 0.047) were significantly higher in the CzIE(+) group than in the CzIE(-) group. Overall, 22% of isolates demonstrated CzIE.5 Although the prevalence is low, high treatment failure rates for these isolates suggests the need for rapid testing for CzIE isolates to effectively guide treatment, which is not currently performed outside of research studies. Overall, with this study only including 12 IE patients (with only 1 receiving cefazolin) it is hard to interpret these findings for this specific patient population.
Furthermore, another study by Miller et al. prospectively looked at 77 patients from 3 Argentinian hospitals with MSSA bacteremia, all treated with cefazolin. Whole-genome sequencing was performed on all isolates showing the prevalence of CzIE at 54.5%. Patients with MSSA exhibiting CzIE had increased 30-day mortality (39.5% vs 15.2%, P=0.034) compared to those without CzIE. This study included only 15 patients with complicated bacteremia, with 8 being IE.6 It is important to note that ASP are not available in Argentina, making cefazolin the primary agent of use for MSSA bacteremia, which could explain the high prevalence CzIE+ MSSA.
Conclusions
Although the retrospective studies cited above overall show no difference in outcomes between patients treated with cefazolin versus anti-staphylococcal penicillins (ASP), such as Oxacillin or Nafcillin, for MSSA bacteremia, it is suggested from the subsequent findings of the prospective trials that CzIE isolates pose a significant risk for cefazolin treatment failure. With the expanding use of cefazolin as first-line treatment for serious MSSA infections there may be a need for rapid testing for CzIE isolates to mitigate the risk of treatment failure.
Based on recent studies, the prevalence of MSSA isolates containing CzIE is still not fully understood. However, with the severe consequences at stake for IE patients, the risk of treatment failure with cefazolin may just outweigh the benefits of its favorable side effect profile and ease of use. Still, consideration must be made when using cefazolin as a first line agent for MSSA IE.
References:
Asgeirsson H, Thalme A, Weiland O. Staphylococcus aureus bacteraemia and endocarditis – epidemiology and outcome: a review. Infect Dis (Lond). 2018;50(3):175-192. doi:10.1080/23744235.2017.1392039
Baddour LM, Wilson WR, Bayer AS, et al. Infective Endocarditis in Adults: Diagnosis, Antimicrobial Therapy, and Management of Complications: A Scientific Statement for Healthcare Professionals From the American Heart Association [published correction appears in Circulation. 2015 Oct 27;132(17):e215] [published correction appears in Circulation. 2016 Aug 23;134(8):e113] [published correction appears in Circulation. 2018 Jul 31;138(5):e78-e79]. Circulation. 2015;132(15):1435-1486. doi:10.1161/CIR.0000000000000296
Eljaaly K, Alshehri S, Erstad BL. Systematic Review and Meta-analysis of the Safety of Antistaphylococcal Penicillins Compared to Cefazolin. Antimicrob Agents Chemother. 2018 Mar 27;62(4):e01816-17. doi: 10.1128/AAC.01816-17. PMID: 29437617; PMCID: PMC5913998.
Lee B, Tam I, Weigel B 4th, Breeze JL, Paulus JK, Nelson J, Allison GM. Comparative outcomes of β-lactam antibiotics in outpatient parenteral antibiotic therapy: treatment success, readmissions and antibiotic switches. J Antimicrob Chemother. 2015 Aug;70(8):2389-96. doi: 10.1093/jac/dkv130. Epub 2015 May 29. PMID: 26024869; PMCID: PMC4580536.
Lee S, Song KH, Jung SI, et al. Comparative outcomes of cefazolin versus nafcillin for methicillin-susceptible Staphylococcus aureus bacteraemia: a prospective multicentre cohort study in Korea. Clin Microbiol Infect. 2018;24(2):152-158. doi:10.1016/j.cmi.2017.07.001
Miller WR, Seas C, Carvajal LP, et al. The Cefazolin Inoculum Effect Is Associated With Increased Mortality in Methicillin-Susceptible Staphylococcus aureus Bacteremia. Open Forum Infect Dis. 2018;5(6):ofy123. Published 2018 May 23. doi:10.1093/ofid/ofy123
Wang SK, Gilchrist A, Loukitcheva A, et al. Prevalence of a Cefazolin Inoculum Effect Associated with blaZ Gene Types among Methicillin-Susceptible Staphylococcus aureus Isolates from Four Major Medical Centers in Chicago. Antimicrob Agents Chemother. 2018;62(8):e00382-18. Published 2018 Jul 27. doi:10.1128/AAC.00382-18
Weis S, Kesselmeier M, Davis JS, et al. Cefazolin versus anti-staphylococcal penicillins for the treatment of patients with Staphylococcus aureus bacteraemia. Clin Microbiol Infect. 2019;25(7):818-827. doi:10.1016/j.cmi.2019.03.010
Youngster I, Shenoy ES, Hooper DC, Nelson SB. Comparative evaluation of the tolerability of cefazolin and nafcillin for treatment of methicillin-susceptible Staphylococcus aureus infections in the outpatient setting. Clin Infect Dis. 2014 Aug 1;59(3):369-75. doi: 10.1093/cid/ciu301. Epub 2014 Apr 29. PMID: 24785233; PMCID: PMC4110443
Since 2009, UNMC has offered a supplementary educational experience in HIV patient care to interested medical students. This program, officially called the Comprehensive HIV Enhanced Medical Education Track (EMET), is designed to foster interest and training in care for people with HIV (PWH). This type of training is critical to maintaining a physician population with the skills and experience to treat PWH.
In a recent publication authored by many UNMC ID faculty, including Dr. Jasmine Marcelin, Susan Swindells, Dr. Nada Fadul, and Dr. Sara Bares, the successes of the EMET program are explored through the lens of feedback from the 14 existing graduates of the program. For the full details, see the study here.
From right to left: Dr. Jasmine Marcelin, Dr. Susan Swindells, Dr. Nada Fadul, and Dr. Sara Bares. They recently co-authored a publication centered around UNMC’s HIV EMET program and the importance of incorporating HIV care as a piece of medical school curriculum.
Some highlights of the publication are below:
Two-thirds of graduates who applied to an Internal Medicine residency went on to pursue an ID fellowship
71% of EMET students completed at least one abstract and 64% published at least one publication during their time in the EMET program
100% of EMET graduates agreed that participation in this program increased their comfort caring for PWH and awareness of barriers to care this population may experience.
Similarly, 100% of graduates would recommend the HIV EMET program to future students, citing impactful clinical and mentoring experiences as a particular strength of the program
For more on the EMET program at UNMC, see this page. For a look at the recent successes of current HIV EMET students, see our recent blog post.
Sam approaching a scent detection box, where she correctly identified a UTI sample. Good girl! (Maurer 2016)
Sit. Stay. Roll over. Diagnose an infection? It seems that, in addition to being man’s best friend, dogs make pretty good infectious disease doctors. Or at least that’s the conclusion of two studies which trained dogs to identify UTIs or C. difficile infections in real patient samples. The results were impressive!
In the first study, Sam (pictured right) and other dogs were trained to identify the presence of bacteria. They were then tested with 687 urine samples, one-third of which were infected. These dogs correctly identified the UTI samples at near 100% accuracy. This stellar success rate was not affected by pathogen either, as dogs were able to identify E. coli, Enterococcus, Klebsiella, and S. aureus all at greater than 99% sensitivity and 91% specificity. Even when samples were diluted 1:1000, UTI samples were correctly identified 100% of the time.
Chase (Top), a Border Collie Pointer and Piper (Bottom), a German Shepherd who were trained to identify C. difficile in stool samples. (Taylor 2018)
In another study, two dogs (Piper and Chase, pictured left) were trained to identify toxin-positive C. difficile in stool samples, which they were able to do at 80-90% sensitivity and ~85% specificity.
While you are unlikely to start seeing dogs in your local microbiology laboratory any time soon, this phenomenon is not without real-world applications. As the first study notes in its discussion:
“One month after the study was completed, 1 of the dogs (Abe) spontaneously alerted to a person visiting the training center. The patient had been feeling ill, but had not suspected a UTI. Based on Abe’s alerting behavior, the patient had a medical exam and a urine culture was performed the next day, and physicians confirmed bacteriuria and a clinical diagnosis of UTI.”
That being said, there is a leap between the olfactory doggy detection of bacteria and the clinical diagnosis of infectious syndromes based on symptoms…and I can’t even get my dog to consistently lay down on command. For more details, methods, and study design, see the links below.
Study 1: Maurer M, McCulloch M, Willey AM, Hirsch W, Dewey D. Detection of Bacteriuria by Canine Olfaction. Open Forum Infect Dis. 2016;3(2):ofw051. Published 2016 Mar 9. doi:10.1093/ofid/ofw051
Study 2: Taylor MT, McCready J, Broukhanski G, Kirpalaney S, Lutz H, Powis J. Using Dog Scent Detection as a Point-of-Care Tool to Identify Toxigenic Clostridium difficile in Stool. Open Forum Infect Dis. 2018;5(8):ofy179. Published 2018 Aug 22. doi:10.1093/ofid/ofy179
Associate Professor, Department of Internal Medicine Associate Medical Director, Infection Control & Epidemiology Co-Director, Digital Innovation and Social Media Strategy
Dr. Cawcutt is an author on a new review article focusing on the relationship between infection and chronic pain persisting even after resolution of acute illness.
Acute infection can cause chronic pain?
Yes, it can. Pain is a common feature accompanying infection and one of the hallmark features of inflammation. While most infections are cleared by the body, with or without medical intervention, this pain can stick around long after the pathogen is gone.
How does this happen?
There are many different ways this can happen, many of which are explained in detail in this article. In general, the stress of an infection or the medical treatments of infection on the body can cause the immune system to continue to act long past pathogen eradication.
Where can I read more?
For a more technical (and interesting!) rationale for molecular mimicry, central nervous system sensitization, bystander activation, and antimicrobial toxicity in causing chronic post-infectious pain, see the linked article. You will also find additional information on the common bacterial, viral, psychogenic and pharmaceutical causes of post-infectious pain syndromes.
The Division of Infectious Diseases at the University of Nebraska Medical Center in Omaha, NE is recruiting an infectious diseases physician with interests or experience in infection prevention/healthcare epidemiology to serve as the Medical Director of the Infection Control Assessment and Promotion Program (ICAP). This is an exciting opportunity to lead, manage, and direct continued development of the ICAP. You will serve as an expert advisor to the NE Department of Health and Human Services and lead a multidisciplinary team of professionals including infection preventionists, infectious diseases physicians, and ID-trained pharmacists. The physician hired will have the opportunity for a gratifying faculty position and career in the UNMC Division of Infectious Diseases and will be expected to participate fully in the clinical, education, and research missions of the Division.
Pictured left, the Infection Control Assessment and Promotion Program (ICAP) and Nebraska Antimicrobial Stewardship Assessment and Promotion Program (ASAP) team.
About ICAP: Working closely with the Nebraska Department of Health and Human Services, ICAP offers no cost, peer-to-peer infection control assessments and recommendations. Our goal is to improve infection prevention practices in a broad range of healthcare settings and improve the capability to respond to infectious disease outbreaks. This model is unique in bringing experienced “outside eyes” to individual hospitals, long-term care centers, dialysis centers and outpatient/surgery centers.
Know the perfect person for this opportunity? Please spread the word and share this application.
Current Clinical Scholar Dan Ramirez, PharmD, and program coordinator Nikki Regan at a recent conference supported by the Clinical Scholars program.
The UNMC/Nebraska Medicine Specialty Care Center is looking for minority or predominantly minority-serving, front-line clinical care providers to participate in a 12 month HIV prevention, diagnosis and management mentorship program.
The Clinical Scholars Program is sponsored by the Midwest AIDS Education and Training Center. The program is open to clinical care providers including physicians, PAs, APRNs, and pharmacists, and provides a FREE one year training course consisting of didactic and preceptorship opportunities. Applicants should have a basic understanding of HIV, and be motivated to apply general principles of HIV prevention, management and care collaboration to their primary care or related practice.
Professor, Department of Internal Medicine Chief, Division of Infectious Diseases Medical Director, Infection Control & Epidemiology Associate Medical Director, Antimicrobial Stewardship
Dr. Rupp recently assisted in the creation of new clinical guidelines aimed at prevention of central line-associated bloodstream infections.
What are clinical guidelines and why are they important?
Clinical guidelines are a crucial component of evidence-based medicine. They are issued to standardize medical care across the nation and are often determined using an extensive literature review process with input from panels of experts in the field. These guidelines were updated with input from the Society for Healthcare Epidemiology of America (SHEA), the Infectious Diseases Society of America (IDSA), the Association for Professionals in Infection Control and Epidemiology (APIC), the American Hospital Association (AHA), and The Joint Commission, as well as representation by the Centers for Disease Control and Prevention (CDC).
Why do guidelines need to be updated?
Best medical practices are often a moving target, especially in infectious disease. Pathogens change over time, as does medical technology and the scientific literature describing clinical problems. Guideline updates are one of the most straightforward ways that research can update clinical practice to ensure we are always acting in the best interest of patients.
What are the major changes in this guideline update?
There are 4 major changes with this 2022 update:
The subclavian vein is recommended for central venous catheter (CVC) insertion in the intensive care setting. Previous recommendations advised avoiding femoral vein for access, which remains valid.
Ultrasound guidance for catheter insertion is bolstered by greater evidence and now is more strongly recommended, although strict attention to sterile technique is advised.
The use of chlorhexidine-containing dressings is now considered an “essential practice”; previously, this was recommended only during periods of high infectious risk.
Routine replacement of administration sets not used for blood, blood products, or lipid formulations can be performed at intervals of up to 7 days, instead of the previous recommended interval of no longer than 4 days.
Are there any other changes?
Yes! There are several other guideline changes outlined in the updated guidelines. For details, guideline creation methods, and additional changes, see the full guideline document here.
Thanks to Dr. Rupp for his contribution to this vital process to evidence-based medicine!
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