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Home , Aztreonam, Cefazolin, Cefepime, Cefotaxime, Ceftazidime, Ceftriaxone

author by in septic patients in the ER Miquel EkkelenkampeLibrary University Medical Center Utrecht

ESCMID © ESCMID eLibrary by author Miquel Ekkelenkamp Antibiotics in septic patients in the ER

Disclosure of speaker’s interests

(Potential) conflict of interest None author Potentially relevant company relationships in Noneby connection with event 1

• Sponsorship or research funding2 Polyphor AG (through European eLibraryCommision Innovative Medicines Initatiative)

• Fee or other (financial) payment3 • Shareholder4 ESCMID5 • Other relationship,© ESCMID i.e. … eLibrary by author

2 definitions

• “Life-threatening organ dysfunction due to a dysregulated host response to .”

• Acute increase in 2 or more points in SOFA scoreauthor by • Quick SOFA (for screening): 2 or 3 of: – : SBP less than or equal to 100 mmHg – Altered mental status (any GCS less than 15) – Tachypnoea: RR greater thaneLibrary or equal to 22

• Septic shock: – “Sepsis in which underlying circulatory and cellular/metabolic abnormalitiesESCMID are profound enough to substantially increase mortality.”© ESCMID eLibrary by author Clinical reasoning in infectious diseases

author by Symptoms Disease Treatment eLibrary (Diagnosis)

ESCMID © ESCMID eLibrary by author Clinical reasoning in infectious diseases

Pathogen author by Symptoms Disease Treatment eLibrary

ESCMID © ESCMID eLibrary by author Clinical reasoning in infectious diseases

Pathogen Susceptibility author by Symptoms Disease Treatment eLibrary

ESCMID © ESCMID eLibrary by author Antibiotics for sepsis in ER =

• Choice similar rationale as other : – Treatment usually started before culture results Severity of disease – Less room to “miss” a pathogen author by • R/ should cover the likely pathogens – Also cover likely resistant species

• R/ should be “suitable” foreLibrary sepsis – Preferably (rapidly) bactericidal, intravenous

• R/ should be supported by clinical evidence of efficacy – Based onESCMID infectious syndrome – Based© onESCMID activity vs pathogen eLibrary by author – If registered for “sepsis” that would also be nice author Which infections areby the main causes of sepsis? eLibrary

ESCMID © ESCMID eLibrary by author Main focus bloodstream infection

• Community-acquired – Urinary tract – Respiratory tract 60-95% author – Abdominal / biliary tract by

• Nosocomial bacteremia: Main foci HAI (all): – 1: Intravascular catheter (40%)eLibrary-Respiratory tract 23.5% – 2: Urinary tract (8%) -Surgical site infections 19.6% -Urinary tract 19% – 3: Surgical site infection (5%) -Catheter-related infections 12.2% – 4: Digestive tract (5%) -Gastro-intestinal 7.6% – 5: PulmonaryESCMID (4%) – 20% unknown © ESCMID eLibraryECDC pointby prevalence author survey hospital- acquired infections 2011-2012

Nethmap 2009, SWAB 2010; EDCD surveillance report 2011-12; Laupland e.a., Clin Microbiol Rev 2014; Søgaard e.a. Clin Microbiol Infect 2015; Cardoso e.a. Acta Med Portug 2013 author Which pathogens areby the main causes of sepsis? eLibrary

ESCMID © ESCMID eLibrary by author Community-acquired bacteremia

• 1: • 2: pneumoniae 60-70% • 3: aureus • 4: species author by Nosocomial bacteremia eLibrary • 1. Coagulase-negative staphylococci • 2. E. coli Low • 3. S. aureus pathogenicity • 4. EnterococciESCMID • 5. Klebsiella© ESCMID spp eLibrary by author • Some institutions: Candida, P. aeruginosa, ,

Refs: see previous slide Anaerobes Gram-positive Gram-negative

Gr- Gr+ CoNS Enterococci S. aureus Streps H. infl Enterobacteriales Non-ferm Acinetobacter

author by

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ESCMID © ESCMID eLibrary by author Anaerobes Gram-positive Gram-negative

Gr- Gr+ CoNS Enterococci S. aureus Streps H. infl Enterobacteriales Non-ferm

Penicillin Peni Acinetobacter Augm / author Pseudomonas Piptazo / tazobactamby 1st gen: Metronida- 2nd gen: zole 3rd gen:eLibrary 3rd gen: 4th gen: / Mero/imi ESCMID Clinda © ESCMIDClindamycin eLibrary by authorAztreonam / / Ciprofloxacin / author by

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ESCMID © ESCMIDAre we allowed eLibraryto byuse author these drugs for sepsis? FDA labels

author by

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ESCMID © ESCMID eLibrary by author

www.accessdata.fda.gov/scripts/cder/daf/ Guidelines, community-acquired sepsis (of unknown origin)

• The Netherlands (SWAB-guideline): – Cefuroxime OR ceftriaxone OR amoxi-clav +/- gentamicin / tobramycin – Risk factors for ESBL: add gentamicin or tobramycinauthor – Known ESBL-positive: by • Spain (Zaragoza University Hospital): – Ceftriaxone +/- gentamicin – Risk factors for ESBL: carbapenemeLibrary • Surviving sepsis guideline 2016 (no distinction HA-sepsis): – “empiric broad-spectrum therapy to cover all LIKELY pathogens”, if shock “at least ESCMID2 antibiotics of different classes” • Sanford© Guide ESCMID (no distinction eLibrary HA-sepsis): by author – Vancomycin + meropenem or imipenem or piperacillin- – Alternative: daptomycin + cefepime or piperacillin-tazobactam Basically

• Preferably treat with a beta-lactam antibiotic – I.e.: , , or • Bactericidal author • Usually well-known safety profile by • Usually inexpensive

• If necessary: add additional antibiotic – To cover gaps in the desiredeLibrary antibiotic spectrum – Some people say “for synergy” (limited indications)

• Always take into account: – Likely focus,ESCMID risk factors for certain pathogens (antibiotic use, comorbidity,© ESCMID etc) eLibrary by author – PRIOR CULTURES (positive and negative) Beta-lactams: 60% of total antibiotic use

author by

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Beta-lactams ESCMID © ESCMID eLibrary by author Anaerobes Gram-positive Gram-negative

Gr- Gr+ CoNS Enterococci S. aureus Streps H. infl Enterobacteriales Non-ferm Acinetobacter

author Pseudomonas Community-acquiredby sepsis: -Enterobacteriaceae: E. coli, Klebsiella -Streptococci (incl pneumococci) -S. aureus eLibrary

ESCMID © ESCMID eLibrary by author Anaerobes Gram-positive Gram-negative

Gr- Gr+ CoNS Enterococci S. aureus Streps H. infl Enterobacteriales Non-ferm

Penicillin Peni Acinetobacter Augm Amoxicillin / clavulanic acidauthor Pseudomonas Piptazo Piperacillin / tazobactamby

st Metronida- 1 gen: cefazolin zole 2nd gen: cefuroxime 3rd gen:eLibrary ceftriaxone 3rd gen: ceftazidime 4th gen: cefepime Meropenem / imipenem Mero/imi ESCMID Clinda © ESCMIDClindamycin eLibrary by authorAztreonam Vancomycin / daptomycin / linezolid Colistin Ciprofloxacin Gentamicin / tobramycin Anaerobes Gram-positive Gram-negative

Gr- Gr+ CoNS Enterococci S. aureus Streps H. infl Enterobacteriales Non-ferm Acinetobacter

author Pseudomonas by

S. aureus eLibrary MRSA MSSA ESCMID © ESCMID eLibrary by author Anaerobes Gram-positive Gram-negative

Gr- Gr+ CoNS Enterococci S. aureus Streps H. infl Enterobacteriales Non-ferm Acinetobacter

author Pseudomonas by

S. aureus eLibrary Enterobacteriales MRSA MSSA ESBL AMP-C Carba-R ESCMID © ESCMID eLibrary by author Anaerobes Gram-positive Gram-negative

Gr- Gr+ CoNS Enterococci S. aureus Streps H. infl Enterobacteriales Non-ferm Acinetobacter

author Pseudomonas by

S. aureus eLibrary Enterobacteriales MRSA MSSA ESBL AMP-C Carba-R MRSA outpatients:ESCMID ESBL outpatients: <0.1-18© / 100,000ESCMID pt years eLibrary by 2.6%author-40% E.coli Laupland CMR 2014 Talan, 2014 EARS-Net data 2015 Castillo 2015 Anaerobes Gram-positive Gram-negative

Gr- Gr+ CoNS Enterococci S. aureus Streps HI Enterobacteriales NF MRSA ESBL AMP-C CRE

author Pseudomonas by

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ESCMID © ESCMID eLibrary by author Anaerobes Gram-positive Gram-negative

Gr- Gr+ CoNS Enterococci S. aureus Streps HI Enterobacteriales NF MRSA ESBL AMP-C CRE

author Pseudomonas by

Amox/clav A/C AmoxicillineLibrary / clavulanate Cefuroxime Ceftriaxone Mero/imi ESCMIDM/I Meropenem / imipenem © ESCMID eLibraryGentamicin by author / tobramycin / Colistin Anaerobes Gram-positive Gram-negative

Gr- Gr+ CoNS Enterococci S. aureus Streps HI Enterobacteriales NF MRSA ESBL AMP-C CRE

author Pseudomonas by

Amox/clav A/C AmoxicillineLibrary / clavulanate Cefuroxime Ceftriaxone Mero/imi ESCMIDM/I Meropenem / imipenem © ESCMID eLibraryGentamicin by author / tobramycin / amikacin Vancomycin / linezolid / daptomycin Anaerobes Gram-positive Gram-negative

Gr- Gr+ CoNS Enterococci S. aureus Streps HI Enterobacteriales NF MRSA ESBL AMP-C CRE

Or should we consider an

intra-abdominal focus? author Pseudomonas by Metronida- zole Amox/clav A/C AmoxicillineLibrary / clavulanate Cefuroxime Ceftriaxone Mero/imi ESCMIDMeropenem / imipenem © ESCMID eLibraryGentamicin by author / tobramycin / amikacin Clinda Ciprofloxacin Healthcare-associated sepsis

• Circulating hospital-specific pathogens – Same micro-organism but more resistant (MRSA,author ESBL, CRE) – Different micro-organism: P. aeruginosa, A. baumannii, Enterobacters, ’s, etc. by

• Immunocompromized population – Underlying illness, post-operativeeLibrary status, intravascular access, immunosuppressant medication – Susceptible to wider range of (opportunistic) pathogens: and other non-fermenters, yeast and fungi ESCMID © ESCMID eLibrary by author Anaerobes Gram-positive Gram-negative

Gr- Gr+ CoNS Enterococci S. aureus Streps HI Enterobacteriaceae NF

MRSA ESBL AMP-C CRE Acinetobacter author Pseudomonas Amox-clv A-C Amoxicillin-clavulanate Pip-tzb P-T Piperacillin-tazobactam by P Cefuroxime Ceftriaxone CeftazidimeeLibrary Ct Cefepime Cp Cp

Ertapen E Mero/imi ESCMIDM/I Meropenem / imipenem M/I © ESCMID eLibraryGentamicin by author / tobramycin / amikacin Colistin Vancomycin / linezolid / daptomycin Anaerobes Gram-positive Gram-negative

Gr- Gr+ CoNS Enterococci S. aureus Streps HI Enterobacteriaceae NF

MRSA ESBL AMP-C CRE Acinetobacter author Pseudomonas Amox-clv A-C Amoxicillin-clavulanate Pip-tzb P-T Piperacillin-tazobactam by P Cefuroxime Ceftriaxone CeftazidimeeLibrary Ct Cefepime Cp Cp

Ertapen E Ertapenem Mero/imi ESCMIDM/I Meropenem / imipenem M/I © ESCMID eLibraryGentamicin by author / tobramycin / amikacin Colistin Vancomycin / linezolid / daptomycin Anaerobes Gram-positive Gram-negative

Gr- Gr+ CoNS Enterococci S. aureus Streps HI Enterobacteriaceae NF

MRSA ESBL AMP-C CRE Acinetobacter author Pseudomonas Amox-clv A-C Amoxicillin-clavulanate Pip-tzb P-T Piperacillin-tazobactam by P Cefuroxime Ceftriaxone eLibraryCeftazidime Ct Cefepime Cp Cp

Ertapen E Ertapenem Mero/imi ESCMIDM/I Meropenem / imipenem M/I © ESCMID eLibraryGentamicin by author / tobramycin / amikacin Colistin Vancomycin / linezolid / daptomycin Sepsis e.c.i.: choice of antibiotics (1)

• Choice dependent on: – Patient group: e.g. community-acquired vs healthcareauthor-associated – Local epidemiology: general resistance rates,by outbreaks – Severity of illness (can you afford to miss something?) – Prior culture results

• Empiric therapy: in principleeLibrary a beta-lactam – Where necessary antibiotics are added for coverage of resistant micro- organisms or anaerobes – Prior cultureESCMID results always have to be considered © ESCMID eLibrary by author Sepsis e.c.i.: choice of antibiotics (2)

• Gram-positives: – Cover MRSA? author • Gram-negatives: by – Cover ESBL? – Cover AMP-C? Empiric additional – Cover carbapenem-resistance?eLibrary sufficient? – Cover P. aeruginosa? Acinetobacter?

• Anaerobes: cover at all? ESCMID • Fungi ©(yeasts): ESCMID cover at all? eLibrary by author Empiric therapy tailored to apparent / diagnosed focus

• Guidelines empirical R/ (should be) available per diagnosis – author – by – Intra-abdominal infection – Skin and soft tissue infection (, arthritis) – – eLibrary – Et cetera • Specific pathogens (not) considered ESCMID • Outcomes© ESCMID of specific tests eLibrary can be taken intoby considerationauthor • Anamnesis to be taken into consideration For instance: community-acquired bacterial meningitis in adults

• Main pathogens – 1: Streptococcus pneumoniaea author – 2: meningitidis by – 3: Elderly / immunocompromized – 4: monocytogenes

• Additional requirement: antibioticeLibrary must have good penetration in – (No clavulanic acid, no 1st or 2nd generation cephalosporins) ESCMID © ESCMID eLibrary by author Anaerobes Gram-positive Gram-negative

Entero- Menigo- - + CoNS Listeria H. infl Non-ferm Gr Gr cocci S. aureus Streps coccus Enterobacteriales

Penicillin Penicillin Acinetobacter Augm Amoxicillin author Pseudomonas Piptazo Piperacillin / tazobactamby

st Metronida- 1 gen: cefazolin zole 2nd gen: cefuroxime 3rd gen:eLibrary ceftriaxone 3rd gen: ceftazidime 4th gen: cefepime Meropenem / imipenem Mero/imi ESCMID Clinda © ESCMIDClindamycin eLibrary by authorAztreonam Vancomycin / daptomycin / linezolid Colistin Ciprofloxacin Gentamicin / tobramycin Anaerobes Gram-positive Gram-negative

Entero- Menigo- - + CoNS Listeria H. infl Non-ferm Gr Gr cocci S. aureus Streps coccus Enterobacteriales

Penicillin Penicillin Acinetobacter Augm Amoxicillin author Pseudomonas Piptazo Piperacillin / tazobactamby

Metronida- zole 3rd gen:eLibrary ceftriaxone 3rd gen: ceftazidime 4th gen: cefepime Meropenem / imipenem Mero/imi ESCMID Clinda Clindamycin Empiric treatmentsAztreonam © ESCMID eLibrary(dependent by author on center / patient): Vancomycin / daptomycin / linezolid -Penicillin / amoxicillinColistin monotherapy -CeftriaxoneCiprofloxacin / monotherapy -Amoxicillin + ceftriaxone/cefotaxime Gentamicin / tobramycin For instance community-acquired pneumonia

• Main pathogens: – 1: Viruses author – 2: – 3: Haemophilus influenzae by – 4: Legionella pneumophila – 5: pneumoniae Usually mild disease, self-limiting – 6: Chlamydia pneumoniae eLibrary/ psittaci – 7: Enterobacteriales Pre-conditions, severe disease – 8: Staphylococcos aureus (and often colonizers) ESCMID • Risk factors© ESCMID for specific pathogens: eLibrary by author – Travel, contact with animals, abscesses, aspiration…

www.who.int Pathogens in CAP

• 1: S. pneumoniae (pneumococcus) – Main pathogen, probably more than half of infections – Very susceptible to beta-lactam antibiotics, often not culturedauthor

• 2: Viruses by – In particular in mild pneumonia

• 3: “Atypical” – Legionella, Mycoplasma, ChlamydiaeLibrary, (Coxiella) – Do not respond to beta-lactam therapy – Mycoplasma more frequent in children; usually self-limiting, occurs in epidemics – LegionellaESCMIDmost severe infections, but relatively rare • 4: H. influenzae© ESCMID, S. aureus, Gram eLibrary-negatives by author – Often colonizers, overestimation based on culture results – S. aureus, Gram-negatives particularly severe disease / pre-existing conditions Considerations in antibiotics for CAP

• Main pathogen: S. pneumoniae. – Always to be covered, preferably with penicillin / amoxicillinauthor • In case of severe CAP: broad coverage, in byparticular include Legionella pneumophila – Some guidelines: include coverage Enterobacteriales and S. aureus eLibrary • H. influenzae in practice (far) less common cause of typical CAP

• In studies no advantage empirical therapy for atypical pathogens – Severe infectionsESCMID with Mycoplasma or Chlamydia very rare © ESCMID eLibrary by author • Different classifications of severity – CURB-65, PSI, bedside evaluation Viral Gram-positive Gram-negative “Atypical”

S. pneumoniae S. aureus H.influenzae E. Coli Pseudo- Klebsiella monas Coxiella Legionella Chlamydia 0.1-27% R? Mycoplasma Usually treatable with (high) iv R/ author Penicill / amoxi Pen/amox by Very limited Amoxicillin-clavulanic acid resistance 2nd-3rd gen cephalosporins

7-10% R? eLibrary Doxycycline / tetracycline Doxy/ tetra

4-33% R Macrolides ESCMID ©1 -2%ESCMID R? eLibraryCiprofloxacin by author / moxifloxacin Viral Gram-positive Gram-negative “Atypical”

S. pneumoniae S. aureus H.influenzae E. Coli Pseudo- Klebsiella monas Coxiella Legionella Chlamydia 0.1-27% R? Mild pneumonia: focus on Mycoplasma Usually treatable S. pneumoniae with (high) iv R/ author Penicill / amoxi Pen/amox by Very limited Amoxicillin-clavulanic acid resistance 2nd-3rd gen cephalosporins

7-10% R? eLibrary Doxycycline / tetracycline Doxy/ tetra

4-33% R Macrolides Macrolides ESCMID ©1 -2%ESCMID R? eLibraryCiprofloxacin by author Levofloxacin / moxifloxacin Viral Gram-positive Gram-negative “Atypical”

S. pneumoniae S. aureus H.influenzae E. Coli Pseudo- Klebsiella monas

No reaction: add coverage Coxiella Legionella Chlamydia 0.1-27% R? for atypical pathogens / Mycoplasma Usually treatable H. influenzae with (high) iv R/ author Penicill / amoxi Pen/amox by Very limited Amoxicillin-clavulanic acid resistance 2nd-3rd gen cephalosporins

7-10% R? eLibrary Doxycycline / tetracycline Doxy/ tetra

4-33% R Macrolides Macrolides ESCMID ©1 -2%ESCMID R? eLibraryCiprofloxacin by author Levofloxacin / moxifloxacin Viral Gram-positive Gram-negative “Atypical”

S. pneumoniae S. aureus H.influenzae E. Coli Pseudo- Klebsiella monas Coxiella

Severe pneumonia: cover full Legionella Chlamydia Mycoplasma 0.1-27% R? spectrum of lung pathogens, Usually treatable with (high) iv R/ in particular Legionellaauthor Penicill / amoxi Pen/amox by Very limited Amoxicillin-clavulanic acid resistance 2nd-3rd gen cephalosporins

7-10% R? eLibrary Doxycycline / tetracycline Doxy/ tetra

4-33% R Macrolides Macrolides ESCMID ©1 -2%ESCMID R? eLibraryCiprofloxacin by author Levofloxacin / moxifloxacin Guideline CAP British Thoracic Society 2009, updated 2015

• Treated in community (CRB-65 of 0-1) – Amoxicillin (oral) author by • Hospitalized, low severity – Amoxicillin (oral) eLibrary • Hospitalized, moderate severity – Amoxicillin + (oral, if possible)

• HospitalizedESCMID, high severity (CURB ≥ 3) – Iv. broad© ESCMID-spectrum beta-lactam eLibrary + iv. macrolide by author

British Thoracic Society 2009, annotated to NICE recommendations 2015 Guideline CAP Dutch SWAB guideline 2015

• Treated in community (CRB-65 of 0-1) – Amoxicillin (oral), alternative doxycycline author by • Hospitalized, moderate severity – Amoxicillin (oral or iv.) eLibrary • Hospitalized, high severity – Broad-spectrum beta-lactam (iv.) (pending Legionella-results)

• HospitalizedESCMID, ICU (CURB ≥ 3) – Broad©- spectrumESCMID beta-lactam eLibrary + fluoroquinolone by author

www.swab.nl Summary: directed therapy in sepsis

• Follow your guidelines – But don’t stop thinking... (additional risk factors?) – Guidelines based on likely pathogens and their susceptibilityauthor by

eLibrary • Severity disease, co-morbidity or age may be indication for more extensive therapy – For instance meningitis, depending on co-morbidity and age: • NarrowESCMID spectrum (meningococcus/pneumococcus) to broad coverage – For© instance ESCMID pneumonia, dependingeLibrary on severity: by author • Narrow spectrum (pneumococcus) to iv. broad spectrum author by

eLibrary

ESCMID © ESCMID eLibrary by author Thank you for your attention