Eli Opacich PharmD BCPS BCCCP December 2 nd 2020 Financial Disclosures None Learning Objectives Assess pharmacotherapy updates in sepsis and septic shock Employ antimicrobial stewardship practices related ID: 931426
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Slide1
Pharmacotherapy Considerations in Sepsis and COVID-19
Eli Opacich,
PharmD
, BCPS, BCCCP
December 2
nd
2020
Slide2Financial Disclosures:
None
Slide3Learning Objectives
Assess pharmacotherapy updates in sepsis and septic shock
Employ antimicrobial stewardship practices related
to sepsis
Evaluate treatment options for COVID 19
Slide4Sepsis Definitions
Sepsis
-
life-threatening organ dysfunction caused by a dysregulated host response to infection (Sepsis-3)
Organ dysfunction is defined by the 2016 SCCM/ESICM task force as an increase of two or more points in the SOFA score
Mortality ≥ 10%
Septic shock
-
sepsis that has circulatory, cellular, and metabolic abnormalities that are associated with a greater risk of mortality than sepsis alone
patients who fulfill the criteria for sepsis who, despite adequate fluid resuscitation, require vasopressors to maintain a mean arterial pressure (MAP) ≥65 mmHg and have a lactate >2 mmol/L
Mortality ≥ 40%
Slide5SOFA and Sepsis-3
Slide6The “Golden Hour” of Sepsis
Every hour of delay in the administration of antibiotics decreased the chances of survival by 7.6% (2006)
Since this study most treatment protocols have focused on administering antibiotics as soon as possible
Surviving Sepsis Guidelines – proposed bundles to be started within a certain time period
6
hrs
-> 3
hrs
-> 1
hr
Empiric broad-spectrum therapy with one or more intravenous antimicrobials to cover all likely pathogens should be started immediately for patients presenting with sepsis or septic shock
IDSA did not endorse the most recent Surviving Sepsis Guidelines
Duration of hypotension before initiation of effective antimicrobial therapy is the critical determinant of survival in human septic shock. Critical Care Medicine. 2006
The Surviving Sepsis Campaign Bundle: 2018 Update. Critical Care Medicine. 2018
Slide7Duration of hypotension before initiation of effective antimicrobial therapy is the critical determinant of survival in human septic shock. Critical Care Medicine. 2006
Slide8Duration of hypotension before initiation of effective antimicrobial therapy is the critical determinant of survival in human septic shock. Critical Care Medicine. 2006
Criticisms:
Retrospective (1989 – 2004)
Correlation ≠ causation
8% reduction per hour is implausibly enormous
Overall mortality of 56% (septic shock)
Only ½ of pts received
abx
w/in 6
hrs
of hypotension
Slide917,990 patients who received antibiotics after sepsis identification
In-hospital mortality was 29.7%
Conclusions:
The results of the analysis of this large population of patients with severe sepsis and septic shock demonstrate that delay in first antibiotic administration was associated with increased in-hospital mortality. In addition, there was a linear increase in the risk of mortality for each hour delay in antibiotic administration. These results underscore the importance of early identification and treatment of septic patients in the hospital setting.
Empiric Antibiotic Treatment Reduces Mortality in Severe Sepsis and Septic Shock From the First Hour: Results From a Guideline-Based Performance Improvement Program. Critical Care Medicine. 2014
Slide10Empiric Antibiotic Treatment Reduces Mortality in Severe Sepsis and Septic Shock From the First Hour: Results From a Guideline-Based Performance Improvement Program. Critical Care Medicine. 2014
Slide11Implementation of earlier antibiotic administration in patients with severe sepsis and septic shock in Japan: a descriptive analysis of a prospective observational study. Critical Care. 2019
Slide12Outcome of Immediate Versus Early Antibiotics in Severe Sepsis and Septic Shock: A Systematic Review and Meta-analysis. Annals of Emergency Medicine. 2020
Slide13Phantasi
Trial
RCT of 2,698 pts in the Netherlands
Abx in the ambulance vs in the ER
Ceftriaxone 2g IV x 1 vs usual care
Early intervention received
abx
96 mins sooner
No difference in 28 or 90 day mortality
Septic shock only 3% of the study population
Prehospital antibiotics in the ambulance for sepsis: a
multicentre
, open label,
randomised
trial. Lancet Respir Med. 2018
Slide14CHEST 2019
Give all the
abx
up front to maximize appropriateness
Abx first, ask questions later
Full commitment to antimicrobial stewardship
De-escalate or DC as indicated
Broader ≠ Better
Tailor
abx
to the individual patient to maximize the likelihood of appropriateness
Empiric antibacterial therapy for patients with sepsis ought to
fi
rst consider the microbiology of infection and the presence of multi drug resistant risk factors
Should Broad-Spectrum Antibiotics Be Routinely Administered to All Patients With Sepsis as Soon as Possible? Yes. CHEST 2019
Should Broad-Spectrum Antibiotics Be Routinely Administered to All Patients With Sepsis as Soon as Possible?
No
. CHEST 2019
Slide15Administer antibiotics immediately
Risks of withholding
abx
outweigh risks of inappropriate treatment
Concern for increased mortality with delays in therapy
Commit to antimicrobial stewardship
Do not administer antibiotics
Presentations may not be clearly due to infection
Fewer than 60% of patients admitted to intensive care units with a diagnosis of sepsis are ultimately confirmed to have definite or even probable infection
Absence of shock allows time to collect more data
Early Administration of Antibiotics for Suspected Sepsis. NEJM. 2019
Slide16Distinguishing sepsis from noninfectious syndromes
Time to initiation of empiric antibiotic therapy
Combination and multi drug therapy
Procalcitonin
Duration of therapy
Infectious Diseases Society of America (IDSA) POSITION STATEMENT: Why IDSA Did Not Endorse the Surviving Sepsis Campaign Guidelines. Clinical Infectious Diseases. 2018
Slide17Sepsis Hysteria?
Unrealistic expectations of outcomes
Timely vs Early antibiotics
Evidence for early antibiotics is underwhelming
Up to 40% of pts admitted with sepsis not found to have a bacterial infection
Sepsis hysteria: excess hype and unrealistic expectations. Correspondence. Lancet 2019
Slide18Retrospective cohort of 2,579 pts in the Netherlands with clinically suspected sepsis in two tertiary ICUs
Plausibility of infection determined post hoc in discussion with senior critical care physicians and ID specialists
F
ound that up to 43 % of patients treated for sepsis were unlikely to have had an infection on post-hoc assessment
Likelihood of infection in patients with presumed sepsis at the time of intensive care unit admission: a cohort study. Critical Care. 2015
Slide19Likelihood of infection in patients with presumed sepsis at the time of intensive care unit admission: a cohort study. Critical Care. 2015
Slide20Timeliness of antibiotics for patients with sepsis and septic shock. Journal of Thoracic Disease. 2019
Slide21Risk of Subsequent Sepsis Within 90 Days After a Hospital Stay by Type of Antibiotic Exposure. Clinical Infectious Diseases. 2018
Slide22Cohort study on 17,430 pts
with sepsis and positive clinical cultures within 2 days of admission
The most common culture-positive sites were:
urine 52.1%
blood 40.0%
respiratory tract 16.7%
The most common pathogens were:
Escherichia coli 33.7%
S aureus 21.3%
Streptococcus species 13.5%
Prevalence of Antibiotic-Resistant Pathogens in Culture-Proven Sepsis and Outcomes Associated With Inadequate and Broad-Spectrum Empiric Antibiotic Use. JAMA Open Network. 2020
Slide2381.6% received adequate empiric antibiotics
Empiric therapy targeted resistant organisms in 67.0% of cases (primarily vancomycin and anti-
Pseudomonal
β-lactams), but resistant organisms were uncommon (MRSA 11.7%), (CTX-RO 13.1%), (VRE 2.1%), (ESBLs 0.8%)
Both inadequate and unnecessarily broad empiric antibiotics were associated with higher mortality after detailed risk adjustment (inadequate empiric antibiotics: odds ratio, 1.19; 95% CI, 1.03-1.37;
P
= .02; unnecessarily broad empiric antibiotics: odds ratio, 1.22; 95%CI, 1.06-1.40;
P
= .007).
CONCLUSIONS AND RELEVANCE In this study, most patients with community-onset sepsis did not have resistant pathogens, yet broad-spectrum antibiotics were frequently administered. Both inadequate and unnecessarily broad empiric antibiotics were associated with higher mortality. These findings underscore the need for better tests to rapidly identify patients with resistant pathogens and for more judicious use of broad-spectrum antibiotics for empiric sepsis treatment
Prevalence of Antibiotic-Resistant Pathogens in Culture-Proven Sepsis and Outcomes Associated With Inadequate and Broad-Spectrum Empiric Antibiotic Use. JAMA Open Network. 2020
Slide24Take Home Message
In septic shock – give antibiotics ASAP
In hemodynamically stable pts with suspected sepsis, consider establishing an accurate diagnosis and deploying indication specific antibiotics
Slide25Health Care Associated Pneumonia
“HCAP”
Slide26Health Care Associated Pneumonia
“HCAP”
Defined in the 2005 IDSA Hospital Acquired Pneumonia Guidelines
Attempt to characterize pts at higher risk for multi drug resistant organisms
HCAP included any patient who:
hospitalized in an acute care hospital for two or more days within 90 days of the infection
resided in a nursing home or long-term care facility
received recent intravenous antibiotic therapy, chemotherapy, or wound care within the past 30 days of the current infection
attended a hospital or hemodialysis clinic
Led to massive overtreatment
Guidelines for the Management of Adults with Hospital-acquired, Ventilator-associated, and Healthcare-associated Pneumonia
.
Am J Respir Crit Care Med. 2005
Slide27IDSA 2019
HCAP
Diagnosis and Treatment of Adults with Community-acquired Pneumonia An Official Clinical Practice Guideline of the American Thoracic Society and Infectious Diseases Society of America. Am J Respir Crit Care Med. 2019
Slide28IDSA CAP 2019
Risk factors for MRSA and Pseudomonas:
Previous history, especially isolated from the respiratory tract
Recent hospitalization and exposure to parenteral antibiotics (
prev
90 days)
Slide29Aspiration Pneumonia
Slide30Aspiration Pneumonia
Aspiration Pneumonitis
Inhalation of gastric contents which may quickly progress to respiratory failure
CXR may show infiltrates
Supportive treatment
Generally a rapid improvement within 48
hrs
Antibiotics not routinely necessary
Aspiration Pneumonia
CXR shows infiltrates
Generally Tx as CAP
Aspiration Pneumonia. Review Article. NEJM. 2019
Diagnosis and Treatment of Adults with Community-acquired Pneumonia
An Of
fi
cial Clinical Practice Guideline of the American Thoracic Society and Infectious Diseases Society of America.
Am J Respir Crit Care Med. 2019
Slide31Retrospective cohort of 200 pts w/ aspiration pneumonitis
38% received
abx
62% received supportive care
No difference in mortality or likelihood of transfer to critical care
Pts receiving prophylactic
abx
were more likely to have an escalation in
abx
and have fewer antibiotic free days
Conclusion:
Prophylactic antimicrobial therapy for patients with acute aspiration pneumonitis does not offer clinical benefit and may generate antibiotic selective pressures that results in the need for escalation of antibiotic therapy among those who develop aspiration pneumonia
Prophylactic Antimicrobial Therapy for Acute Aspiration Pneumonitis. Clinical Infectious Disease. 2018
Slide32Diagnosis and Treatment of Adults with Community-acquired Pneumonia
An Of
fi
cial Clinical Practice Guideline of the American Thoracic Society and Infectious Diseases Society of America.
Am J Respir Crit Care Med. 2019
Slide33Eli’s Aspiration Pneumonia Treatment Algorithm
Did they aspirate stool?
YES
NO
Pip/
tazo
ceftriaxone
Slide34Procalcitonin
Slide35Procalcitonin
False positives
Invasive candida infections
Cdiff
Burns
Trauma
Surgery
Bowel ischemia
Pancreatitis
Intracerebral hemorrhage
Ischemic stroke
Shock of any kind (septic, anaphylactic, hemorrhagic, or cardiogenic)
Malignancies
Renal insufficiency
Post natal
Kawasaki disease
False negatives
Localized infections
Tonsillitis
Sinusitis
Cystitis
Uncomplicated SSTIs, abscesses,
empyemas
If drawn too early in the course of the infection
UpToDate.
Procalcitonin use in lower respiratory tract infections. Accessed 12-1-20
Slide36Procalcitonin (PCT)-guided antibiotic stewardship: an international experts consensus on optimized clinical use.
Clin Chem Lab Med. 2019
Slide37Procalcitonin (PCT)-guided antibiotic stewardship: an international experts consensus on optimized clinical use.
Clin Chem Lab Med. 2019
Slide38Procalcitonin (PCT)-guided antibiotic stewardship: an international experts consensus on optimized clinical use.
Clin Chem Lab Med. 2019
Slide39Vancomycin + piperacillin/tazobactam nephrotoxicity
Slide40Alternative antibiotic combinations
Cefepime, meropenem if risk for MDRO / ESBL
Early Reassessment of Empiric Therapy: Antibiotic Time-Outs
MRSA nasal PCR
Avoid inappropriate use
Cellulitis, CAP
Slide41MRSA Nasal PCR
Slide42For CAP / HCAP the NPV was 98%
For VAP the NPV was 94.8%
Conclusion:
Nares screening for MRSA had a high specificity and NPV for ruling out MRSA pneumonia
, particularly in cases of CAP/HCAP. Based on the NPV, MRSA nares screening is a valuable tool for AMS to streamline empiric antibiotic therapy, especially among patients with pneumonia who are not colonized with MRSA
The Clinical Utility of Methicillin-Resistant
Staphylococcus aureus
(MRSA) Nasal Screening to Rule Out MRSA Pneumonia: A Diagnostic Meta-analysis With Antimicrobial Stewardship Implications. Clinical Infectious Diseases. 2018
Slide43The NPV of MRSA nares screening for ruling out MRSA infection was 96.5% overall
NPV:
for bloodstream infections 96.5%
for intra-abdominal cultures 98.6%
for respiratory cultures 96.1%
for wound cultures 93.1%
Conclusion: Given the high NPVs, MRSA nares screening may be a powerful stewardship tool for de-escalation and avoidance of empirical anti-MRSA therapy.
Determining the Utility of Methicillin-Resistant
Staphylococcus aureus
Nares Screening in Antimicrobial Stewardship. Clinical Infectious Diseases. 2019
Slide44UTIs
Slide45“UTIs”
Criteria for Culture
:
WBC 51-100/HPF or >100/HPF
Nitrites positive
Abnormal bacteria (Moderate/Many) or Yeast present (Budding and/or Hyphae)
AND
WBC 11-20/HPF or higher
Abnormal bacteria (Moderate/Many) or Yeast present (Budding and/or Hyphae)
AND
Leukocyte Esterase Small/Moderate/Large (while continuing to flag only Moderate and Large as abnormal)
Slide46De-escalation
Slide47Ert
Prospective observation study of 712 pts
Conclusions: De-escalation therapy for severe sepsis and septic shock is a safe strategy associated with a lower mortality. Efforts to increase the frequency of this strategy are fully justified.
De-escalation of empirical therapy is associated with lower mortality in patients with severe sepsis and septic shock. Intensive Care Med 2014
Slide48De-escalation
De-escalation of empirical therapy is associated with lower mortality in patients with severe sepsis and septic shock. Intensive Care Med 2014
Slide49Single center retrospective cohort of 279 pts with nosocomial pneumonia and a negative respiratory culture
De-escalation of anti-MRSA agent led to:
No difference in mortality
Shorter hospital and ICU length of stays
Less AKI
Outcomes Associated With De-escalating Therapy for Methicillin-Resistant
Staphylococcus aureus
in Culture-Negative Nosocomial Pneumonia. CHEST. 2019
Slide50Retrospective of 107 pts with sepsis or septic shock from pneumonia in the ICU
De-escalation did not show any difference in mortality or MDR pathogen occurrence
Safety of antimicrobial de-escalation for culture-negative severe pneumonia. Journal of Critical Care. 2019
Slide51Blood Cultures
Slide52Blood Culture PCR:
Verigene
Slide53Retrospective cohort of 801 pts w/ bacteremia
85.3% of blood cultures were positive within 24 hours
Anaerobic bacteria more common in the prolonged time to positive group
The probability of bacteremia, if BC had remained negative for 24 hours, was 1.8%
Time to positivity of blood cultures supports early re-evaluation of empiric broad-spectrum antimicrobial therapy. PLOS ONE. 2019.
Slide54How to De-escalate?
Slide55COVID-19
Slide56Slide57COVID-19 illness in native and immunosuppressed states: A clinical–therapeutic staging proposal
. J Heart Lung Transplant. 2020
Slide58COVID Treatment Options
Lopinavir
/ ritonavir
Hydroxychloroquine
Azithromycin
Tocilizumab
Convalescent plasma
Slide59Remdesivir
Nucleoside analog prodrug with potent in vitro activity against numerous human and zoonotic coronaviruses
Binds to the viral RNA-dependent RNA polymerase, inhibiting viral replication through premature termination of RNA transcription
Originally developed in response to the 2014–2016 Ebola outbreak in West Africa.
First FDA approved drug for COVID on Oct 22, 2020
Slide60Remdesivir
:
Monitoring
Transfusion Reactions
Hypotension
Nausea / Vomiting
Diaphoresis
Shivering
Adverse Effects
Transient AST / ALT elevations
Hold if LFTs increase 5 X ULN
Renal FunctionNot recommended in CrCl < 30Excipient cyclodextrin (SBECD) – accumulates in kidney dysfxnRemoved by HD, CRRTClinical significance uncertainBenefits may outweigh risks in select patients
Slide61No difference in viral load by quantitative PCR
No difference in time to viral clearance
No statistically significant benefit found w/
remdesivir
Suggestion of possible benefit in time to improvement
Study was underpowered
Remdesivir
in adults with severe COVID-19: a
randomised
, double-blind, placebo-controlled,
multicentre
trial. JAMA 2020
Slide62Remdesivir
:
ACTT-1 Trial
Slide631062 pts double blind, placebo controlled RCT
Remdesivir
shortened time to recovery in hospitalized pts w/ COVID
10 vs 15 days
Mortality rates at 29 days
11.4% w/ remdesivir15.2% w/ placebo
No significant ADR concerns
Remdesivir
: ACTT-1 Trial
Not statistically significant
Slide64Remdesivir: ACTT-1 Trial
Remdesivir
for the Treatment of Covid-19 — Final Report. NEJM 2020
Slide65Remdesivir: ACTT-1 Trial
Remdesivir
for the Treatment of Covid-19 — Final Report. NEJM 2020
Slide66Remdesivir: ACTT-1 Trial
Remdesivir
for the Treatment of Covid-19 — Final Report. NEJM 2020
Slide67Remdesivir
:
SOLIDARITY Trial – Interim Results
Large international clinical trial launched by WHO
Over 12,000 patients in 500 hospital sites in over 30 countries
Published interim results on 15 October 2020 – not yet peer reviewed or published in a journal (as of 12-1-20)
Found that all 4 treatments evaluated (
remdesivir
, hydroxychloroquine, lopinavir/ritonavir and interferon
β1
a
) had little or no effect on overall mortality, initiation of ventilation and duration of hospital stay in hospitalized patients
https://www.who.int/emergencies/diseases/novel-coronavirus-2019/global-research-on-novel-coronavirus-2019-ncov/solidarity-clinical-trial-for-covid-19-treatments
Slide68SOLIDARITY Trial
https://www.medrxiv.org/content/10.1101/2020.10.15.20209817v1
Slide69Remdesivir
ACTT-1
Double blind, randomized, placebo controlled trial
1,062 patients randomized to
remdesvir
vs placebo
10 countries (mostly the U.S.)
Primary endpoint was time to recovery
SOLIDARITY
Open label, randomized, adaptive
2750 patients received
remdesivir
vs 4,088 no study drug30 countries (no U.S.)Primary endpoint was mortality
Slide70Dexamethasone
Slide712104 pts randomized to receive dexamethasone or usual care
Dexamethasone 6 mg IV or PO daily
Dexamethasone reduced 28 day mortality in pts on mechanical ventilation or oxygen supplementation but not in pts receiving no respiratory support
Dexamethasone in Hospitalized Patients with Covid-19 — Preliminary Report. NEJM. 2020
Slide72RECOVERY Trial
Slide73RECOVERY Trial
Slide74Anticoagulation
Slide75Association of Treatment Dose Anticoagulation with In-Hospital Survival Among Hospitalized Patients With COVID-19
Retrospective, cohort trial of 2,773 hospitalized patients with COVID at Mount Sinai, NYC
Conclusion:
our
fi
ndings suggest that systemic treatment dose AC may be associated with improved outcomes among patients hospitalized with COVID-19.
Association of Treatment Dose Anticoagulation with In-Hospital Survival Among Hospitalized Patients With COVID-19. Letter. JACC. 2020
Slide76Association of Treatment Dose Anticoagulation with In-Hospital Survival Among Hospitalized Patients With COVID-19
Slide7720 pts randomized to therapeutic enoxaparin vs prophylactic anticoagulation
Pts w/ ARDS on mechanical ventilation w/ d-dimer > 1
Patients of the therapeutic group had a higher ratio of successful liberation from mechanical ventilation (hazard ratio: 4.0 [95% CI 1.035–15.053]), p = 0.031 and more ventilator-free days (15 days [interquartile range IQR 6–16] versus 0 days [IQR 0–11]), p = 0.028 when compared to the prophylactic group.
Conclusion:
Therapeutic enoxaparin improves gas exchange and decreases the need for mechanical ventilation in severe COVID–19.
Therapeutic versus prophylactic anticoagulation for severe COVID-19: A randomized phase II clinical trial (HESACOVID). Thrombosis Research. 2020
Slide78HESACOVID Trial
Slide79HESACOVID Trial
Slide80HESACOVID Trial
Slide81Convalescent Plasma
Slide82Open label RCT of 464 hospitalized COVID pts given convalescent plasma vs std of care
2 doses of 200 mL conv. plasma, 24
hrs
apart
Neutralizing antibodies not measured a priori
No difference in d-dimers, ferritin, CRP, LDH, neutralizing antibody concentrations
Conclusion:
Convalescent plasma was not associated with a reduction in progression to severe covid-19 or all cause mortality.
Convalescent plasma in the management of moderate covid-19 in adults in India: open label phase II
multicentre
randomised
controlled trial (PLACID Trial). BMJ. 2020
Slide83Ert
Ert
Double blind, randomize, placebo controlled trial in Argentina (high titer plasma?)
228 pts randomized to convalescent plasma vs 105 pts received placebo (2:1 ratio)
No difference in outcomes at 30 days
Similar ADRs
A Randomized Trial of Convalescent Plasma in Covid-19 Severe Pneumonia. NEJM. 2020
Slide84Tocilizumab
Slide85Tocilizumab
Gupta S et al.
Design: Observational, multicenter cohort study
Location: 68 hospitals in the U.S.
Patient Population: 3924 adults admitted to intensive care, of whom 433 received tocilizumab within the first 2 days after admission
Outcome:
After risk adjustment, estimated 30-day mortality was 27.5% in patients who received tocilizumab and 37.1% in those who did not
(risks difference, 9.6%; 95% confidence interval, 3.1%–16.0%).
Stone JH et al.
Design: Randomized, double-blind, placebo-controlled, manufacturer-funded trial
Location: 7 Boston hospitals
Patient Population: 243 adults with COVID-19 pneumonia and elevated inflammatory markers but requiring less than 10 L of oxygen per minute and not mechanically ventilated
Intervention: Randomization 2:1 to 8 mg/kg of tocilizumab or placebo
Outcome:
No significant difference was seen in the need for intubation or death
(hazard ratio, 0.83; 95% CI, 0.38–1.18), or disease worsening (HR, 1.11; 95% CI, 0.59–2.10).
Stone JH et al.
Design: Randomized, double-blind, placebo-controlled, manufacturer-funded trial
Location: 7 Boston hospitals
Patient Population: 243 adults with COVID-19 pneumonia and elevated inflammatory markers but requiring less than 10 L of oxygen per minute and not mechanically ventilated
Intervention: Randomization 2:1 to 8 mg/kg of tocilizumab or placebo
Outcome:
No significant difference was seen in the need for intubation or death
(hazard ratio, 0.83; 95% CI, 0.38–1.18),
or disease worsening
(HR, 1.11; 95% CI, 0.59–2.10).
Hermine O et al.
Design: Open-label randomized trial
Location: 9 French hospitals
Patient population: 131 patients hospitalized with COVID-19 pneumonia requiring at least 3 L of oxygen per minute but not in intensive care or mechanically ventilated
Intervention: 8 mg/kg of tocilizumab, up to 2 doses (on day 1 and day 3), versus standard of care
Outcome:
No difference in mortality was seen at day 28
. On day 14, the combined rate of death and noninvasive or mechanical ventilation was 24% with tocilizumab versus 36% with standard of care (HR, 0.58; 90% credible interval, 0.33–1.0).
Does Tocilizumab Have a Role in the Treatment of COVID-19? Journal Watch. Nov 10, 2020
Slide86Time to Reassess Tocilizumab’s Role in COVID-19 Pneumonia.
JAMA. 2020
Slide87FDA EUA: baricitinib
EUA November 19
th
2020
Approved in combination w/
remdesivir
for adults and
peds
> 2
yo
requiring supplemental o2, mechanical ventilation, or ECMO
Janus kinase inhibitorACTT-2 Trial1 day improvement in time to recovery vs remdesivir7 vs 8 daysImprovement in clinical status at Day 15Improvement in mortality or respiratory progression at day 29Improved mortality at 29 days5.1% vs 7.8%Not yet published
https://www.fda.gov/media/143823/download
Slide88Baricitinib
https://www.embopress.org/doi/full/10.15252/emmm.202012697
Slide89Bacterial Co-Infection in COVID Pneumonia
Slide90Bacterial co-infection?
Most COVID pneumonia pts receive empiric antibiotics
Generally low rates of bacterial co-infection
One meta analysis suggests (May 2020)
7% rate of bacterial co-infection in hospitalized pts
14% rate in ICU pts
Co-infections in people with COVID-19: a systematic review and meta-analysis. Journal of Infection. 2020
Slide91Bacterial co-infection?
Another meta analysis (July 2020):
bacterial co-infection (estimated on presentation) was identified in 3.5% of patients
secondary bacterial infection in 14.3% of patients
The overall proportion of COVID-19 patients with bacterial infection was 6.9%
Bacterial infection was more common in critically ill patients (8.1%)
Authors conclusion: Bacterial co-infection is relatively infrequent in hospitalized patients with COVID-19. The majority of these patients may not require empirical antibacterial treatment.
Bacterial co-infection and secondary infection in patients with COVID-19: a living rapid review and meta-analysis. Clinical Microbiology and Infection. 2020
Slide921705 pts w/ COVID selected from 38 MI hospitals
56% were prescribed early empiric antibiotics
3.5% had a confirmed community-onset bacterial infection
As COVID test turnaround time improved, empiric
abx
use declined
Conclusion: The prevalence of confirmed community-onset bacterial co-infections was low.
Empiric Antibacterial Therapy and Community-onset Bacterial Co-infection in Patients Hospitalized with COVID-19: A Multi-Hospital Cohort Study. Clinical Infectious Diseases. 2020
Slide93Bacterial co-infection in a French ICU
(September 2020)
28% rate of bacterial co-infection at ICU admission of patients with severe SARSCoV-2 pneumonia
MSSA
(31%)
Haemophilus
influenzae
(2
2%)
Streptococcus pneumoniae (19%) Enterobacteriaceae (16%) Pseudomonas aeruginosa (6%) Moraxella catarrhalis (3%) Acinetobacter baumannii (3%)Authors conclusion: our results encourage the systematic administration of an empiric antibiotic monotherapy with a 3rd generation cephalosporin, with a prompt de-escalation as soon as possible
(92% sensitive to a 3
rd
generation cephalosporin)
Bacterial and viral co‑infections in patients with severe SARS‑CoV‑2 pneumonia admitted to a French ICU. Annals of Intensive Care. 2020
Slide94Proposed algorithm for initiating antibiotics
Antimicrobial stewardship in ICUs during the COVID‑19 pandemic: back to the 90s? Intensive care med. 2020
Slide95COVID Treatment Guidelines
Slide96NIH vs IDSA Treatment Guidelines
Remdesivir
and Immune Modulators: alone, in combination, or not at all? ASHP Webinar. 11-24-20
Slide97WHO Guidelines
https://www.bmj.com/content/370/bmj.m3379