Recognition and Management of - PowerPoint Presentation

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Recognition and Management of

Bacterial Pneumonia in Patients With COVID-19#2: Antimicrobial Stewardship and Treatment

Provided by ProCE, LLC and supported by educational grants from bioMérieux; Melinta Therapeutics, LLC; and Merck Sharp & Dohme Corp.

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ProCE.com

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3CE Activity Information and Accreditation

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This activity is jointly provided by ProCE, LLC and the Society of Infectious Diseases Pharmacists. ProCE, LLC is accredited by the Accreditation Council for Pharmacy Education as a provider of continuing pharmacy education. ACPE Universal Activity Number 0221-9999-21-223-L01-P has been assigned to this live knowledge-based activity (initial release date 8-24-21). This activity is approved for 1.0 contact hour (0.1 CEU) in states that recognize ACPE providers. The activity is provided at no cost to learners. Learners must complete the online posttest and activity evaluation within 30 days of the activity to receive pharmacy CE credit. No partial credit will be given. Statements of completion will be issued online at www.ProCE.com, and proof of completion will be posted in NABP CPE Monitor profiles.

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CE Activity Information and AccreditationTarget Audience

The target audience for this activity includes pharmacists, including community pharmacists, ambulatory care, and infectious diseases pharmacists, pharmacy directors, and other pharmacy professionals responsible for the treatment and management of bacterial pneumonia in patients with COVID-19.Learning ObjectivesAt the conclusion of this activity, learners should be able to:

Describe antimicrobial stewardship strategies and tools in the armamentarium that can be utilized to aid in the management of bacterial pneumonia in patients with COVID-19Given a patient case, design a therapeutic plan for a patient with bacterial pneumonia and COVID-19FundingThis activity is supported by educational grants from bioMérieux; Melinta Therapeutics, LLC; and Merck Sharp & Dohme Corp.44

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5Disclosure of Conflicts of Interest

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ProCE requires instructors, planners, managers, and other individuals who are in a position to control the content of this activity to disclose any relevant conflict of interest (COI) they may have as related to the content of this activity. All identified COI are thoroughly vetted and resolved according to ProCE policy. ProCE is committed to providing its learners with high-quality CME/CE activities and related materials that promote improvements or quality in healthcare and not a specific proprietary business interest of a commercial interest.

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DisclosuresThe 

faculty reported the following relevant financial relationships or relationships to products or devices they have with ineligible companies related to the content of this CME/CE activity:Angelina Davis, PharmD, MS, BCPS, BCIDP, has disclosed that she has received consulting fees from Merck.

Velliyur Viswesh, PharmD, BCIDP, BCCCP, has disclosed that he has received consulting fees from Shionogi and received fees for non-CME/CE services from the American College of Clinical Pharmacy and the Society of Infectious Diseases Pharmacists.The planners/managers reported the following relationships:Zachary Schwartz, MSc, ELS, and Petra Cravens, PhD; have no relevant conflicts of interest to report.ProCE staff members have no relevant conflicts of interest to report.6

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7Disclosure of Unlabeled Use

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This educational activity may contain discussion of published and/or investigational uses of agents that are not indicated by the FDA. The planners of this activity do not recommend the use of any agent outside of the labeled indications.The opinions expressed in the educational activity are those of the faculty and do not necessarily represent the views of the planners. Please refer to the official prescribing information for each product for discussion of approved indications, contraindications, and warnings.

Disclaimer

Learners have an implied responsibility to use the newly acquired information to enhance patient outcomes and their own professional development. The information presented in this activity is not meant to serve as a guideline for patient management. Any procedures, medications, or other courses of diagnosis or treatment discussed or suggested in this activity should not be used by healthcare professionals without evaluation of their patient’s conditions and possible contraindications and/or dangers in use, review of any applicable manufacturer’s product information, and comparison with recommendations of other authorities.

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8Faculty

Angelina Davis, PharmD, MS, BCPS, BCIDPDASON Liaison Clinical Pharmacist

Infectious DiseasesDuke Antimicrobial Stewardship Outreach Network (DASON)Duke UniversityDurham, North CarolinaVelliyur Viswesh, PharmD, BCIDP, BCCCPAssociate Professor, College of PharmacyRoseman University of Health SciencesHenderson, NevadaInfectious Disease and Critical Care Pharmacist, Department of Pharmacy PracticeValley Hospital Medical CenterLas Vegas, Nevada

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Angelina Davis, PharmD, MS, BCPS, BCIDP

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Antimicrobial Stewardship in a Global Crisis10

“Although antimicrobial stewardship programs have not traditionally been involved in pandemic response efforts, many aspects of the management of the COVID-19 pandemic in the United States, particularly in hospitals,

may be augmented by traditional stewardship expertise.”idsociety.org/covid-19-real-time-learning-network/disease-manifestations--complications/co-infection-and-Antimicrobial-StewardshipPhoto by Anna Shvets from Pexels and retrieved from pexels.com/search/world%20chaos/The image on this slide has been removed intentionally due to Copyright

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Antibiotic overuse during the COVID-19 pandemic can be attributed to which of the following?Fear

High rates of bacterial coinfectionDiagnostic uncertaintyA and BA and C

11

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The Perfect Storm

12

Wunderink. Ann Am Thorac Soc. 2020;17: 531.

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The Dilemma: Bacterial Infections and COVID-19A recent meta-analysis found that, before April 16, 2020, 71.9% of hospitalized patients with COVID-19 received antibiotics

Only 6.9% of these admissions were associated with bacterial infection13

Langford. Clin Microbiol Infect. 2020;26:1622.The image on this slide has been removed intentionally due to Copyright

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Clinical Case PresentationSJ is a 28-yr-old male with a PMH of hypertension, bipolar disorder, anxiety, and obesity admitted for acute hypoxic respiratory failure after discharge from the ED 4 days prior with a positive COVID-19 PCR. Patient presented with worsening SOB and chest pain. Sats upon arrival 82% and pO2 41 on NRB mask and placed on HHFNC 30 L/min.

CXR: Interval increase in multifocal consolidation since prior exam

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Temp: 99.8°FHR: 85-98 bpmBP: 99-138/74-87 mm Hg

WBC: 6.34 10

9

/L (3.50-10.50 10

9

/L)

Hb: 16.1 g/dL

PLT: 226 10

9

/L (150-450 10

9

/L)

SCr: 1.21 mg/dL (0.7-1.2 mg/dL)

PCT: 0.21 ng/mL; Day 3: 0.05 ng/mL

IL-6: 69.4 pg/mL (2.5-7.0 pg/mL)

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The Antimicrobial Stewardship ArsenalDedicated personnel and resources

Radiological imagingGuidelinesClinical pathwaysRapid diagnostics and laboratory testingAntibiotic time-outProspective audit with intervention and feedback

Education15

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Chest Radiography (COVID-19)Chest radiograph normal: up to 63%

Bilateral lung involvement: 72.9%Ground glass: 68.5% Coarse horizontal linear opacitiesConsolidationPeripheral and lower lung involvementLobar consolidation (coinfection)

16Cleverley. BMJ. 2020;370:m2426.The image on this slide has been removed intentionally due to Copyright

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Empiric Antibiotic PrescribingRoutine antibiotic use not indicated in confirmed COVID-19 infection Diagnostic uncertainty and/or clinical suspicion drives empiric use

Likely bacterial pathogens consistent with CAPGuidelines and clinical pathways are beneficial to optimize prescribingKey considerations:Empiric antibiotic regimen

RemdesivirDexamethasone or other systemic corticosteroids Adjunctive therapy (eg, tocilizumab, baricitinib)17

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Which antimicrobial stewardship activities are effective in the mgmt of bacterial infection in pts hospitalized with COVID-19?

1:1 provider educationMRSA nasal screeningImplementing rapid diagnostics All of the aboveA and C

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The Role of PCTPCT testing is FDA approved to help manage antibiotic treatment for lower respiratory tract infections and sepsis

PCT elevation suggests bacterial infectionLow PCT suggests viral infection or resolution of bacterial infectionLimitations:

Serial levels False positives and negativesVariability among pathogens with unclear interpretation for special populations (eg, CKD, surgery, trauma, immunocompromise) Ferritin-to-PCT ratio ≥877 may be useful19fda.gov/news-events/press-announcements/fda-clears-test-help-manage-antibiotic-treatment-lower-respiratory-tract-infections-and-sepsisGharamti. Open Forum Infect Dis. 2021;8.

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20PCT-Guided Antibiotic Therapy for CAP

Evaluation at Time of Admission

Follow-up Evaluation Every 2-3 Days

PCT Cut-off

Recommendation Regarding Use of Antibiotics

Overruling the Algorithm

Follow-up/Other Comments

PCT Cut-off

PCT Kinetics

Recommendation Regarding Use of Antibiotics

Overruling the Algorithm

Follow-up/

Other Comments

<0.1

m

g

/L

Low PCT levels make a bacterial CAP unlikely Other diagnostic tests should be considered

Initiation of antibiotics is advised in all patients who have strong suspicion of bacterial CAP or are clinically unstable

Reassess patients’ condition and recheck PCT level after 6-24 hr in all patients from whom antibiotics were withheld

<0.1

m

g

/L

>90%

Cessation of therapy strongly encouraged

Consider continuation of antibiotics if patients are clinically unstable or have abscess

Clinical

re-evaluation as appropriate

≤0.25

m

g

/L

≤0.25

m

g

/L

>80%

Cessation of therapy encouraged

>0.25

m

g

/L

Initiation of therapy encouraged

Recheck PCT level every 2-3 days to consider early cessation of antibiotics

>0.25

m

g

/L

Cessation of therapy discouraged

Consider treatment to have failed if PCT level does not decrease adequately

>0.5

m

g

/L

Initiation of therapy strongly encouraged

>

0.5

m

g

/

L

Cessation of therapy strongly discouraged

Branche. Curr Opin Infect Dis. 2019;32:130.

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Rapid Diagnostics and Laboratory TestingRespiratory cultureCOVID-19 (RT-PCR, antigen)

Rapid influenza A/B (incidence low)Legionella testing (PCR, urinary antigen)Urine pneumococcal antigen testingMultiplex molecular assays (BioFire

FilmArray Pneumonia/Pneumonia plus Panel) 21

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Clinical Utility of MRSA Nasal ScreeningRespiratory cultures are often difficult to attain, and results to guide antibiotic streamlining and de-escalation in pneumonia are frequently unavailable

Studies suggest that MRSA pneumonia can be accurately and safely ruled out if the MRSA nasal screen is negative (>90% NPV)A negative screen can support anti-MRSA therapy discontinuation22

Parente. Clin Infect Dis. 2018;67:1. Dangerfield. Antimicrob Agents Chemother. 2014;58:859. Smith. J Crit Care. 2017;38:168.AuthorsSensitivity, %Specificity, %PPV, %NPV, %

Parente et al

70.9

90.3

44.8

96.5

Dangerfield et al

88.0

90.1

35.4

99.2

Smith et al

91.89

84.3

37.36

99.03

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Potential Impact of the BioFire Panel on Antibiotic UsePotential for antimicrobial modification in 179/253 (70.8%) patients

De-escalation or discontinuation of vancomycin (38%) and piperacillin/tazobactam (23%) most common23

Potential ModificationAntimicrobials, nPatients, n (%)No. of HoursAppropriate de-escalation/discontinuation206122 (48.2)

18,284.07

Appropriate escalation/initiation

11

11 (4.3)

184.66

Inappropriate de-escalation/discontinuation

4

4 (1.6)

Inappropriate escalation/continuation

42

42 (16.6)

No change

74 (29.2)

Unable to assess

*

16

Buchan. J Clin Microbiol. 2020;58:e00135.

*

No stop date was listed for antimicrobials, concomitant infection was present, or antimicrobials were used for longer durations than would be used for a lower respiratory tract infection (>30 days).

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For more information, visit:

idsociety.org/clinical-practice/antimicrobial-stewardship2/antimicrobial-stewardship/

Additional Useful InterventionsGuidelinesClinical pathwaysAntibiotic time-outProspective audit with intervention and feedbackEducation24

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Velliyur Viswesh, PharmD, BCIDP, BCCCP

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Principles of Treatment of Bacterial Pneumonia and Overview of Therapeutic Options

emedicinehealth.com/bacterial_pneumonia/article_em.htm

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Treatment of Bacterial Pneumonia in Patients With COVID-19As previously mentioned, antibacterials are not indicated in most patients with COVID-19

However, if antibacterials are to be used, does the approach change due to the presence of COVID-19?Generally speaking, no: The presence of COVID-19 doesn’t truly affect antibiotic selection for bacterial pneumoniaIt should be noted that use of systemic corticosteroids in COVID-19 patients may reduce the utility of WBC counts as a marker of response to infection

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Treatment of Inpatient Bacterial Pneumonia in Patients With COVID-19Subsequently, antibiotic selection should be similar to those without COVID-19Based on guideline recommendations, this includes:

Categorization into CAP, HAP, or VAPAssessment of risk factors to determine empiric antibiotic selectionAppropriate follow-up testing and culture and susceptibility results to facilitate prompt de-escalation to targeted antibioticsAlthough the general approach is well described, we will now summarize and address some of the controversial aspects to guideline recommendations

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What IV regimen is best for CAP in the ICU requiring mechanical ventilation (no other risk factors)?

Ceftriaxone + doxycyclineCeftriaxone + azithromycin + vancomycinCeftriaxone + azithromycinCeftriaxone + moxifloxacin

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2019 IDSA guideline recommendations for inpatient adults with CAP:

Empiric Antibiotics for Hospitalized Adults With CAP

Controversies in above recommendations:β-lactam + levo/moxifloxacin recommendation for severe CAPMRSA and Pseudomonas coverage recommendations30

Severity

Standard Regimen

Add MRSA Coverage?

Add

Pseudomonas

Coverage?

Nonsevere inpatient CAP

β

-lactam + macrolide

OR

Levo/moxifloxacin

History of respiratory MRSA? Yes

Hospitalization/IV antibiotics within

90 days? No

History of respiratory

Pseudomonas

? Yes

Hospitalization/IV antibiotics within

90 days? No

Severe (vented or on pressors) inpatient CAP

β

-lactam + macrolide

OR

β

-lactam + Levo/moxifloxacin

History of respiratory MRSA? Yes

Hospitalization/IV antibiotics within

90 days? Yes

History of respiratory

Pseudomonas

? Yes

Hospitalization/IV antibiotics within

90 days? Yes

Metlay. Am J Respir Crit Care Med. 2019;200:e45.

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Controversy 1: β-lactam + Respiratory Quinolone in Severe CAPSligl et al compared macrolide-based regimens with other

regimens in 9850 ICU patients with severe CAP across 28 observational studies↓ mortality with macrolide-based regimens (21% vs 24%; P = .02)

Vardakas et al compared fluoroquinolones with macrolides, both in combination with a β-lactam, in ~17,000 inpatients with CAPAgain, quinolones had ↑ mortality (RR: 1.33; CI: 1.15-1.54)Take-home: β-lactam + quinolone should NOT be used over β-lactam + macrolide; guidelines also rate as low-quality evidence31Sligl. Crit Care Med. 2014;42:420. Vardakas. Clin Microbiol Infect. 2017;23:234. β-lactam + quinolone for CAP?

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Controversy 2: Empiric MRSA Coverage for Inpatient CAPGuidelines mention “history of respiratory MRSA isolation” but don’t distinguish MRSA by culture vs by nasal PCR

Note: MRSA nasal PCR has high NPV (95%+), so it is good for MRSA rule-out and de-escalation; however, PPV is poor (~37%), so it cannot be reliably used to initiate empiric MRSA coverage32

Smith. J Crit Care. 2017;38:168. Metlay. Am J Respir Crit Care Med. 2019;200:e45.MRSA coverage for CAP?

Elimination of healthcare-associated pneumonia (HCAP) classification leaves ambiguity in approach for such patients

Guidelines recommend development of locally validated risk factors

Otherwise, the most consistently noted MRSA risk factors are nursing home residence and IV antibiotics within the past 90 days

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Controversy 3:Empiric Pseudomonas Coverage for Inpatient CAPAgain, locally validated risk factors should be developed;

patients who would previously have been characterized as HCAP often prompt antipseudomonal coverage33

Metlay. Am J Respir Crit Care Med. 2019;200:e45.Pseudomonas coverage for CAP?

Various risk factors have been noted in studies, but the most consistent ones are again nursing home residence and IV antibiotics within the past 90 days

Take-home: Empiric MRSA and

Pseudomonas

coverage in CAP should be driven by local risk factors. Nursing home residence and IV antibiotics in the past 90 days are risk factors to consider. If used, prompt de-escalation if negative PCR/culture

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What IV regimen is best for a patient who develops pneumonia on hospital Day 8 (no other risk factors)?Cefepime monotherapy

Cefepime + vancomycinCefepime + vancomycin + ciprofloxacinCefepime + vancomycin + tobramycin

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Empiric Antibiotics for HAP and VAPGenerally, all patients with HAP/VAP should receive empiric coverage against MRSA and Pseudomonas. Specifically, guidelines recommend:

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PathogenRisk Factors Warranting Empiric CoverageCommentsMRSA

History of MRSA in respiratory tract

Mechanical ventilation or vasopressors

IV antibiotics in past 90 days

Unknown rate of MRSA

VAP: >10% of

S aureus

is MRSA

HAP: >20% of

S aureus

is MRSA

For almost all institutions, empiric MRSA coverage is warranted

Vancomycin or linezolid recommended;

no preference noted

Pseudomonas

spp

Antipseudomonal is indicated for

all

HAP/VAP

Dual antipseudomonal therapy recommended if:

History of

Pseudomonas

in respiratory tract

Mechanical ventilation or vasopressors

IV antibiotics in past 90 days

Unknown rate of core

β

-lactam resistance

>10% of

Pseudomonas

resistant to core

β

-lactam

ARDS or acute renal replacement at onset

≥5 days hospitalization prior to onset

Core

β

-lactam can be cefepime, ceftazidime, piperacillin/tazobactam, or mero/imipenem

Second antipseudomonal can be cipro/levofloxacin or an aminoglycoside, but double-coverage is a controversial topic

Kalil. Clin Infect Dis. 2016;63:e61.

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Controversy 1:Dual Antipseudomonal Therapy—Risk Factors36

Luu. Pharmacotherapy. 2020;40:1089.

The IDSA guidelines identified risk factors warranting dual antipseudomonal therapy based on their own meta-analysisHowever, various studies have found differences in risk factors associated with

β-lactam resistanceInstitutions are encouraged to identify locally validated risk factors that predict >10% resistance to core β-lactams in patients with HAP/VAP

Take-home: In the absence of locally validated risk factors, consider dual anti-pseudomonal therapy based on guideline-based risk factors.

Double cover

Pseudomonas

in HAP/VAP?

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Controversy 2:Dual Antipseudomonal Therapy—AntibioticsDual antipseudomonal therapy is to increase the likelihood of having an agent against which the isolate is susceptible

However, a few studies have found that addition of a fluoroquinolone has minimal to no impact on the overall likelihood of susceptibilityBachna et al found addition of levofloxacin ↑ susceptibility by only 2%Similarly, Johnson et al found addition of ciprofloxacin ↑ susceptibility by only 1% to 2%Take-home: Aminoglycosides are the preferred second antipseudomonal (supported by multiple combination antibiogram studies, as well).

37Bachna. Open Forum Infect Dis. 2017;4:S496. Johnson. Am J Health Syst Pharm. 2011;68:119. Luu. Pharmacotherapy. 2020;40:1089. Song. Ther Adv Infect Dis. 2017;4:165.Double cover Pseudomonas in HAP/VAP?

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Summary of Empiric Antibiotic Selection in Inpatient Bacterial Pneumonia38

Preferred antibiotics

β-lactam + macrolideOther considerationsConsider empiric coverage of MRSA/Pseudomonas based on:Locally validated risk factorsIV antibiotics in past 90 daysNursing home residenceDC MRSA coverage if MRSA nasal PCR negativeDC Pseudomonas coverage promptly if culture negativeCAP

Preferred antibiotics

Antipseudomonal

β

-lactam + vancomycin/linezolid

Other considerations

Dual antipseudomonal therapy with an aminoglycoside (over fluoroquinolones) in the presence of guideline-based risk factors

DC MRSA coverage if MRSA nasal PCR negative

Consider DC

Pseudomonas

coverage if culture negative on a case-by-case basis

HAP/VAP

Slide39

Role of Newer Antibiotics in CAPIndicated for CAP: lefamulin, delafloxacin, omadacyclineProvide MRSA and atypical coverageAll approved/studied as monotherapy for CAP

None specifically recommended in current guidelinesDelafloxacin and omadacycline unlikely to have significant advantages over other agents in their class for CAPLefamulin may have a limited role in patients’ intolerant to both β

-lactams and fluoroquinolones; will be interesting to see whether lefamulin use expands given concerns with adverse events with fluoroquinolones39

Slide40

Role of Newer Antibiotics in HAP and VAPIndicated for HAP and/or VAP: ceftolozane/tazobactam, ceftazidime/avibactam, imipenem/relebactam, cefiderocolUse of these agents should be reserved based on each agent’s unique niche, summarized below

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DrugLikely Place in TherapyCommentsCeftolozane/ tazobactam

Pseudomonas spp nonsusceptible to conventional

β

-lactams

Dose

for HAP/VAP is higher than other indications

Currently in shortage of supply due to global recall

Ceftazidime/ avibactam

Pseudomonas

spp nonsusceptible to conventional

β

-lactams

KPC-positive (a carbapenemase)

Enterobacterales

Activity

only against KPC and OXA-48 carbapenemases

No activity against IMP, VIM, NDM

Imipenem/ relebactam

Pseudomonas

spp nonsusceptible to conventional

β

-lactams

KPC-positive (a carbapenemase)

Enterobacterales

Activity

only against KPC carbapenemases

No activity against OXA, IMP, VIM, NDM

Cefiderocol

Pseudomonas

spp nonsusceptible to conventional

β

-lactams

Acinetobacter

spp nonsusceptible to conventional

β

-lactams

Metallo-

β

-lactamase–producing

Enterobacterales

Broadest

spectrum Gram-negative, including most carbapenemases and other challenging pathogens

Increased mortality in XDR

Acinetobacter

?

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Bringing it Back to COVID-19Regardless of pneumonia subtype (CAP, HAP, VAP), bacterial coinfection is not common in the setting of COVID-19As such, antibiotic utilization should be minimized as much as possible using stewardship and diagnostic strategies

Antibiotic use in patients with COVID-19 should be minimalNo more than 5 days for most CAP or 7 days for most HAP/VAPMRSA coverage can be discontinued if MRSA nasal PCR is negativePseudomonas coverage can be de-escalated if not detected by culture in CAP; for HAP/VAP, this may be considered on a case-by-case basis

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Clinical Case PresentationSJ is a 28-yr-old male with a PMH of hypertension, bipolar disorder, anxiety, and obesity admitted for acute hypoxic respiratory failure after discharge from the ED 4 days prior with a positive COVID-19 PCR. Patient presented with worsening SOB and chest pain. Sats upon arrival 82% and pO2 41 on NRB mask and placed on HHFNC 30 L/min.

CXR: interval increase in multifocal consolidation since prior exam

42

Temp: 99.8°FHR: 85-98 bpmBP: 99-138/74-87 mm HgWBC: 6.34 10

9

/L (3.50-10.50 10

9

/L)

Hb: 16.1 g/dL

PLT: 226 10

9

/L (150-450 10

9

/L)

SCr: 1.21 mg/dL (0.7-1.2 mg/dL)

PCT: 0.21 ng/mL; Day 3: 0.05 ng/mL

IL-6: 69.4 pg/mL (2.5-7.0 pg/mL)

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Question and Answer Session

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