10/8/21 1 2021 Annual Meeting & Exhibition November 4-7, 2021 | San Diego, California Winning the Battle on Antibiotic- Resistant Gram-Negative Infections Elias B. Chahine, PharmD, FCCP, FASCP, FFSHP, BCPS, BCIDP Professor of Pharmacy Practice Palm Beach Atlantic University Gregory School of Pharmacy Jonathan C. Cho, PharmD, MBA, BCIDP, BCPS Director of Pharmacy Director of PGY-2 Infectious Diseases Residency Program MountainView Hospital 1 2021 Annual Meeting & Exhibition November 4-7, 2021 | San Diego, California Meet the Speaker: Elias Chahine • Professor of Pharmacy Practice • Palm Beach Atlantic University • Clinical Pharmacy Specialist • Wellington Regional Medical Center • Academic Leadership Fellow • American Association of Colleges of Pharmacy • PGY-1 Pharmacy Resident • Mary Imogene Bassett Hospital & Columbia University • Doctor of Pharmacy • Lebanese American University 2
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2021 Annual Meeting & ExhibitionNovember 4-7, 2021 | San Diego, California
Winning the Battle on Antibiotic-Resistant Gram-Negative Infections
Elias B. Chahine, PharmD, FCCP, FASCP, FFSHP, BCPS, BCIDPProfessor of Pharmacy PracticePalm Beach Atlantic UniversityGregory School of Pharmacy
Jonathan C. Cho, PharmD, MBA, BCIDP, BCPSDirector of Pharmacy
Director of PGY-2 Infectious Diseases Residency ProgramMountainView Hospital
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Meet the Speaker: Elias Chahine• Professor of Pharmacy Practice
• Palm Beach Atlantic University
• Clinical Pharmacy Specialist• Wellington Regional Medical Center
• Academic Leadership Fellow• American Association of Colleges of Pharmacy
• PGY-1 Pharmacy Resident• Mary Imogene Bassett Hospital & Columbia University
• Doctor of Pharmacy• Lebanese American University
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Meet the Speaker: Jonathan Cho• Director of Pharmacy & PGY-2 Infectious
Diseases Residency Program Director• MountainView Hospital
• Author/Editor of “Infectious Diseases: A Case Study Approach”• McGraw-Hill Education
• PGY-1 & PGY-2 Infectious Diseases Resident• Lee Health
• Doctor of Pharmacy• University of the Pacific
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Disclosures
•Elias Chahine• Advisory board for Theratechnologies• Speakers’ bureau for Paratek
• Jonathan Cho• Advisory board for AcelRx• Speakers’ bureau for Allergan
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Pharmacist Learning Objectives
• Describe recent epidemiological trends of antibiotic-resistant gram-negative organisms• Identify key aspects to the diagnosis of antibiotic-resistant gram-
negative infections• Compare and contrast the available treatment options for infections
caused by extended-spectrum β-lactamase-producing Enterobacterales(ESBL-E), carbapenem-resistant Enterobacterales (CRE), and Pseudomonas aeruginosa with difficult-to-treat resistance (DTR)• Develop a personalized treatment plan for an older adult with an
antibiotic-resistant gram-negative infection
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Pharmacy Technician Learning Objectives
• Describe recent epidemiological trends of antibiotic-resistant gram-negative organisms.• Identify the available treatment options for infections caused by
antibiotic-resistant gram-negative organisms.
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Abbreviations
• ABSSSIs: acute bacterial skin and skin structure infections
2021 Annual Meeting & ExhibitionNovember 4-7, 2021 | San Diego, California
Outline
• Epidemiology of antibiotic-resistant gram-negative organisms• Diagnostic considerations for resistant gram-negative infections• New antibiotics for resistant gram-negative infections• General approach to management of ESBL-E• General approach to management of CRE• General approach to management of DTR P. aeruginosa• Special considerations for older adults
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Background
• 20-50% of antimicrobial use is inappropriate• ~30% is considered unnecessary
• 1 out of 5 emergency department visits are for ADRs due to antibiotic use• >$10 billion spent on antibiotics; >$3.5 billion among hospitalized
patients• >2.8 million antibiotic-resistant infections annually in US• >35,000 deaths• Clostridioides difficile infection: >223,000 cases and >12,000 deaths
Centers for Disease Control and Prevention. 2019 AR Threats Report. American Hospital Association. Hospital Statistics, 2018 Edition.
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Antimicrobial Resistance Development
Centers for Disease Control and Prevention. 2019 AR Threats Report.
Centers for Disease Control and Prevention. 2019 AR Threats Report.
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Question
Which pathogen is classified as a serious threat by the CDC?
A) Carbapenem-resistant Acinetobacter
B) Clostridioides difficile
C) DTR Pseudomonas aeruginosa
D) Drug-resistant Neisseria gonorrhoeae
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Diagnosing Resistant Gram-Negative Infection
• Diagnosis depends on site of infection, but techniques include:• Gram-staining and characteristics • Commercially available automated systems [Microscan, Phoenix, Thermo
2021 Annual Meeting & ExhibitionNovember 4-7, 2021 | San Diego, California
Ceftazidime/Avibactam – Avycaz®
Drug Class Approval Year
Route of Administration
Noteworthy Spectrum of Activity
Indications
Cephalosporin β-lactamase
inhibitor combination
2015 IV ESBL-EAmpC
CRE (KPC, OXA-48)DTR P. aeruginosa
cIAIscUTIs
HABP/VABP
Prescribing Information
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Ceftazidime/Avibactam – Safety Profile
Contraindications Warnings and Precautions
Common Adverse Reactions
Drug Interactions
Serious hypersensitivity to ceftazidime, avibactam, or other cephalosporins
Decreased efficacy in adults with cIAIs and a CrCl between 30 and 50 mL/minHypersensitivity reactionsSeizures and other CNS adverse reactions
Adults: diarrhea, nausea, and vomitingPediatrics: vomiting, diarrhea, rash, and infusion site phlebitis
ProbenecidLaboratory tests to detect glucose in the urine
Prescribing Information
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Delafloxacin – Baxdela®
Drug Class Approval Year
Routes of Administration
Noteworthy Spectrum of Activity
Indications
Fluoroquinolone 2017 IVPO
MRSAS. pneumoniae
Other streptococciESBL-E
P. aeruginosa
ABSSSIsCABP
Prescribing Information
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Delafloxacin – Safety ProfileContraindications Warnings and Precautions Common Adverse
ReactionsDrug Interactions
Hypersensitivity to delafloxacin or other fluoroquinolones
Hypersensitivity reactions Tendinitis and tendon rupturePeripheral neuropathyPsychiatric and other CNS adverse effectsExacerbation of myasthenia gravisAortic aneurysm and dissectionBlood glucose disturbances
Nausea,diarrhea, headache, elevated LFTs, and vomitingIntravenous formulation: accumulation of sulfobutylether-β-cyclodextrin in patients with renal impairment
Oral formulation: antacids containing aluminum ormagnesium, sucralfate, metal cations such as iron, multivitamins containing zinc or iron, didanosine buffered tablets or the pediatric powder for oral solution
Prescribing Information
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Eravacycline – XeravaTM
Drug Class Approval Year
Route of Administration
Noteworthy Spectrum of Activity
Indications
Tetracycline 2018 IV MRSAStreptococci
VREESBL-EAmpC
CRE (KPC, MBL)DTR A. baumanniiDTR S. maltophilia
NTM
cIAIs
Prescribing Information
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Eravacycline – Safety Profile
Contraindications Warnings and Precautions Common Adverse Reactions
Drug Interactions
Hypersensitivity to eravacycline or other tetracyclines
Hypersensitivity reactionsTooth discoloration and enamel hyperplasia in children up to 8 years of ageInhibition of bone growth in children up to 8 years of ageFetal harm
Infusion site reactions, nausea, and vomiting
Strong CYP3A inducers such as rifampinAnticoagulants
Prescribing Information
Lower risk of Clostridioides difficile infection compared to β-lactams
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Omadacycline – Nuzyra®Drug Class Approval
YearRoutes of
AdministrationNoteworthy
Spectrum of ActivityIndications
Tetracycline 2018 IVPO
MRSAS. pneumoniae
Other streptococciVRE
ESBL-EAmpC
CRE (KPC)DTR A. baumanniiDTR S. maltophilia
NTM
ABSSSIsCABP
Prescribing Information
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Omadacycline – Safety ProfileContraindications Warnings and Precautions Common Adverse
ReactionsDrug Interactions
Hypersensitivity to omadacycline or other tetracyclines
Mortality imbalance in patients with CABPHypersensitivity reactionsTooth discoloration and enamel hyperplasia in children up to 8 years of ageInhibition of bone growth in children up to 8 years of ageFetal harm
Nausea, vomiting, infusion site reactions, elevated LFTs, hypertension, headache, diarrhea, insomnia, and constipation
AnticoagulantsOral formulation: aluminum, calcium, magnesium, bismuth subsalicylate, and iron containing preparations
Prescribing Information
Lower risk of Clostridioides difficile infection compared to β-lactams
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DosingNew antimicrobial Usual dosing for resistant infections Dose adjustment for
renal impairmentCefiderocol 2 g q8h, infused over 3 h Yes
Ceftazidime/avibactam 2.5 g q8h, infused over 3 h Yes
Ceftolozane/tazobactam Cystitis: 1.5 g q8h, infused over 1 hOther: 3 g q8, infused over 3 h
Yes
Eravacycline 1 mg/kg q12h, infused over 1 h No
Imipenem/cilastatin/relebactam 1.25 g q6h, infused over 30 min Yes
Meropenem/vaborbactam 4 g q8h, infused over 3 h Yes
Plazomicin Cystitis: 15 mg/kg x 1, infused over 30 minOther: 15 mg/kg x 1, then based on PK
Yes
Tamma PD. Clin Infect Dis. 2021;72(7):e169-e183.Prescribing information
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Question
Which antibiotic is known to be nephrotoxic?
A) Ceftazidime/avibactam
B) Ceftolozane/tazobactam
C) Omadacycline
D) Plazomicin
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Question
Which antibiotic is known to interact with valproic acid?
A) Ceftazidime/avibactam
B) Eravacycline
C) Imipenem/cilastatin/relebactam
D) Plazomicin
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• Alternative treatment options:• Fluoroquinolones (toxicities)• Carbapenems (intravenous)
• Other treatment options:• Amoxicillin/clavulanate (higher failure rate than fluoroquinolones)• Aminoglycosides (toxicities, lacking data)• Fosfomycin (can consider for E. coli but contains fosA gene [hydrolysis]
intrinsic to K. pneumoniae and other gram-negative pathogens)
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• If a carbapenem is initiated and susceptibility to other preferred options are found, patient should be transitioned to fluoroquinolones or sulfamethoxazole/trimethoprim• Nitrofurantoin and fosfomycin should not be considered options
• Do not achieve adequate concentrations in renal parenchyma
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• Oral options can be considered once patient is hemodynamically stable, source control is achieved, and susceptibility is known
• Nitrofurantoin, fosfomycin, doxycycline, amoxicillin/clavulanate have poor/unreliable serum concentrations
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ESBL-E Treatment Considerations
• Piperacillin/tazobactam and cefepime should be avoided even if found susceptible• Exception: if initially started for treatment of cystitis and patient improves,
can continue therapy on piperacillin/tazobactam or cefepime• When ESBL enzymes are present, MIC testing may be inaccurate
• If validated phenotypic ESBL test does not indicate ESBL production, antimicrobial selection from susceptibility results can occur• If blaCTX-M gene is not detected, treatment with carbapenem is still
preferred as other ESBL genes may still be present
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• Alternative treatment options:• Meropenem (if ertapenem-R but meropenem-S)
• Other treatment options:• Ceftazidime/avibactam, meropenem/vaborbactam, imipenem/cilastatin/relebactam• Cefiderocol (clinical trials did not show increased mortality in urinary sources)• Fosfomycin (can consider for E. coli)• Colistin (nephrotoxicity; do not use polymyxin B due to non-renal clearance)
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CRE cUTI or Pyelonephritis
• Preferred treatment options: • Ceftazidime/avibactam• Meropenem/vaborbactam• Imipenem/cilastatin/relebactam• Cefiderocol• Meropenem (via extended-infusion if ertapenem-R but meropenem-S)
• Alternative treatment options:• Aminoglycosides
• Nitrofurantoin and fosfomycin should not be considered options
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CRE Non-Urinary Source
• Treatment options if ertapenem-R but meropenem-S: • Meropenem (via extended-infusion)• Ceftazidime/avibactam (alternative)
• Meropenem/vaborbactam and imipenem/cilastatin/relebactam should not be used
• Treatment options if ertapenem-R and meropenem-R:• Ceftazidime/avibactam• Meropenem/vaborbactam• Imipenem/cilastatin/relebactam• Cefiderocol (alternative due to higher mortality in clinical trials)• Colistin (last resort)
• If known exposure to MBL, use ceftazidime/avibactam + aztreonam or cefiderocol• If treating intra-abdominal infection, tigecycline or eravacycline can be considered
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General Approach to Management of CRE
KPCCeftazidime/avibactam
Meropenem/vaborbactamImipenem/relebactam
CefiderocolTigecycline
Eravacycline
MBLCeftazidime/avibactam + aztreonam
Cefiderocol
TigecyclineEravacycline
OXA-48
Ceftazidime/avibactam
CefiderocolTigecycline
Eravacycline
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Preferred treatmentsAlternative treatments
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Patient Case #1
• D.A. is a 67-year-old female being treated for uncomplicated cystitis due to KPC-producing Klebsiella pneumoniae. • She has NKDA and has a normal diet. • All other labs are WNL and her CrCl is 65
mL/min. • She is currently taking valproic acid,
famotidine, and aspirin.• What antimicrobial therapy would you
recommend for DA?
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DTR-P. aeruginosa Uncomplicated Cystitis
• Preferred treatment options: • Ceftolozane/tazobactam• Ceftazidime/avibactam• Imipenem/cilastatin/relebactam• Cefiderocol• Aminoglycosides (no added benefit with plazomicin)
• Alternative treatment options:• Colistin (nephrotoxicity; do not use Polymyxin B due to non-renal clearance)
• Do not use fosfomycin (high rates of clinical failure as P. aeruginosa intrinsically contains fosA gene [hydrolysis])
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• Alternative treatment options:• Cefiderocol• Aminoglycosides (no added benefit with Plazomicin)
• Combination therapy not recommended if in vitro susceptibility to a first-line antimicrobial is known• Empiric “double coverage” can be considered
• If susceptibility to a first-line agent is unknown or not demonstrated, aminoglycosides or polymyxins can be considered with a first-line agent
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Patient Case #2
• J.T. is a 66-year-old male being treated with piperacillin/tazobactam 4.5g IV q8h, infused over 4-hours, and gentamicin (pharmacy to dose) for suspected DTR-P. aeruginosa bacteremia, likely from a urinary source. • His CrCl is 105 mL/min, he is hemodynamically stable, and he is not
immunocompromised. • Three days later, blood cultures confirmed P. aeruginosa that is susceptible
to gentamicin, intermediate to ceftolozane/tazobactam and ceftazidime/avibactam, and resistant to everything else.• Antimicrobial therapy was changed to ceftolozane/tazobactam.• Do you agree with the course of antimicrobial therapy?
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General Approach to Management of ESBL-E
Cystitis
NitrofurantoinTMP/SMX
Amoxicillin/clavulanateAminoglycoside
Fosfomycin
FluoroquinoloneCarbapenem
cUTIs or pyelonephritis
CarbapenemFluoroquinolone
TMP/SMX
N/A
Systemic
Carbapenem
Oral step-down:Fluoroquinolone
TMP/SMX
Tamma PD. Clin Infect Dis. 2021;72(7):e169-e183.
Preferred treatmentsAlternative treatments
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General Approach to Management of CRE
Cystitis
Nitrofurantoin
FluoroquinoloneTMP/SMX
Aminoglycoside
Ceftazidime/avibactamMeropenem/vaborbactam
Imipenem/relebactam
CefiderocolColistin
cUTIs or pyelonephritis
Ceftazidime/avibactam
Meropenem/vaborbactamImipenem/relebactam
Cefiderocol
Aminoglycoside
Systemic
Ceftazidime/avibactamMeropenem/vaborbactam
Imipenem/relebactam
CefiderocolTigecycline
Eravacycline
Tamma PD. Clin Infect Dis. 2021;72(7):e169-e183.
Preferred treatmentsAlternative treatments
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General Approach to Management of DTR P. aeruginosa