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The Weekly Corona with Dr. Raquel Lamarche

As our institution, state, country, and the world grapple with the impacts of SARS-CoV-2, causing COVID19, there are lots of ongoing discussions about coronaviruses. Dr. Raquel Lamarche is a PGY1 Internal Medicine/Pediatrics resident at UNMC, who will be summarizing updates about SARS-CoV-2 and hopefully make information easier to digest, with additional outlines of implications for graduate medical education. Last week we started with a primer on Human Coronaviruses (HCoVs). This week we will look at what we know about treatment so far.

“(2003) In the event that SARS CoV re-emerges, we will need clarification of the effectiveness of treatments through controlled trials.” Red Book. 

We have generally treated HCoVs (Human Coronaviruses) with supportive care. Steroids, type-1 interferons, convalescent plasma, ribavirin, and lopinavir/ritonavir, were all used in the 2002 SARS-CoV-1 outbreak, albeit, without controlled data, thus NO proof of efficacy. Likewise, throughout this SARS-CoV-2 pandemic, patients from multiple countries have received off-label therapies mostly without controls. 

“(2020) This tragedy of not discovering new therapies during an outbreak cannot be repeated,” Dr. Andre Kalil, UNMC Infectious Diseases 

I discussed the need for quality evidence with my significant other, an ER-resident in NYC. “People are dying in front of our faces; I would try anything to save their lives. You just can’t be a strategic scientist while you are flooded, getting your hands dirty, Raquel, ” he said. Those words are enough to send a chill down the spine.  Physicians are wired to fight for their patients and may act instinctively when faced with death and uncertainty. 

But the fact remains: NO control groups = NO conclusions about clinical efficacy or safety.

Thankfully, there are some ongoing studies to help make decisions. Here’s what we know about potential treatments for SARS-CoV-2:

Remdesivir

MECHANISM

  • Broad-spectrum antiviral; an adenosine analog pro-drug that shuts down viral replication by inhibiting RNA-dependent RNA polymerase. Initially developed by Gilead Sciences to combat Ebola.

THE EVIDENCE

HOPE LEVEL: moderate-high

Lopinavir/ritonavir

MECHANISM.

  • Inhibition of viral protease, which results in inhibition of viral replication. Lopinavir is quickly broken down by human proteases; thus, it is given with low levels of ritonavir, another protease inhibitor, and potent CYP3A4 inhibitor that “boosts” lopinavir concentrations.

THE EVIDENCE

HOPE LEVEL: low

Chloroquine and hydroxychloroquine 

MECHANISM

  1. Inhibition of viral release into the host cell. Endosomal acidification blockade, which is required to activate proteases that release viral particles into the cell.
  2. Reduction of viral infectivity. Inhibition of protein glycosylation and proteolytic maturation of viral proteins.
  3. Immune modulation. Reduction of toll-like receptors, cGAS-STING signaling, and release of pro-inflammatory cytokines.

THE EVIDENCE

HOPE LEVEL: moderate

Anti-IL6 Agents (Tocilizumab, Siltuximab, Sarilumab)

MECHANISM.

  • IL-6 activates T cells and macrophages. May be of benefit for patients with cytokine storm.

THE EVIDENCE

HOPE LEVEL: maybe moderate in patient with cytokine storm

Steroids

THE EVIDENCE

  • “Early (replicative phase)” hydrocortisone treatment  associated with a higher SARS-CoV-2 plasma viral load.
  • Wu et al. found that among patients with ARDS due to SARS-CoV-2, using methylprednisolone correlated with reduced mortality.
  • Based on indirect evidence from critically ill patients in general, Surviving Sepsis guidelines weakly recommend steroids for intubated patients with ARDS and elevated C-reactive protein or patients with an independent indication for steroids.

HOPE LEVEL: 0. Use steroids only as indicated for co-existing processes.

Antibiotics 

THE EVIDENCE

HOPE LEVEL: 0 unless you are treating known bacterial co-infection (if you choose otherwise, you won’t go to ID heaven)

Convalescent plasma

MECHANISM

  • It is possible that convalescent plasma that contains antibodies to SARS-CoV-2 might be effective against the infection (if they are neutralizing antibodies).

THE EVIDENCE

HOPE LEVEL: low-moderate. It may seem intuitive that this would work, but it’s not always the case.

Here are some comprehensive reviews with more detailed information, all written by some phenomenal ID pharmacists:

  1. COVID-19 Treatment: A Review of Early and Emerging Options, By Erin McCreery, PharmD and Jason Pogue, PharmD
  2. UNMC COVID-19 Antiviral and Pharmacotherapy Information, by Bryan Alexander, UNMC PharmD and the UNMC Antimicrobial Stewardship Team
  3. Treatment of Coronavirus Disease 2019 (COVID-19): Investigational Drugs and Other Therapies by Scott J Bergman, UNMC ID PharmD 

There are no answers yet. Nevertheless, we are hopeful and always learning. Now more than ever, it is crucial that we stay together, sharing our experiences, and supporting science.

#PharmToExamTable: What is the evidence for continuous infusion dosing of cefazolin?

The following is a clinical review written by Corey Paz, PharmD. Recent graduate of UNMC College of Pharmacy and new PGY1 Pharmacy Resident at Gunderson Health System in LaCrosse, Wisconsin. Follow him on Twitter @coreypaz.

Corey was supervised by Scott Bergman, PharmD, FCCP, FIDSA, BCPS. Pharmacy Coordinator for Antimicrobial Stewardship at Nebraska Medicine and Clinical Associate Professor in the UNMC Dept of Pharmacy Practice and Science. Follow him on Twitter @bergmanscott.

Cefazolin is a first-generation cephalosporin (ß-lactam antibiotic) used for the treatment of Gram-positive bacterial infections and some Gram-negative organisms.  It has potent activity against common Gram-positive bacteria including Staphylococcus aureus (methicillin-susceptible only, MIC90 = 2 mcg/mL)1 and beta-hemolytic Streptococci such as Streptococcus pyogenes (Group A) and Streptococcus agalactiae (Group B).  The volume of distribution of cefazolin is ~10 L, and it is 75-85% plasma bound.  In comparison to four other first-generation cephalosporins (cephaloridine, cephalothin, cephalexin, cephanone), cefazolin has the smallest apparent volume of distribution which in part explains its high levels in the blood and popularity over the others2.  The reported half-life of the drug in adults is 1.8 h (IV).

Based on its pharmacodynamic profile, cefazolin needs to be administered at least twice per day by IV bolus to achieve therapeutic concentrations for the most susceptible organisms1.  In patients with severe infection, the usual dosage range is 1 to 2 g IV every 8 h in patients when renal function is normal2.  Cefazolin is a preferred agent for patients being discharged from the hospital that require IV antibiotics due to its efficacy and safety.3,4  One option to avoid frequent re-dosing is to administer cefazolin as a constant infusion over 24 h.5

Due to time-dependent pharmacodynamics, the efficacy of cephalosporins is associated with time above the minimum inhibitory concentration (T>MIC)1.  The optimal bactericidal action of cephalosporins reportedly occurs at approximately four times the MIC for the infecting pathogen6.  Increasing the dose (>MIC) of a ß-lactam antibiotic does not improve bactericidal activity, but rather increases the risk of adverse effects.  Strategies utilized to maximize the efficacy of ß-lactams include (1) decreasing the dosing interval (2) extending the infusion time of the drug and (3) administering the drug as a continuous infusion following a loading dose.

Livingston & Wang (1992) first demonstrated the superiority of continuous infusion dose administration for cefazolin versus standard intermittent dose administration using rats.  The study explored identical quantities of cefazolin administered either intermittently or continuously after shock in a subcutaneous abscess model with 2×108 S. aureus.  Rats were divided into three groups: (1) controls, which received no drug treatment; (2) rats intermittently dosed at either 30 or 60 mg/kg intraperitoneally every 8 h for three doses daily, and (3) rats receiving continuous drug infusion consisting of 30 or 60 mg/kg intraperitoneally as a loading dose followed by 90 or 180 mg/kg continuously infused over a 24 h time period (Figure 1).

Administration of cefazolin as a loading dose (30 mg/kg) followed by a continuous infusion (90 mg/kg over 24 hours) resulted in significantly more drug being present in the tissue than the identical quantity of cefazolin given as intermittent bolus doses.6  Seven days after inoculation, abscess number, diameter, and weight were measured. Within the continuous infusion group, a standard quantity of cefazolin (120 mg/kg/day) significantly decreased the number and size of the abscess compared with intermittent dosing after hemorrhagic shock.

In a retrospective cohort study, Zeller et al. (2008) investigated the use of continuous intravenous cefazolin in patients who were discharged home with parenteral antibiotic therapy on an outpatient basis.  At home, antibiotic therapy was administered twice a day, over a 12 h period, by a visiting nurse through a portable infusion device, either a constant-infusion pump or an elastomeric infusion system (single-use).  Patients unable to discharge home were transferred to a rehabilitation center or remained inpatient until the end of parenteral therapy.  Drug therapy was initiated with a loading dose, infused over 10 minutes, of 1 g when the daily dose was ≤4 g or of 2 g when the daily dose was >4 g, followed immediately by the continuous infusion of 60 to 80 mg/kg of body weight.  For example, the dosing regimen of 70 kg individual would be as follows: 2 g of cefazolin infused over 10 minutes followed by 4200 mg (60 mg/kg * 70 kg) total daily dose divided twice a day (2100 mg/dose over 12 hours each).   The median treatment duration was 42 days, and the median daily cefazolin dose was 6 g.  The median follow-up time was 25 months.  Overall, 82 (93%) of the 88 patients were considered to have been cured (53 patients) or probably cured (29 patients)7.

In summary, cefazolin is a first-generation cephalosporin with bactericidal activity against methicillin-susceptible Gram-positive organisms and some Gram-negative organisms.  Two separate studies provided evidence favoring the administration of a continuous infusion of cefazolin following a loading dose compared to intermittent administration.  The emphasis for clinical application not only stems from the results of each study, but also from the pharmacodynamic profile of cefazolin.  The time-dependent efficacy plays an instrumental role in the flexibility of drug administration.  Doses ranging from 60 mg/kg/day to 120 mg/kg/day have demonstrated efficacy and fall within the suggested 12 g/day maximum dose whether administered over two 12 h intervals or one 24 h interval.

With appropriate clinical judgement, monitoring, and follow-up, administration of cefazolin (6g/d) by continuous infusion targeting susceptible pathogens may be considered in specific clinical scenarios.

References

  1. Howard, G., Begg, E., Chambers, S., Brincat, J., Zhang, M., & Kirkpatrick, C. (2002). Free and total cefazolin plasma and interstitial fluid concentrations at steady state during continuous infusion. Journal of Antimicrobial Chemotherapy, 50, 429-432.
  2. Kirby, W., Regamey, C. (1973). Pharmacokinetics of Cefazolin Compared with Four Other Cephalosporins. The Journal of Infectious Diseases, 128, S341-S346.
  3. Youngster, I., Shenoy, E., Hooper D., and Nelson S. (2014) Comparative evaluation of the tolerability of cefazolin and nafcillin for the treatment of methicillin-susceptible Staphylococcus aureus infections in the outpatient setting. Clinical Infectious Diseases, 50, 369-375.
  4. Lee, B., Tam I., Weigel IV, B., Beeze, J., Paulus J., Nelson, J., Allison, G. (2015) Comparative outcomes of β-lactam antibiotics in outpatient parenteral antibiotic therapy: treatment success, readmissions and antibiotic switches. Journal of Antimicrobial Chemotherapy, 70, 2389-2396.
  5. Harris, A., Shrestha, N., Allison. G., Keller, S., Bhavan, K., Zurlo, J., et al. (2019) 2018 IDSA Clinical Practice Guideline for the management of outpatient parenteral therapy. Clinical Infectious Diseases, 68, e1-e35.
  6. Livingston, D., Wang, M. (1992). Continuous Infusion of Cefazolin Is Superior to Intermittent Dosing in Decreasing Infection After Hemorrhagic Shock. The American Journal of Surgery, 165, 203-207.
  7. Zeller, V., Durand, F., Kitzis, M., Lhotellier, L., Ziza, J., Mamoudy, P., & Desplaces, N. (2008). Continuous Cefazolin Infusion To Treat Bone and Joint Infections: Clinical Efficacy, Feasibility, Safety, and Serum and Bone Concentrations. Antimicrobial Agents and Chemotherapy, 883-887.


     

The Weekly Corona with Dr. Raquel Lamarche

As our institution, state, country, and the world grapple with the impacts of SARS-CoV-2, causing COVID19, there are lots of ongoing discussions about coronaviruses.

Dr. Raquel Lamarche is a PGY1 Internal Medicine/Pediatrics resident at UNMC, who will be summarizing updates about SARS-CoV-2 and hopefully make information easier to digest, with additional outlines of implications for graduate medical education.

TODAY’S PRIMER: Human Coronaviruses (HCoVs)

Four HCoVs cause mild upper respiratory infections (common cold): 229E, OC43, NL63, and HKU1. Less frequently, these can be associated with lower respiratory tract infections, primarily in infants and the immunocompromised.

Three HCoVs are related to lower respiratory infections and responsible for recent epidemics:

1. SARS-CoV-1. This virus was responsible for the 2002-2003 global outbreak of severe acute respiratory syndrome (SARS). The virus causes a spectrum of disease, including asymptomatic infections and mild illness.

The outbreak lasted for 9-months, resulting in 8096 reported cases and 774 deaths. SARS-CoV disproportionately affected adults, who typically presented with fever, myalgia, headache, malaise, followed by dyspnea 5-7 days later. 25% of adults developed watery diarrhea. 20% developed respiratory distress requiring intubation and mechanical ventilation.

The overall mortality rate was 10%, with most deaths occurring in the 3rd week of illness. The case-fatality rate in people older than 60 approached 50%. Notably, no infant or child deaths were documented. The horseshoe bat is the natural reservoir of SARS-CoV-like viruses. The virus is thought to have evolved through civet cats or intermediate animal hosts in the wet markets of China.

The 2002-2003 global outbreak was controlled due to the rapid identification of cases, contact tracing, quarantine, and isolation. We always wondered whether a large scale re-emergence of SARS-CoV would ever occur and as Italians would say, “eccoci qui,” here we are.

2. MERS-CoV. This was a novel virus identified in 2012. The disease caused by this virus was called Middle-East respiratory syndrome (MERS).[It is important to note that while this virus and disease were unfortunately named for the region of the world where they were identified, it is generally recommended to avoid naming diseases after geographic regions, race/ethnicity, etc., as this can lead to stigma associated with the disease].

MERS is associated with a severe respiratory illness similar to that with SARS-CoV, resulting in 2494 cases and 858 deaths. Cases continue today but are primarily contained in the Middle East. Data suggests that the virus evolved from bats, with dromedary camels acting as intermediate hosts.

Preventing transmission from camels is challenging, given the prevalent use of camels in some Middle Eastern countries. The case-fatality rate is high, estimated at 35%, but may partially reflect surveillance bias for more severe disease. (Red Book, 31st edition)

3. SARS-CoV-2. This is the virus causing the current pandemic. The disease, now known as COVID-19, was first reported in Wuhan, China, in late December 2019. Click the link for the current number of US cases. This virus likely originated in chrysanthemum bats. There is probably an intermediate host between bats and humans, and preliminary data suggest it is the pangolin.

The virus uses a densely glycosylated spike (S) protein to enter host cells and binds with high affinity to the angiotensin-converting enzyme 2 (ACE2) receptor in humans like SARS-CoV. It is still unclear why SARS-CoV-2 is more easily transmissible than SARS-CoV-1 or MERS-CoV.

This virus is actively mutating, which means the virulence and transmission will shift over time in unpredictable ways. See genomic epidemiology of novel coronavirus. Genetic analyses of 103 SARS-CoV-2 genomes indicated that we have two different types of the virus:
• L Haplotype (∼70%) is more prevalent and causes more severe illness
• S Haplotype (∼30%), less prevalent, and causes milder illness

SARS-CoV-2: severe acute respiratory syndrome coronavirus-2; COVID-19: coronavirus disease-2019; ACE-2: angiotensin converting enzyme-2; ARDS: acute respiratory distress syndrome; HLH: hemophagocytic lympho-histiocytosis; PRN: as needed, CPR: cardio-pulmonary resuscitation

Transmission is via LARGE D-R-O-P-L-E-T-S. Droplet transmission is prevented by using standard surgical-masks. If those droplets are aerosolized, the virus can prevail for up to 3 hours in the aerosols. The CDC recommends airborne precautions especially during aerosol-generating procedures (sputum induction, open suctioning of airways, intubation, tracheostomy, CPAP, bag-mask ventilation).

Contact transmission implies virus-containing droplets settling on surfaces, a person touching such contaminated surfaces/objects and transferring the virus to their faces and mucous membranes. The virus can survive for up to four days on surfaces. To prevent this form of transmission, you can:
• Avoid touching your face (I’m sure your face is itching now)
• Disinfecting surfaces with 0.5% sodium hypochlorite
• Cleaning hands with an alcohol-based sanitizer
• Be mindful of your stethoscope and sanitize it often

Clinical Overview: Incubation 2-14 days; median of 4-5 days. Rare patients may have a more prolonged incubation of up to 24 days; this potentially long incubation period could have implications for quarantine policies and prevention of spread. Clinical signs/symptoms include:
• Upper respiratory infection symptoms
• Lower respiratory symptoms (shortness of breath)
• Fever (may not be present in up to 50% of cases)
• Less commonly, gastrointestinal symptoms like diarrhea or nausea in 10% of patients
• The elderly may have hypoxemia with no increased work of breathing
• Physical examination is nonspecific
• Lymphopenia is present in ~80% of patients
• Elevated CRP in 60% of the patients. Poor prognostic factor
• SARS-CoV-2 is not associated with elevated procalcitonin (95% patients had pro-calcitonin below 0.5)

In future Weekly Corona posts, we will explore what we know about personal protective equipment for COVID-19, treatment options, impacts on medical education, and more. Stay tuned!

Endnote: As we sift through the mountains of information about COVID-19, it is helpful to keep a few reliable resources bookmarked. Review these often, at least weekly, for updates:
• World Health Organization https://www.who.int/emergencies/diseases/novel-coronavirus-2019
• Centers for Disease Control & Prevention https://www.cdc.gov/coronavirus/2019-ncov/index.html
• Infectious Diseases Society of America https://www.idsociety.org/public-health/COVID-19-Resource-Center/
• Nebraska Medicine https://www.nebraskamed.com/for-providers/covid19
• University of Washington https://covid-19.uwmedicine.org/Pages/default.aspx
• Our World in Data https://ourworldindata.org/coronavirus 

At the center of the 2018 West Nile Virus season, UNMC ID physicians encountered an unusual presentation

In 2018, we experienced a particularly severe West Nile Virus season, with an unusually high amount of neuroinvasive disease. Last summer, our senior ID Fellow Dr. Lindsey Rearigh shared an informational blog post about the disease, and more recently, she and Dr. Sara Bares published a case report in the Journal of Neurovirology describing a a patient with an unusual presentation of West Nile Virus disease. Dr. Rearigh shared a summary of her case with us:

What is your publication about?

This is a case presentation that describes a young, healthy adult patient who presented with uveomeningeal syndrome as the initial manifestation of neuroinvasive West Nile Virus (WNV) disease. Uveomeningeal syndrome includes intraocular and meningeal inflammation often from an infectious process such as WNV and would be classified as neuroinvasive disease (i.e. involving the central nervous system).  WNV can have an array of clinical presentations ranging from asymptomatic to febrile illness with vomiting and diffuse myalgias (muscle aches) and even to neuroinvasive disease characterized by meningioencephalitis and flaccid paralysis.

Why is this interesting?

Previously, neuroinvasive and ocular WNV were seen primarily in patients who were elderly (age>50) or had compromised immune systems (due to conditions such as diabetes or malignancy). Our patient was young and healthy, raising concerns for increased WNV virulence. This is coupled with concerns of increased prevalence of neuroinvasive WNV seen in 2018, a year in which approximately half of all cases in Nebraska were diagnosed as neuroinvasive disease.

What future questions does this case raise?

Interestingly, our patient improved on high dose steroids. The standard of care for WNV is usually supportive; the role of corticosteroids remains controversial with concerns for prolonged recovery. There are case reports demonstrating improved outcomes in WNV-associated flaccid paralysis and meningoencephalitis but the evidence is still limited, leaving room for further research in this area.

Citation: Rearigh, L., Kedar, S. & Bares, S.H. J. Neurovirol. (2019). https://doi.org/10.1007/s13365-019-00808-0 

Contraception and Antiretroviral Therapy: Important Interactions to Keep in Mind

Dr. Kimberly Scarsi recently published an important study in Lancet HIV: “Antiretroviral therapy and vaginally administered contraceptive hormones: a three-arm, pharmacokinetic study.”  We were excited to learn more about and feature her work!

Could you please give us a brief summary of the study you performed?

This was a pharmacokinetic evaluation of the effect of antiretroviral therapy (ART) on vaginally administered hormones. Overall, 84 women participated in the study across 21 AIDS Clinical Trials Group (ACTG) and IMPAACT clinical trial sites in Asia, South America, sub-Saharan Africa, and the United States. The participants were all women living with HIV, either not yet on ART or were receiving ART containing efavirenz- or atazanavir/ritonavir, and agreed to use a vaginal ring containing ethinyl estradiol and etonogestrel continuously over 3 weeks. We were able to compare the hormone (ethinyl estradiol and etonogestrel) exposure in both ART groups compared to the control group of women not yet receiving ART.

What was the impetus to conduct this study?

Effective family planning, which often involves the use of hormonal contraception, is an important component of care for women living with HIV. It allows women to plan for desired pregnancies, and planned pregnancies are associated with lower maternal and infant morbidity and mortality, particularly in low- and middle-income countries. Unfortunately, some hormones have drug interactions with some antiretrovirals that may jeopardize hormone effectiveness or tolerability. This is especially true for efavirenz-based ART, which is still the most commonly used regimen worldwide, particularly in low- and middle-income countries where most women with HIV live.

Non-orally administered hormones was believed to reduce the risk of these drug-drug interactions. For hormones administered by a vaginal ring, the mechanism of their effectiveness is systemic exposure (e.g. in the plasma) and ovulation suppression, rather than only local effects (like an intrauterine device). Therefore, the impact of the drug interaction between orally administered medications that may influence hormone exposure is important to understand, yet had not been performed. The study team sought to determine whether estrogen and progestin administered by a vaginal ring would be affected by oral ART containing either efavirenz or atazanavir/ritonavir.

What were some key findings?

The results showed that hormone concentrations were significantly changed by both types of ART. Efavirenz-based ART decreased both ethinyl estradiol and etonogestrel hormones, raising concerns for lack of efficacy and the risk of unintended pregnancies. While the atazanavir/ritonavir-based ART increased progestin exposure (providing reassurance that the contraceptive effectiveness would be maintained), it decreased estrogen exposure, which may increase the risk of mid-cycle bleeding.

While the findings are directionally similar to what we’ve seen with ART and oral hormones to date, the vaginal ring ART-hormone interaction resulted in even larger changes in hormone exposure than what was observed in the oral studies. We aren’t sure if difference is related to the difference in route of hormone administration, or perhaps more likely, differences in the studied population (primarily Caucasian, healthy volunteer in the oral study, racially and ethnically diverse women living with HIV in our study).

What are future directions for work studying the interaction between contraceptives and ART?

The importance of understanding the pharmacology of vaginally administered drugs has particular relevance as vaginal rings are being developed for multipurpose prevention of both HIV and pregnancy. This study has raised awareness that both local and systemic drug interactions need to be evaluated early in vaginal ring development in order to optimize co-prescribing therapies.

For this study, we have ongoing work evaluating the influence of pharmacogenetics on the extent of the drug interaction observed between the vaginally administered hormone and ART. In addition, we are evaluating the effect of the vaginal ring on the vaginal microbiome, as well as the effect of the vaginal microbiome on hormone exposure.

My work outside of this study is includes evaluating and managing drug interactions with other types of contraceptives, especially subdermal implants, with antiretroviral therapy. I have a study that is going to be wrapping up soon in Uganda, which is evaluating using dose adjustment of hormones to overcome the common drug-drug interaction with efavirnez-based ART.

You can read more about Dr. Scarsi’s work here, as well as a commentary from other HIV researchers expanding on the value of this study.  Follow Dr. Scarsi on Twitter at @KimScarsi, and her co-author Dr. Katy Godfrey @katygodfrey6. 


 

Journal Club: Should vancomycin be given as prophylaxis for Clostridioides difficile infections?

The following is a review by one of our fellows, Dr. Randy McCreery, who at a recent journal club presented a paper by Johnson, et al.: Effectiveness of Oral Vancomycin for Prevention of Healthcare Facility-Onset Clostridioides difficile Infection in Targeted Patients During Systemic Antibiotic Exposure, Clinical Infectious Diseases, 28 September 2019.

In addition, Drs. McCreery, Cawcutt, Cortes-Penfield & Van Schooneveld published a letter to the editor of Clinical Infectious Diseases based on this journal club review and blog post. Read the official letter here. A formal reply to this letter, was also published here.

Why was it important to review this article?

This article attempts to address an important question: with nearly 500,000 infections and 15,000 deaths annually (CDC) attributed to Clostridioides difficile, how might we further reduce the incidence of this disease beyond the antimicrobial stewardship and infection control procedures that we are already employing?  To date, most of the data on chemoprophylaxis for preventing Clostridioides difficile infections (CDI) is retrospective, and thus, more prospective, randomized data is needed.  This article not only provides important new data from a prospective randomized trial, but it also provides a summary of the available retrospective data to date.

Who did they study?

Admitted patients who were felt to be high risk for developing healthcare facility onset CDI were studied.  High risk was based upon age (> 60), recent hospitalization (< 30 days), and recent and current use of antibiotics (during the prior and current hospitalization).

What did they do and where did they do it?

Patients were enrolled over a 7-month period at a single, 961-bed, tertiary hospital in Winston-Salem, North Carolina, in a prospective, randomized, open-label study. One hundred high risk patients were randomized, 50 in each arm, to receive either oral vancomycin prophylaxis (OVP) or no prophylactic therapy.  OVP was given for the duration of systemic antibiotic therapy plus an additional 5 days at a dose of 125 mg daily.  Patients received an average of 12 days of OVP.

What did they find?

They found that 6 patients in the control arm developed healthcare facility onset CDI (the primary end point) vs none in the prophylactic arm, and this was statistically significant (p = 0.03).

Key points from the article:

  • The article attempts to answer an important question, but drawing definitive conclusions from this trial remains difficult.
  • The screening method used in this study to identify patients at high risk of developing CDI may not perform similarly in all institutions. Thus, the external validity of this study remains questionable.
  • The trial was small and without a placebo arm, both of which can be a source of bias.
    • Randomization of small numbers of patients may not evenly distribute important risk factors. While the authors argue that the imbalances in risk factors in this study, mainly high-risk antibiotic exposure, likely favored development of more CDI in the prophylaxis group thus strengthening their conclusion that OVP can prevent CDI, a larger trial with more balanced exposures would present a clearer picture as to the true effect of OVP in preventing CDI.
    • Related to the lack of a placebo, nowhere in the article does it account for how many tests for CDI were run in either group nor the number of patients in each group that developed diarrhea.  These are important data to include because they are the components of the primary end point.  Differences in these data between groups may have been due to procedural bias due to a lack of placebo and blinding of both patients and healthcare personnel leading to differences in the primary outcome.

  • The definition of healthcare facility onset CDI did not include a toxin assay. Given that CDI is a toxin mediated disease, toxin reporting (or PCR cycle time that predicts toxin as has been recently reported by Senchyna et al.) may have been able to distinguish disease from colonization in the control group.  This calls into question the method by which the primary outcome measurement was made.  Is it possible that given no toxin assay was performed in the control group, that only colonization was detected, and diarrhea was present for another reason?  Is it possible that colonization would have been detected in the OVP group had the vancomycin not decreased colonization causing PCR assays to be negative?
  • New VRE colonization was evaluated as a secondary endpoint. While no patients in the OVP arm were found to have new VRE colonization, there was a baseline colonization rate of 42%, and 36% of patients in the OVP group were not tested.  With such a high rate of baseline colonization and so many patients that did not undergo analysis, the study design is likely underpowered to detect any meaningful difference in conversion from VRE negative to VRE positive in the OVP group.  The control group should also be tested to account for any baseline conversion rates.  This metric was not reported either.
  • Telephone surveys completed post-discharge were low, < 50% in each arm making any conclusions related to outcomes beyond the hospital stay challenging to assess.
  • No information was included regarding how many patients were screened versus the number enrolled. The algorithm to identify those eligible was simple and did not seem excessively restrictive.  The exclusion criteria may have made many who were started on antibiotics at admission difficult to enroll because the expiration time for starting OVP (< 72hrs after antibiotic initiation) would lapse at or near the time the patients became eligible for enrollment (admitted for > 72 hrs).  If this was the case, the authors should say so in addition to any other reason why it took 7 months to enroll 106 patients in a 961-bed hospital.
  • OVP also seemed to be well tolerated
  • Cost estimates were quite favorable in the OVP group with around $26 per prophylactic course. With a number needed to treat of 9, that would equate to an average of $236 to prevent one case of CDI.  That was compared to the authors estimate of $2,648 in additional hospital costs per episode of hospital onset CDI.

Conclusion:

While this study demonstrated less positive PCR tests in the OVP group, the lack of key clinical data makes the conclusion limited and inadequate to inform active clinical practice. The jury remains out on the efficacy of OVP pending a larger, randomized, ideally placebo controlled, multicenter study.

Steven W Johnson, Shannon V Brown, David H Priest, Effectiveness of Oral Vancomycin for Prevention of Healthcare Facility-Onset Clostridioides difficile Infection in Targeted Patients During Systemic Antibiotic Exposure, Clinical Infectious Diseases, , ciz966, https://doi.org/10.1093/cid/ciz966


 

About our First Year Fellows – Dr. Clayton Mowrer

Tell us about the position you are starting:

I am a quarter of the way through my first two years of a four year adventure as an Internal Medicine/Pediatrics Infectious Diseases fellow here at UNMC. I will spend these first two years here learning adult ID, followed by two years at Children’s Hospital and Medical Center here in Omaha, where I will learn pediatric ID. I could not be more excited!

Tell us about your background:

I was born and raised in Kansas City. Went to undergrad in Tulsa, then moved up to the NW for a while before moving back to KC for med school at Kansas City University of Medicine and Biosciences (KCUMB) and grad school for my MBA at Rockhurst University, then moved on to med-peds residency at University of Missouri-Kansas City (UMKC). #ChiefsKingdom!

Why did you choose to come work at UNMC?

There was an unmistakable sense of friendliness, collegiality, and sense of collaboration within the department when I interviewed. And there was not a single interview that I did not actually enjoy. Add on top of that the fact that UNMC has a fantastic reputation in the field of ID, with a wide range of experts in their respective fields. It was also important to me to have a vast breadth of clinical exposure, as well as support for various research and academic endeavors. This has certainly proven true, and the support and guidance we receive as fellows is top notch.

What makes you excited about working in ID?

I could go on and on, but I’ll hold back. To put it briefly, ID is a field in which the microscopic world interacts with macroscopic individual and population in ways that are extraordinarily complex and beautiful. It is a field which touches on all systems of the body and requires knowledge of all sub-specialties. And it is a constantly evolving (sorry for the pun) field – a field of study that was made for the curious.

Tell us something about yourself that is unrelated to medicine?

My wife and I love to travel, and we do so at every opportunity we get. I have personally road-tripped to every state in the continental US, and between the two of us, we have been all over the world. I love camping and hiking and just being as outdoors and active as possible. I’m also a prior soccer and tennis player.

COVID-19 – What is UNMC ID doing?

Although it has not been officially declared a pandemic by the World Health Organization (WHO), as of this morning, there were 81, 191 confirmed cases of COVID-19 and 2,768 deaths worldwide. To date, 57 of these cases are within US borders, and there are increasing cases throughout the world.

UNMC & Nebraska Medicine have had our quarantine and biocontainment units active and caring for patients with known COVID-19 (also known as SARS-CoV-2) infection. Our multidisciplinary teams are working hard to prevent spread of infection, to care for those with infection and now, we are launching into research for future treatments.  

The first study in the US, a NIH sponsored randomized, controlled trial of the antiviral medication (remdesivir) has begun. Dr. André Kalil is the Primary Investigator, with several co-investigators from our team caring for patients with COVID-19. See a short video clip of Dr. Kalil discussing the trial here.

Dr. Andre Kalil – PI for the new clinical trial on remdesivir for treatment of COVID-19.

With no known effective treatments to date, the trial starts at a critical time, as officials from the CDC have cautioned that Americans should prepare for community spread of COVID-19 here within the US borders. The CDC has guidance on ways to prepare here.

There are several ways our UNMC, Nebraska Medicine, NETEC and state-wide infection control assessment and promotion program (ICAP) are working on providing the best possible care for current and future patients.

There are resources for donning and doffing (of personal protective equipment), updates, training and education from NETEC; and ongoing updates from UNMC/NM and our Global Center for Health and Security. As always, we will strive to keep you updated on our mission to continue to provide exceptional care for our patients.

Freedom is in the Air: My Visit to Sudan, a Born-again Country

Here at UNMC ID, we are thrilled to share the global, and personal efforts, of our faculty. Please take a moment to read this excellent piece by Dr. Nada Fadul; Associate Professor, Division of Infectious Diseases, UNMC

Sudan felt different this time. It was the middle of December 2019, the first anniversary of the Sudanese Revolution that caught the world’s attention. The country is going through a severe economic crisis; bread and gas lines are everywhere, yet the atmosphere is full of hope and enthusiasm. 

Our visit was organized by the Association of Sudanese American Professors in America (www.asapa.online). As part of the visit, we toured several universities to conduct informational sessions and needs assessments.  We were met with great enthusiasm about the possibility of collaboration with US high education institutions due to sanctions listing Sudan as a State Sponsor of Terrorism (SST) for over 24 years.  Being on the SST list prevented Sudan from accessing new technology and knowledge exchange with the US. The needs  in the institutions we visited are enormous and the faculty are doing their best with very limited resources. Our agenda at the University of Shendi included a meeting with the Dean of Medicine, the Preisdent of the University, and other faculty, followed by a ceremony celebrating the anniversary of the revolution. I gave a presentation on “Updates in Infectious Diseases” and we had an interesting discussion on the challenges around handwashing, a basic infection control method in the hospital where there is only one sink in the whole floor. The next day we were taken on a tour of the Bajrawia pyramids in the Kingdom of Meroe,  one of the ancient Nubian kingdoms, by a graduate of the University of Shendi School of Archeology.The highlight of my trip was our visit to the HIV clinic and the National Tropical Diseases Hospital. On the way there, we passed by the Army Headquarters and I was mesmerized by the revolutionary murals.  We arrived at the Tropical Diseases Hospital shortly after noon. The medical director was gracious enough to take time from her busy day to give us a tour of the hospital, their small lab with little microbiology capabilities, and the outpatient clinic. We then proceeded to the Omdurman VCT and ART Center,the largest HIV clinic in the country providing care to over 4,000 patients. The center was a renovated building sponsored by the United Nations Development Program. Sudan is not a recipient of President Emergency Plan for AIDS Relief (PEPFAR) which puts it at a disadvantage when attempting to control the epidemic. The Global Fund provides the antiretroviral medications to the clinic’s pharmacy which then distribute them to patients. The regimens were mostly outdated and limited in options. The HIV clinic lab did not have capabilities for viral load nor CD4 count, making clinical assessment the only way to assess response to antiretrovirals. 

In spite of the difficult working environment, the HIV clinic staff is dedicated to making a difference in these patients’ lives. The center is well equipped with highly skilled counselors who conduct  needs assessments of patients’ medical, psychosocial, and mental health. All of their assessments are done and stored in paper files as the center does not access to an electronic medical record. There is a dedicated pediatrics clinic space and waiting room as well as a dedicated pediatrics counselor. Several needs were identified including staff training and capacity building, assistance with equipment, and assistance with access to US agencies funding programs for comprehensive HIV care and prevention. Stigma was identified as a major challenge to retaining patients in HIV care as well as concerns about confidentiality.

We concluded our trip with a 1-day conference “Towards Sustainable Development in Sudan: Challenges and Opportunities” attended by the Ministers of Health, Economics, and Irrigation. The Minister of Health delivered a presentation on his transitional period health strategy, including an outbreak response and improving access to preventive services. He emphasized the need to address health disparities in the country, especially war-torn regions in Darfur and Nuba Mountains among other regions. I followed with a presentation on “How Research can Inform Healthcare Policy” and emphasized the role of implementation and dissemination science as well as health outcomes research in the next phase of health transformation. The conference provided a great opportunity for networking with faculty from different universities and staff from the Minister of Health. 

Overall, our visit was successful and we were very inspired to see a new Sudan that is full of hope for a bright future. The economy is in bad shape and the healthcare system is in dire need of help, but I am confident that the dedicated Sudanese inside and outside of Sudan will be able to rebuild the country. 

Helping Our Patients Beyond the Clinic

Rachelle Carr (left) and Dr. Susan Swindells receive donations for the Specialty Care Clinic hygiene pantry

As we start a new year, we thought it would be appropriate to share a story that reminds me of what is fundamental to a life in medicine: helping those we have the power to help.

The Nebraska Medicine Specialty Care Center houses our HIV clinic as well as a hygiene pantry that stocks supplies to help patients who don’t have access to these products, supplementing the medical care patients receive and helping break down some of the barriers to good health.  In October, Carly McCulloch, an education graduate student at the College of Saint Mary, organized a hygiene drive to benefit our pantry.

“Access to hygiene items brings a sense of dignity to tough situations,” Mary wrote in her letter asking folks to contribute to her drive.  In addition to collecting a huge number of personal hygiene products, Mary included notes of positivity from herself and donors to support those receiving the supplies.

Let’s keep Carly’s example in mind and remember that there are always ways to help those who need it, and the most fundamental supplies can make a huge impact.  We are so grateful to Carly for the time and effort she spent collecting and organizing donations of our hygiene pantry.

Hygiene supplies and notes of positivity ready to go out to patients!


 

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