Division of Infectious Diseases

#PharmToExamTable: Treatment of Clostridioides difficile infection in adults: Guideline review

This month’s #PharmToExamTable question was answered by Andre Wilt, PharmD 2020 Graduate of UNMC College of Pharmacy, who is now a pharmacy manager at PharmScript

(Reviewed by Scott Bergman PharmD and Andrew Watkins PharmD)

Clostridioides difficile infection (CDI) is the most common cause of infectious diarrhea in healthcare settings. The pathogenesis of CDI begins as an ingestion of toxigenic C. difficile spores which colonize the colonic microbiota (flora). Exposure to antibiotics, particularly clindamycin, fluoroquinolones, and cephalosporins leads to a disruption of the normal colonic microbiota. This disruption causes C. difficile overgrowth and production of exotoxin A and B, leading to manifestations of diarrhea and inflammation of the colon (colitis). CDI is defined as 3 or more unformed stools within 24 hours, during or after antibiotic use, that presents with diarrhea, fever, leukocytosis or abdominal pain. Diagnosis includes the presence of symptoms, a stool test positive for C. difficile toxins or detection of toxigenic C. difficile. CDI severity can range from mild to moderate (non-severe), severe and fulminant colitis (severe with complications). Common risk factors for CDI and recurrent episodes include antibiotic usage, advanced age and gastric acid suppression. The most important initial step in treatment is to discontinue offending antibiotic agents. However, after discontinuing the offending agents, treatment regimens for CDI include oral vancomycin, fidaxomicin, metronidazole and fecal microbiota transplantation specific to severity and recurrence.

Non-severe CDI is clinically defined as leukocytosis with a white blood cell (WBC) count of ≤15,000 cells/mL and an absolute serum creatinine level <1.5 mg/dL. The Infectious Disease Society of America (IDSA) recommends treatment of an initial non-severe CDI episode with either oral vancomycin 125 mg given four times daily for 10 days or fidaxomicin 200 mg given twice daily for 10 days. Alternatively, IDSA recommends treatment with oral metronidazole 500 mg three times daily for 10 days only if access to vancomycin or fidaxomicin is limited.

Severe CDI is clinically defined as leukocytosis with a WBC count of >15,000 cells/mL and an absolute serum creatinine level ≥1.5 mg/dL. For both non-severe and severe CDI, the serum creatinine values are based on absolute values and not in comparison to baseline values, as these are not always available. These criteria do not perform well in patients with chronic kidney disease and as a result further validation is needed. Similar to non-severe CDI, IDSA recommends treatment of an initial severe CDI episode with either oral vancomycin 125 mg given four times daily for 10 days or fidaxomicin 200 mg given twice daily for 10 days.

Fulminant CDI is clinically defined as the presence of hypotension or shock, ileus (intestinal obstruction/immobility) or toxic megacolon. The IDSA preferred regimen for an initial fulminant CDI episode is vancomycin 500 mg four times daily by mouth or nasogastric tube. Alternatively, rectal administration of vancomycin can be considered if ileus is present. Additionally, IDSA recommends the administration of intravenous metronidazole 500 mg three times daily with either oral or rectal vancomycin, especially with the presence of an ileus.

The IDSA guidelines reflect the use of a tapered and/or pulsed vancomycin regimen for the treatment of recurrent CDI. Tapered vancomycin regimens include dosing up to four times daily with a decrease in dosing frequency over several weeks. Pulsed vancomycin dosing regimens include a single dose given every 2-3 days for up to 2-8 weeks. The treatments can be performed in sequentially with a tapered regimen followed by pulsed dosing . The process of a tapered and/or pulsed vancomycin regimen is intended to target the elimination of C. difficile spores. The cycle of increasingly long antibiotic-free periods allows spores to germinate and the pulses of antibiotics eliminate newly germinated vegetative cells.

The IDSA recommends three separate treatment strategies for the first recurrent CDI episode. If metronidazole was used for the initial episode, treatment with the standard CDI regimen of oral vancomycin is recommended. Similarly, if vancomycin was used for the initial episode, treatment with the standard fidaxomicin regimen is recommended. If vancomycin was used for the initial episode, a prolonged taper and pulsed oral vancomycin regimen is recommended. The dosing regimen is as follows: oral vancomycin 125 mg four times daily for 10-14 days, oral vancomycin 125 mg two times daily for 7 days, oral vancomycin 125 mg once daily for 7 days, and then oral vancomycin 125 mg once every 2 or 3 days for 2-8 weeks.

The IDSA preferred treatment for two or more recurrent episodes is a fecal microbiota transplantation. Alternative treatments include again include a tapered and pulsed vancomycin regimen, or a course of vancomycin followed by a “chaser” of oral rifaximin or fidaxomicin.
Evidence for the treatment of CDI using a vancomycin tapered regimen was only studied for recurrent CDI in the primary literature. These included 4 observational studies and 1 clinical trial.

The next blog post will review the evidence to support using tapered oral vancomycin regimens for treatment of recurrent CDI.

References
1. Dipiro JT, Talbert RL, Yee GC, Matzke GR, Wells BG, Posey L, eds. Pharmacotherapy: A Pathophysiological Approach, 10th ed. New York, NY: McGraw-Hill; 2017.
2. Lamont JT, Kelly CP, Bakken JS (2018). Clostridioides (formerly Clostridium) difficile infection in adults: Clinical manifestations and diagnosis. UpToDate. Retrieved March 22, 2020.
3. Lamont JT, Kelly CP, Bakken JS (2020). Clostridioides (formerly Clostridium) difficile infection in adults: Treatment and prevention. UpToDate. Retrieved March 22, 2020.
4. McDonald LC, Gerding DN, Johnson S, et. al. Clinical Practice Guidelines for Clostridium difficile Infection in Adults and Children: 2017 Update by the Infectious Diseases Society of America (IDSA) and Society for Healthcare Epidemiology of America (SHEA). Clin Infect Dis. 2018;66(7):1-48.
5. Tedesco FJ, Gordon D, Fortson WC. Approach to patients with multiple relapses of antibiotic-associated pseudomembranous colitis. Am J Gastroenterol. 1985;80(11):867-868.
6. McFarland LV, Elmer GW, Surawicz CM. Breaking the cycle: Treatment Strategies for 163 Cases of Recurrent Clostridium difficile Disease. Am J Gastroenterol. 2002;97(7):1769-1775.
7. Murphy MM, Patatanian E, Gales MA. Extended duration vancomycin in recurrent Clostridium difficile infection: a systematic review. Ther Adv Infectious Dis. 2018;5(6):111-119.
8. Bakken JS. Staggered and Tapered Antibiotic Withdrawal with Administration of Kefir for Recurrent Clostridium difficile Infection. Clin Infect Dis. 2014;59(6):858-861.
9. Sirbu BD, Soriano MM, Manzo C, et al. Vancomycin Taper and Pulse Regimen with Careful Follow-up for Patients with Recurrent Clostridium difficile Infection. Clin Infect Dis. 2017;65(8):1396-1399.
10. Hota SS, Sales V, Tomlinson G, et al. Oral vancomycin Followed by Fecal Transplantation Versus Tapering Oral Vancomycin Treatment for Recurrent Clostridium difficile Infection: an Open-label, Randomized Controlled trial. Clin Infect Dis. 2017;64(3):265-271.

Welcoming our New Infectious Diseases Fellows: Dr. Casey Zelus

We are excited to welcome Dr. Casey Zelus as a new fellow in our Infectious Diseases program! Read on to learn a little more about her…

Dr. Zelus…with a bagel she baked herself…that is as big as her face!

Tell us about the about the position you are starting
I just started a two year Infectious Disease Fellowship at UNMC, where I will get to explore the interaction between infectious microorganisms and the host immune system. Having recently finished my first month on UNMC’s busy inpatient General ID consult service – was a whirlwind! I’m thrilled with my decision to pursue ID and looking forward to the adventure.

Tell us about your background
I was born in Seattle Washington, but spent the first half of my childhood in Madison, Wisconsin before moving to Denver, Colorado. The allure of Los Angeles lead me to attend undergrad at Loyola Marymount University where I obtained my degree in biochemistry. After 5 years of LA traffic I moved to Omaha, Nebraska to attend Creighton Medical School which is where I ended up meeting my significant other. We couples matched into residency at UNMC and decided to stay in Omaha!

Why did you choose to come work at UNMC
Interestingly, I ended up coming to UNMC because they have a phenomenal Emergency Medicine Residency! My significant other enjoyed his away rotation in UNMC’s ED so much we ended up couples matching into their IM and ED residencies. Initially I thought I would pursue Rheumatology, but abruptly changed my mind after a phenomenal ID rotation my intern year. I subsequently rotated on ID two more times during residency and enjoyed working with the UNMC ID family so much I wanted to stay for fellowship.

What makes you excited about working in ID
I love playing the role of detective and ID is a constant stream of intellectual mysteries that need solving! As I became more involved, I started to realize the broader global implications and profound impact of infectious disease specialists – from combating rising resistance as an antibiotic steward to investigating global pandemics. Combine that with minimal midnight trips to the hospital and the ability to maintain work-life balance, and it was the right choice for me.

Tell us something about yourself that is unrelated to medicine
When I was trying to learn how to bake bread a few years back, I had a terrible time trying to figure out how to make sourdough (one of my favorites)! Finally after some YouTube videos and googling, it turns out I needed to make my own sourdough starter instead of a pack of yeast from the store! Mix some flour and water, then after a few days in a cupboard – voila! Your very own yeast starter. Caution: use a container much bigger than your initial mixture and give it plenty of room to grow, or risk some messy, yeasty clean up!

Learn more about the UNMC Infectious Diseases Fellowship here

Welcoming our New Infectious Diseases Fellows: Dr. Jonathan Ryder

We are excited to welcome Dr. Jonathan Ryder as a new fellow in our Infectious Diseases program! Read on to learn a little more about him…

Dr. Ryder exploring the Henry Doorly Zoo in Omaha, NE.

Tell us about the position you are starting
I am starting as a first-year infectious diseases fellow at University of Nebraska Medical Center (UNMC). I will be spending the next two years learning the vast field of infectious diseases through inpatient consultation and outpatient clinics. I will be learning how to improve human health by understanding the biology and pathophysiology of bacteria, viruses, fungi, and parasites as well as the pharmacology of antimicrobials.

Tell us about your background
I was born and raised in central Missouri, graduating from Jefferson City High School. I completed my Bachelor of Science in Biology and History at Truman State University in Kirksville, Missouri. During my time in college, I attended a summer research program at UNMC. I subsequently attended medical school at UNMC, graduating in 2017. I then left UNMC for Indiana University School of Medicine for internal medicine residency. Now, I have circled back for my third stent at UNMC for my infectious disease fellowship!

Why did you choose to come work at UNMC
As previously mentioned, I attended UNMC for medical school and prior to that, a summer research program in undergraduate training. I grew fondly of the city of Omaha during my time here, which I find to be an underrated gem in the Midwest. Omaha has many of the exciting features of a larger city, while having the convenience of a smaller town. Omaha has a great food scene, excellent amateur & college sports atmosphere, extensive bike & running trails, Broadway musicals, affordable cost-of-living, quick commutes, and of course, everyone loves the zoo! Along with Omaha being fun, my wife is also from Nebraska, so being closer to family & having job opportunities was important.

In my opinion UNMC is truly the star of Omaha. UNMC has a world class infectious diseases faculty with leaders in emerging infectious pathogens such as Ebola, biocontainment expertise, HIV treatment, antimicrobial stewardship, and more. The division has grown considerably and continues to do so, as does the entire UNMC campus, which always is adding new buildings!

Lastly, the fellowship program in infectious diseases at UNMC has amazing leadership with a well-balanced curriculum. There is strong emphasis in developing clinical skills while providing ample opportunities for research as well. There is training in general ID, solid organ transplant ID (including liver, kidney, heart, lung, and small bowel/multivisceral), oncology/hematopoietic stem cell transplant ID, orthopedic ID, HIV clinic, infection prevention, and antimicrobial stewardship. This breadth and depth of opportunities was hugely attractive to me for choosing UNMC.

What makes you excited about working in ID
The field of infectious diseases offers so many unique opportunities to me. First, I am quite inquisitive, and the field of infectious diseases challenges my curiosity each day. Infectious diseases is often consulted for some of the more complicated cases in the hospital that either have diagnostic dilemmas or therapeutic challenges. Second, there are many opportunities for practice modalities in infectious disease including academic, group practice, inpatient consultations, HIV clinician, transplant ID, antimicrobial stewardship, etc. The ability to have many options now and in the future allows career flexibility and opportunity. Finally, I truly find the diversity of infectious pathogens to be fascinating, especially the interactions of humans with their environment, ecological impacts of antimicrobials, and evolutionary mechanisms that effect human health.

Tell us something about yourself that is unrelated to medicine
I am unabashedly a huge professional football nerd and Kansas City Chiefs fanatic. You will find me on my couch screaming at the TV nearly every Sunday in the fall and on occasion tailgating with some BBQ. My wife and I are foodies who enjoy adventure and travel. I love to sit down with a good history book on a quiet evening. I am quite active on Twitter (I actually have 2 accounts, one for football and one for #IDTwitter), so follow me @JonathanRyderMD!

Learn more about the UNMC Infectious Diseases Fellowship here.

Our Fellowship Leaders can’t wait to review your applications!

Fellowship application season is open and as the leaders of our ID fellowship, we wanted to highlight some of the exciting aspects of our program.  Our program and our division are growing.  We began in 2011 with 2 fellows, grew to 4 in 2017, 5 in 2020, and are planning to expand to six fellows by 2021.  Our faculty also continues to grow, as we now have 23 physician faculty and 4 full time ID pharmacists with diverse expertise.  Dr. Trevor Van Schooneveld has been the Program Director and Director of the Antimicrobial Stewardship program.  Dr. Zimmer is Associate Program Director and also the director of the Oncology ID program. This year we are looking forward to meeting you on our remote interviews via zoom!

First year fellow Dr. Casey Zelus teaching medical students about blood cultures

Fellows at UNMC enjoy a robust clinical experience that includes not only the typically complex patients seen at a tertiary referral center, but also includes extensive experience caring for immunosuppressed patients.  In addition to our General ID service, where our fellows gain experience in teaching medical students and Internal Medicine residents, we have two separate immunocompromised services that care for oncology and solid organ transplant patients.  We also have an orthopedic infectious diseases rotation where fellows gain experience managing these complex patients and work with faculty who have extensive experience in this area.  We have expanded our ambulatory offerings with the creation of a non-tuberculous mycobacteria (NTM) clinic and a travel clinic.  Fellows have the opportunity to spend time in the microbiology laboratory, as well as learn infection control and antimicrobial stewardship. The faculty at UNMC are nationally recognized experts in their field, and are also very approachable and devoted to the education and success of trainees. They have created extensive educational opportunities, covering topics from opportunistic infections in solid organ and hematopoietic stem recipients to emerging global pathogens and biopreparedness. Fellows gain knowledge in HIV/AIDS management working in our multidisciplinary HIV clinic which cares for over 1200 people with HIV. In addition to having access to world class ID expert antimicrobial stewardship, OPAT, and HIV pharmacists, our division also includes an ID pharmacy residency program and opportunities for research collaboration and rounding with pharmacy students, residents and faculty.

As new career opportunities develop for ID physicians, we have worked to provide our fellows with the skills to engage in these fields.  UNMC ID fellows receive extensive experience in the area of infection control and antimicrobial stewardship.  UNMC also offers the opportunity to stay for an option third year to further develop a research portfolio or pursue additional clinical expertise in subspecialty areas.

Recent graduate Dr. Raj Karnatak presenting his research

An important part of fellowship is developing skills in interpreting and performing research, and we provide our fellows with six months of mentored research experience centered on their career goals.  A research committee assists fellows in mentor identification and project development.  Fellows also participate in a week-long UNMC sponsored research training program, and typically present their work at national conferences like IDWeek and SHEA.

Our goal as program directors is to provide fellows with an educational experience that provides them with skills and knowledge to make them successful in whatever career path they choose.  The opportunities available to ID physicians continue to expand and we hope you will consider UNMC ID.  If you are interested in more information, please feel free to visit our website where you can check out a video to learn more about us. You can also contact us at the following:

Dr. Trevor Van Schooneveld
Program Director, Infectious Diseases Fellowship
Medical Director, Antimicrobial Stewardship Program
University of Nebraska Medical Center
985400 Nebraska Medical Center
Omaha, NE 68198-9400
Email: tvanscho@unmc.edu

Dr. Andrea J. Zimmer
Associate Program Director, Infectious Diseases Fellowship
Director, Oncology Infectious Diseases
University of Nebraska Medical Center
985400 Nebraska Medical Center
Omaha, NE 68198-9400
Email: andreaj.zimmer@unmc.edu

Welcoming our new Infectious Diseases Fellows: Dr. Laura Selby

We are excited to welcome Dr. Laura Selby as a new fellow in our Infectious Diseases program! Read on to learn a little more about her…

Dr. Selby enjoying the Henry Doorly Zoo!

Tell us about the position you are starting
I am starting a 2 year fellowship program to become a board certified Infectious Diseases physician. Infectious Diseases is a subspecialty of internal medicine that focuses on taking care of patients with complex infections, such as bacteremia (infections of the blood), HIV, tick borne illness, and now COVID-19.

Tell us about your background
I was born and raised in a small town in Oregon and grew up on a multigenerational farm. I completed my undergraduate degree in chemistry at Westmont College in Santa Barbara California. I returned to Oregon for medical school and residency in Internal Medicine at Samaritan Health Services, a small community based residency program in Corvallis, Oregon.

Why did you choose to come work at UNMC
I chose to come to UNMC for many reasons, but the primary reason was for the world class training they offer. I never imagined myself moving to Nebraska, but when I came to interview the faculty, facilities, clinical training opportunities, and friendliness of the department was something I couldn’t pass up. I am excited to spend two years training at UNMC and getting to care for Infectious Disease patients in the Omaha area.

What makes you excited about working in ID
Infectious Diseases is one of the few medical specialties that relies heavily on both cutting-edge medical testing but also on good old-fashioned history and physical exam. Taking time to talk to my patients, learning about their history, family, and activities often provides vital clues to the type of infections they are at risk for. At the same time, needing to understand the intricacies of the newest medical diagnostic technologies, makes infectious diseases a fast-paced and fascinating field.

I love getting to work as part of a multidisciplinary team to take care of the sickest patients in the hospital. Infections remains a leading cause of death in hospitalized patients in the United States and worldwide. Severe infections affect patients who are healthy and also those with every known chronic condition, so even while working as an ID physician, I still have to understand the pathology and pathogenesis of non-infectious conditions. As the current COVID-19 pandemic has shown, the areas of research for infectious diseases are endless, and I look forward to participating in research opportunities during my fellowship training and beyond.

Tell us something about yourself that is unrelated to medicine
As I have called the pacific-northwest home for most of my life, I love to camp and hike. My favorite place to hike in the country is Glacier National Park in Montana; the only downside is the high number of bears that share the trails. I am looking forward to exploring a new area of the country during my time at UNMC.

Learn more about the UNMC Infectious Diseases Fellowship here.

What is the optimal dosing of daptomycin for VRE bacteremia?

This month’s #PharmToExamTable question was answered by Xiaoxiao (Monica) Qi, PharmD 2020 UNMC graduate who is pursuing a PGY1 Pharmacy Residency at Avera McKennan Hospital and University Health Center in Sioux Falls, SD.
It was reviewed by:
Scott Bergman, PharmD, BCPS, BCIDP – Antimicrobial Stewardship Coordinator at Nebraska Medicine and Clinical Associate Professor at UNMC College of Pharmacy
Andrew Watkins, PharmD – PGY2 Infectious Diseases Pharmacy Resident at Nebraska Medicine

In healthcare settings, infections due to vancomycin-resistant enterococci (VRE) are commonly encountered. Up to 31% of all enterococcal isolates are vancomycin-resistant in U.S. hospitals(1-4). Bloodstream infection caused by vancomycin-resistant enterococci (VRE) has been associated with higher morbidity, mortality, and prolonged hospital stay(2). Given that very few antibiotics with activity against VRE have been evaluated in the treatment of bacteremia clinically, the options for VRE bloodstream infection are limited. Thus, vancomycin-resistant enterococcal bloodstream infections (VRE-BSIs) are uniquely difficult to treat (5). Currently, only linezolid is approved by the US FDA for treating such a condition, but it does have a few limitations: linezolid resistance has emerged; prolonged use can lead to thrombocytopenia; it’s mechanism of action is bacteriostatic and the clinical success rate of treating VRE bacteremia varies. Recent clinical studies have shown improved clinical and microbiologic outcomes associated with daptomycin over linezolid in VRE-BSI (6).

Daptomycin is an antibiotic that is approved by the FDA for the treatment of bacteremia and right-sided infective endocarditis caused by Staphylococcus aureus (7). Daptomycin exhibits concentration-dependent bactericidal activity against gram-positive pathogens. The pharmacodynamic parameters of such activities are maximum concentration (Cmax)/minimum inhibitory concentration (MIC) or area under the concentration-time curve (AUC)/MIC ratios.5 Although it is not approved by the FDA for the treatment of bacteremia caused by Enterococcus spp., it has both in vitro and in vivo activity against this organism. It could be used in certain conditions, such as prolonged VRE bacteremia endocarditis, where a bactericidal agent is preferred. The usual dose of daptomycin for MRSA bloodstream infections is 6 mg/kg/day (7). However, VRE isolates generally demonstrate MICs 2- to 4-fold higher than those of S. aureus (5). The susceptible breakpoint of daptomycin for Enterococcus spp. has been ≤4 mg/L compared to <1 mg/L for Staphylococci (1). In 2019, The Clinical and Laboratory Standards Institute (CLSI) revised the interpretive criteria of daptomycin for Enterococcus faecium to be called “susceptible dose-dependent” (SDD) at MICs ≤4 mg/L. This is because of the epidemiological profile of the organism, new PK/PD data, emergence of daptomycin-resistant Enterococci, and clinical studies that rendered the previous interpretation of susceptible no longer appropriate for this species. The susceptible dose-dependent (SDD) category is used when susceptibility of an isolate depends on the dosing regimen used (8). For E. faecium, an increased daptomycin dosage of 8–12 mg/kg/day is recommended to treat the organism since it has naturally higher MICs and the pharmacokinetics(PK)/pharmacodynamics (PD) of daptomycin can be optimized with peak serum concentrations increasing linearly with the dose. 

Both in-vivo and in-vitro studies have demonstrated that using higher dosages of daptomycin increased both the degree and speed of bactericidal activity (1,5,7). One study compared in vitro activity of daptomycin at 6 vs. 10 mg/kg/day towards vancomycin-resistant Enterococcus faecium and showed that the higher dosage achieved a more rapid and greater reduction in bacteria (p 6 mg/kg) in two-hundred and forty-five patients were evaluated. Overall, 204 (83%) of all identified Enterococcus faecium were VRE. One-hundred and seventy-three patients (70.3%) had enterococcal bloodstream Infection. The median dose and duration of high dose-daptomycin was 8.2 mg/kg/day (IQR 7.7-9.7) and 10 days (IQR 6-15), respectively. The overall clinical success rate was 89% and microbiological eradication was observed in 93% of patients. This study showed that a high frequency of clinical success and microbiological eradication in patients treated with high-dose daptomycin for enterococcal infections, even in patients with complicated and difficult to treat infections. In terms of safety, no high-dose daptomycin regimen was discontinued due to an elevated CPK and all patients were asymptomatic (10).

Another retrospective cohort study on comparison of different doses for daptomycin has been done in patients hospitalized at Veterans Affairs facilities with VRE-BSI. Britt et al. compared standard-dose (6 mg/kg total body weight), medium-dose (8 mg/kg total body weight), or high-dose (≥10 mg/kg total body weight) daptomycin. A total of 911 patients were included (standard dose, n = 709; medium dose, n = 142; high dose, n = 60). Compared to high-dose daptomycin, both standard-dose and medium-dose daptomycin were associated with worse survival (adjusted HR [aHR], 2.58; P = 0.004). This association persists after adjustments of confounders. High-dose daptomycin was associated with significantly improved microbiological clearance. There was no difference in the risk of CPK elevation among the treatment groups. Despite the comparatively low number of patients that received high-dose daptomycin, the authors concluded that it was associated with improved survival and microbiological clearance in VRE-BSI (5).

A systematic review and meta-analysis was performed on the efficacy and safety of daptomycin versus linezolid in 2019. According to the sub-group analysis, high-dose daptomycin showed an increase in use from 6% in 2006 to 34% in 2012 and corresponding improved mortality benefits, which supports that a high-dose may be beneficial for the treatment of VRE bacteremia (11).

In conclusion, VRE isolates generally have MICs 2- to 4-fold higher than those of S. aureus and are now classified as “Susceptible Dose-Dependent” up to an MIC of 4 mg/L by the CLSI. Based on its concentration-dependent bactericidal activity, high-dose daptomycin (8-12 mg/kg) is needed to optimize pharmacodynamic (PD) parameters of Cmax and AUC over MIC. Current clinical data have shown that high-dose daptomycin is beneficial for the treatment of VRE bacteremia. Although high-dose daptomycin may raise a concern of more CPK elevation, it does not necessarily lead to more severe skeletal muscle toxicity or discontinuation of daptomycin.

References:
1. King EA, McCoy D, Desai S, Nyirenda T, Bicking K. Vancomycin-resistant enterococcal bacteremia and daptomycin: are higher doses necessary? J Antimicrob Chemother 2011 Sep 1;66(9):2112-8.
2. Sader HS, Jones RN. Antimicrobial susceptibility of Gram-positive bacteria isolated from US medical centers: results of the Daptomycin Surveillance Program (2007–2008). Diagn Microbiol Infect Dis. 2009;65:158-62.
3. Casapao AM, Kullar R, Davis SL, Levine DP, Zhao JJ, Potoski, B, et al. Multicenter study of high-dose daptomycin for treatment of enterococcal infections. Antimicrob Agents Chemother 2013 Sep 1;57(9):4190-6.
4. Wisplinghoff H, Bischoff T, Tallent SM, et al. Nosocomial Bloodstream Infections in US Hospitals: Analysis of 24,179 Cases from a Prospective Nationwide Surveillance Study. Clin Infect Dis 2004; 39: 309–17. https://doi.org/10.1086/421946
5. Britt NS, Potter EM, Patel N, Steed ME. Comparative Effectiveness and Safety of Standard-, Medium-, and High-Dose Daptomycin Strategies for the Treatment of Vancomycin-Resistant Enterococcal Bacteremia Among Veterans Affairs Patients. Clin Infect Dis 2017;64(5):605–13.
6. McKinnell JA, Arias CA. Editorial commentary: linezolid vs daptomycin for vancomycin-resistant enterococci: the evidence gap between trials and clinical experience. Clin Infect Dis 2015; 61:879–82.
7. Daptomycin. [Clinical pharmacology]. Elsevier. Tampa (FL): Daptomycin indications. [cited 2020 Mar 13]
8. Satlin MJ, Nicolau DP, Humphries RM, et al. Clinical and Laboratory Standards Institute Subcommittee on Antimicrobial Susceptibility Testing and Ad Hoc Working Group on Revision of Daptomycin Enterococcal Breakpoints, Development of Daptomycin Susceptibility Breakpoints for Enterococcus faecium and Revision of the Breakpoints for Other Enterococcal Species by the Clinical and Laboratory Standards Institute, Clin Infect Dis 2020; 70:1240–46, https://doi.org/10.1093/cid/ciz845.
9. Akins RL, Rybak MJ. Bactericidal Activities of Two Daptomycin Regimens against Clinical Strains of Glycopeptide Intermediate-Resistant Staphylococcus aureus, Vancomycin-Resistant Enterococcus faecium, and Methicillin-Resistant Staphylococcus aureus Isolates in an In Vitro Pharmacodynamic Model with Simulated Endocardial Vegetations. Antimicrob Agents Chemother. 2001 Feb; 45 (2): 454-459.
10. Gonzalez-Ruiz A, Seaton A, Hamed K. Daptomycin: an evidence-based review of its role in the treatment of Gram-positive infections. Infect Drug Resist. 2016;9:47-58. https://doi.org/10.2147/IDR.S99046
11. Shi C, Jin W, Xie Y, Zhou D, Xu S, Li Q, et al. Efficacy and safety of daptomycin versus linezolid treatment in patients with vancomycin-resistant enterococcal bacteraemia: an updated systematic review and meta-analysis. J Glob Antimicrob Resist 2019 Oct 17.

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To treat severe injection-related infections in people with substance use disorder, collaborate

The UNMC OPAT-MAT team

Here’s a too-common infectious diseases consultation:

A 30-year-old man comes to the ER with two weeks of fevers, chills, and back pain, plus increasingly difficult breathing for the past two days. He has injected opioids for the past five years. He has abscesses in the left arm, tenderness in the low spine, and a new heart murmur. His doctors obtain blood cultures, start IV vancomycin, and bring him into the hospital. After a few hours, his blood cultures grow Staphylococcus aureus. An echocardiogram shows infective endocarditis of the mitral valve with destruction of the anterior leaflet and severe mitral regurgitation, a CT of the chest reveals multiple septic pulmonary emboli, and an MRI of the back shows lumbar vertebral osteomyelitis/discitis and psoas abscesses.
What to do?

Perhaps your first instinct is to focus solely on the staphylococci invading his body – to make treating him a matter of advising your hospitalist colleagues which antibiotics to give and for how long, of knowing where to ask the surgeons and interventional radiologists to put their scalpels and needles. This approach is incomplete, but unfortunately, the medical literature tells us it is also typical – patients often receive high-quality care for the treatment of their bloodstream infections while receiving little to no attention or care for the underlying substance use disorder (SUD) at the heart of their problem.

Why does care for patients with SUD hospitalized with serious infections so often come up deficient? In part, because we have socialized rather than medicalized SUD (e.g. cast SUD as an inherent character flaw or immutable condition rather than a treatable physiologic disorder, like infection). The use of stigmatizing language in the medical record – “drug abuser” and “addict” – elicits negative associations among healthcare professionals. As a result, patients with endocarditis related to injection drug use are likely to receive antibiotics but exceedingly unlikely to receive a comprehensive plan of care for their SUD, such as Addiction Medicine or Addiction Psychiatry consultation, medication-assisted treatment, rescue naloxone, or education about safe injection practices and services.

So what does usual care for our patient look like in the US? He will receive IV antibiotics and surgery. Several folks will describe him as an addict in the chart and eventually someone will do it to his face, which will reinforce that his doctors don’t think much of him. The beginning and end of the plan for his SUD will be to tell him that if he wants to live he needs to stop using drugs. Later, he’ll be told that he needs to stay in the hospital for 6 weeks of IV antibiotics (no one will mention the option of letting him finish his IV antibiotics at home with a PICC, because of anxiety that he might inject his drugs through the catheter). At some point, our patient will become so frustrated about languishing in the hospital with no treatment of his SUD that he will leave against medical advice. Perhaps his doctors will write a prescription for oral antibiotics that he may or may not hear about or go pick up, and perhaps he will come back with renewed infection in a week or two, and probably his treatment team will feel that they did their best and will absolve themselves of culpability, saying something like, well, at the end of the day we can’t stop people from making poor life choices.

As an ID physician, and also the medical director of UNMC’s OPAT (home IV antibiotic) program, I think we can do better. First, let’s address the anxiety about PICCs and home IV antibiotic in people who inject drugs (PID). Suzuki et al found that the available data indicates that PID have low (0-2%) rates of PICC misuse with no greater incidence of line infection or thromboembolism than non-PID and similar rates of treatment completion, rehospitalization, disease relapse, and mortality. While other data suggest that OPAT in PID may be labor-intensive on account of more frequent missed visits, line infections, and re-admissions, we must weight these adverse events against the unmeasured adverse events of prolonged hospitalizations: namely, treatment non-completion and failures due to patients leaving AMA, nosocomial infections, and uncontrolled costs. Fortunately, Eaton et al at the University of Alabama at Birmingham have validated a risk assessment tool identifying PID likely to do well with OPAT, and Fanucchi et al showed in a pilot randomized trial that combining OPAT with pharmacologic therapy for SUD in patients with severe injection-related infections resulted in similar infection and drug use outcomes to standard care while shortening hospitalizations by more than three weeks.

The key to success in treating severe injection-related infections in PID is to generate a comprehensive plan for both the patient’s infection and their SUD – and specifically, to offer the patient effective treatment for their SUD that results in harm reduction (i.e. helping these folks to either stop injecting drugs or inject less frequently or in a manner that reduces their risk of developing infections). While SUD treatment is not inherently beyond the scope of infectious disease specialists, here at UNMC we’re blessed with a dedicated Addiction Psychiatry service headed by Drs. Alëna Balasanova and VaKara Meyer Karre.

Starting in Fall 2019, the UNMC ID OPAT team and the Addiction Psychiatry service began working together to identify patients with opioid use disorder severe injection-related infections who, based on the work by Eaton and our own clinical experience, appear likely to do well with early hospital discharge and combination OPAT/MAT. We combine inpatient consultation by Addiction Psychiatry and ID with early (1-2 weeks) follow-up in both ID and psychiatry clinics to help these patients engage and remain in care for both their infection and substance use issues. We believe this approach helps UNMC provide some of our most stigmatized patients with extraordinary care.

Antibiotics At the End-of-Life: Helping or Harming?

UNMC 2nd Year ID Fellow, Clayton Mowrer, D.O., MBA.

Content written by Dr. Clayton Mowrer.

Early in my medical training, my father developed a rapidly-progressive type of cancer. Over the course of several months, his health declined quite quickly, and he was spending more time in the hospital than outside of it. It became uncomfortably clear that pushing forward with invasive and toxic interventions would cause him much more harm and discomfort than it would any benefit. Our family had many gut-wrenching discussions with my dad’s physicians, and we eventually decided that transitioning him to hospice care would be in his best interest in order to focus on keeping him comfortable in his final days of life. Though that time is mostly a blur to me, I do recall that we were able to discharge him from the hospital and he was able to die peacefully, surrounded by family, without the hassles, tests, and complications that come with being in the hospital.

The discussions surrounding end of life (generally defined as the final days or weeks of life) are incredibly difficult. While the goals of palliative and hospice care being that primarily of minimizing suffering and maximizing quality of life, it is not always a clear or easy decision as to which interventions fall under this definition. Most tend to agree that interventions such as CPR, intubation, or medications with high risk for side effects – e.g. chemotherapy – are not in line with the goals of comfort care and are therefore commonly avoided in end of life care; conversely, the approach to the treatment of infections and the use of antibiotics at the end of life is a much more polarizing topic.    

And the discussion of the use of antibiotics is particularly important, as many studies and observations have shown that many patients at the end of life have a high risk of infections due to a weakened immune system, comorbidities, very frequent exposure to healthcare facilities (where infections are easily spread), and adverse effects of medications such as chemotherapy. Consequently, antibiotics are often given in these final days or weeks of life.

However, here is not much known about the true prevalence of infection at the end of life, with research showing that antibiotics are commonly prescribed in terminally ill patients in the absence of clinical evidence of bacterial infection, due in part to the view that antibiotics are historically viewed as relatively benign. But, just as with the general population, antibiotics don’t come without their own risks, and it is important to thoroughly understand the risks and benefits of antibiotic therapy in order to have an informed conversation when the decision to move towards comfort care is made. 

Antibiotics, to be sure, can be quite beneficial if used in the appropriate clinical scenario. Particularly when there is a proven bacterial infection, an appropriate course of antibiotics can provide relief of pain associated with the infection, especially in infections such as urinary tract infections that can cause significant discomfort. Additionally, some patients may have certain events that are important to their quality of life – such as a wedding or graduation – which they would like to attend, and there is evidence that the treatment of a documented infection in terminally ill patients may prolong life just a little bit.

Yet, suspected infections are not often proven, leading to the frequent and long-term use of broad-spectrum antibiotics (known as empiric antibiotics). Such broad-spectrum antibiotics come with risks, including liver and kidney toxicities, as well as an increased risk for developing Clostridiodes difficile infection (C diff) – an infection that can lead to profound diarrhea, resulting in intensified distress. The administration of antibiotics itself can carry some risk if necessary to give intravenously: IV’s can cause irritation to the skin and soft tissue, occasionally leading to further/additional local or disseminated infections. In the setting of patients who may be exhibiting delirium or an altered mental status, restraints could be necessary. 

Patients, their families, and providers should also be aware and take into consideration what the evaluation of a suspected infection entails. Hospitalization, with many blood tests and imaging, is typically involved. In addition – though this is not always a concern for patients and their families, I do believe it is important to consider – there can be a financial burden that accompanies pursuit of infectious diagnostic workup and treatment. Workup of suspected infections are a frequent cause for hospitalizations in terminally ill patients and can lead to prolonged stays and numerous diagnostic tests, which can be costly. 

Finally, studies have shown that greater antibiotic use at the end-of-life is associated with the acquisition of multidrug-resistant organisms. Addressing these organisms has become a priority in the field of medicine worldwide and has been specifically targeted by organizations such as the CDC, who released a recent report regarding the threat of antibiotic-resistant organisms in the United States. 

Patients in end-of-life care and their families, with their medical providers, should include antibiotic use in discussions of goals of care, as, though it can have some benefits, it also carries distinct risk for harms and should be considered in a similar manner as other treatment interventions. In this way, the comfort of the patient can remain the ultimate focus.

I encourage the reader to  read the writings of Timothy Sullivan and Manisha Juthani-Mehta MD (below), on this topic, as they are much more eloquent than I. 

  1. HIV and ID Observations, by Paul Sax, MD 
  2. Antibiotics Are Often Used at the End of Life, But At What Cost? By Timothy Sullivan
  3. Why Infection May Be a Good Way to Die
  4. Infect Dis Clin N Am. 2017 Dec; 31(4): 639–647. https://doi.org/10.1016/j.idc.2017.07.009
  1. JAMA. 2015 Nov 17; 314(19): 2017–2018. https://doi:10.1001/jama.2015.13080
  2. Cancers (Basel). 2016 Sep; 8(9): 84.
  3. Chest. 2010 Sep; 138(3): 588-594.  https://doi.org/10.1378/chest.09-2757
  4. Journal of Pain and Symptom Management. 2003 May; 25(5): 438-443.https://doi.org/10.1016/S0885-3924(03)00040-X
  5. Journal of Pain and Symptom Management. 2000 Nov; 20(5): 326-334. https://doi.org/10.1016/S0885-3924(00)00189-5
  6. Journal of Pain and Symptom Management. 2013 Oct: 46(4): 483-490. https://doi.org/10.1016/j.jpainsymman.2012.09.010

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Physical Barriers for Prevention Amidst a Pandemic – The Roles of Distancing, Masks and Eye Protection

The following content was originally written for the IDSA Journal Club by Dr. Kelly Cawcutt.

As we continue forward in a global pandemic of unprecedented proportions, prevention of continued transmission of SARS-CoV-2 remains critically important. There has been ongoing debate regarding the highest risk factors for transmission, including the risk of potential aerosolized virus versus primary droplet spread. Based on this debate, the appropriate levels of personal protective equipment for both frontline healthcare workers and the general public have also remained somewhat controversial.

In an attempt to answer this question Chu et al recently published a systematic review and meta-analysis assessing physical distancing, face masks of varying types and eye protection within healthcare and non-healthcare settings, to determine if there is evidence for benefit to support ongoing recommendations of their use.

The systematic review included published research related to SARS, MERS and COVID-19. It is of note, that all studies were observational with no randomized controlled trials regarding these 3 infections. Results demonstrated that transmission of infection decreased with physical distancing of at least 1 m (adjusted OR 0.18; 95% CI 0.09-0.38) with a risk reduction of approximately 10% and increasing protection if the distance was extended to 2 m or greater. Additionally, the use of face masks in all settings was associated with decreased transmission of infection (adjusted OR 0.15, 95% CI 0.07-0.34) with a risk reduction of approximately 14%. There were some potential differences in mask type, with decreased transmission with respirators (N95) as compared to surgical or cloth masks. Finally, eye protection (including goggles, faceshields) also demonstrated decreased risk of transmissions with use (adjusted OR 0.22; 95% CI 0.12 -0.39) with the risk reduction of approximately 10%.

This study provides early evidence of the efficacy of continued PPE use to prevent transmission of COVID-19, both in the community and in the healthcare setting, including continued physical distancing, facemask use and eye protection. It should be noted that the impact as facemask and eye protection utilization is not adjusted for duration of time spent with an actively infected person nor the impact of physical distancing in the absence of the masks or eye protection. The variation of impact in different types of masks, including N95s, is difficult at best to interpret due to lack of randomized controlled trials, lack of information on aerosol generating procedures within studies, and potential variations both in mask quality, appropriate fit of masks, donning and doffing and hand hygiene.

Further research is clearly needed to optimize PPE utilization in the setting of existing shortages faced during this pandemic and for ongoing public health and infection control policy on healthcare based PPE recommendations.

Indeed, this is not over yet.

Fighting Fear in COVID-19

“Fear is a reaction. Courage is a decision”
Sir Winston Churchill

COVID-19 has delivered profound impact on each of us, the healthcare system and world. Events like this carry the impact of an earthquake – the life-altering natural disaster from which we simply cannot be the same thereafter. Yet, for COVID-19, the tremors have not yet stopped.

As we have lived through this pandemic as Infectious Diseases physicians and leaders in Infection Control and Employee Health, we also have encountered nearly unprecedented fear within our workplace.

Fear about how many will become ill, and die of COVID-19.

Fear about inadequate testing.

Fear about not having enough PPE or that it will fail.

Fear that frontline healthcare workers will bring COVID-19 home to families.

Fear has overcome us like a tsunami after the earthquake.

Unfortunately, fear itself has a secondary impact in healthcare. It can influence our actions, including maladaptive behaviors such as hoarding PPE, overuse and misuse of PPE or other scarce resources and avoidance of appropriate cares for our patients.

The potential influence of fear in this pandemic has to be discussed. Here are a few of our thoughts:

“Unfortunately, fear and misinformation has spread as fast as the virus.  Ambiguity breeds anxiety and, as this is a novel infection, there are plenty of unknowns and ambiguities.  We’ve tried to be as transparent and honest as possible, shared information as it became available, and admitted when something was unknown.  We’ve really stressed PPE availability and appropriate use as well as administrative and engineering infection prevention interventions. Hopefully, to some degree, this has lessened anxiety and fear for our healthcare providers.”    – Dr. Mark Rupp

“Fear is a normal human reaction. Fear about COVID-19 can take a significant emotional and physical toll. Fear can be exacerbated by misleading or false information. Recognizing and accepting that fear of this virus is widespread is an important step in process. Providing consistent information and education of the facts on COVID-19 is vital to controlling fear. Hopefully these efforts will prove valuable and protect our most valuable resource- our healthcare workers” – Dr. Rick Starlin

“The impact of fear has been significant in our day-to-day lives. Fear introduces bias to our beliefs that may be unfounded, creates a significant burden to carry, and if not understood and addressed, can inadvertently cause further harm. Creating a safe place to ask questions, provide education and training, and to simply process through these emotions is critical during this pandemic. We cannot afford to underestimate the power of fear.” – Dr. Kelly Cawcutt

Please read our full perspective linked below.

https://www.cambridge.org/core/journals/infection-control-and-hospital-epidemiology/article/fighting-fear-in-healthcare-workers-during-the-covid19-pandemic/B98F7E283611FCF4F2E3CF5B7BCD192E

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