antibiotics in sepsis: the basics - escmid

Antibiotics in septic patients in the ER

Miquel Ekkelenkamp

University Medical Center Utrecht

© ESCMID eLibrary by a

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Miquel EkkelenkampAntibiotics in septic patients in the ER

2

Disclosure of speaker’s interests

(Potential) conflict of interest None

Potentially relevant company relationships in

connection with event 1

None

• Sponsorship or research funding2

• Fee or other (financial) payment3

• Shareholder4

• Other relationship, i.e. …5

Polyphor AG (through European

Commision Innovative Medicines

Initatiative)


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Sepsis definitions• “Life-threatening organ dysfunction due to a dysregulated host

response to infection.”

• Acute increase in 2 or more points in SOFA score

• Quick SOFA (for screening): 2 or 3 of:– Hypotension: SBP less than or equal to 100 mmHg

– Altered mental status (any GCS less than 15)

– Tachypnoea: RR greater than or equal to 22

• Septic shock: – “Sepsis in which underlying circulatory and cellular/metabolic

abnormalities are profound enough to substantially increase mortality.”© ESCMID eLibrary b

y author


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Clinical reasoning in infectious diseases

Symptoms Disease Treatment

(Diagnosis)


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Symptoms Treatment

Pathogen

Disease


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Symptoms Treatment

Pathogen Susceptibility

Disease


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Antibiotics for sepsis in ER = empiric therapy

• Choice similar rationale as other infections:– Treatment usually started before culture results

– Less room to “miss” a pathogen

• R/ should cover the likely pathogens– Also cover likely resistant species

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

• R/ should be supported by clinical evidence of efficacy– Based on infectious syndrome

– Based on activity vs pathogen

– If registered for “sepsis” that would also be nice

Severity of disease


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Which infections are the main

causes of sepsis?


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Main focus bloodstream infection

• Community-acquired– Urinary tract

– Respiratory tract

– Abdominal / biliary tract

• Nosocomial bacteremia: – 1: Intravascular catheter (40%)

– 2: Urinary tract (8%)

– 3: Surgical site infection (5%)

– 4: Digestive tract (5%)

– 5: Pulmonary (4%)

– 20% unknown

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

60-95%

Main foci HAI (all):-Respiratory tract 23.5%-Surgical site infections 19.6%-Urinary tract 19%-Catheter-related infections 12.2%-Gastro-intestinal 7.6%

ECDC point prevalence survey hospital-acquired infections 2011-2012


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Which pathogens are the main causes of sepsis?


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Community-acquired bacteremia

• 1. Coagulase-negative staphylococci

• 2. E. coli

• 3. S. aureus

• 4. Enterococci

• 5. Klebsiella spp

• Some institutions: Candida, P. aeruginosa, Acinetobacter, Enterobacter

Low pathogenicity

Refs: see previous slide

• 1: Escherichia coli

• 2: Streptococcus pneumoniae

• 3: Staphylococcus aureus

• 4: Klebsiella species

60-70%

Nosocomial bacteremia


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Gram-positive Gram-negativeAnaerobes

Gr+Gr- S. aureus StrepsEnterococciCoNS Enterobacteriales Non-ferm

Pse

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on

as

Acin

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ba

cte

r

H. infl


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Gram-positive Gram-negativeAnaerobes

Gr+Gr- S. aureus StrepsEnterococciCoNS Enterobacteriales Non-ferm

Pse

ud

om

on

as

Acin

eto

ba

cte

r

H. infl

Penicillin Peni

Augm Amoxicillin / clavulanic acid

Piptazo Piperacillin / tazobactam

1st gen: cefazolin

2nd gen: cefuroxime

3rd gen: ceftriaxone

3rd gen: ceftazidime

Meropenem / imipenemMero/imi

Ciprofloxacin

ClindamycinClinda

Gentamicin / tobramycin

Metronida-

zole

Vancomycin / daptomycin / linezolid

Aztreonam

Colistin

4th gen: cefepime


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Are we allowed to use these

drugs for sepsis?


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FDA labels

www.accessdata.fda.gov/scripts/cder/daf/


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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 tobramycin

– Known ESBL-positive: carbapenem

• Spain (Zaragoza University Hospital): – Ceftriaxone +/- gentamicin

– Risk factors for ESBL: carbapenem

• Surviving sepsis guideline 2016 (no distinction HA-sepsis): – “empiric broad-spectrum therapy to cover all LIKELY pathogens”, if shock

“at least 2 antibiotics of different antibiotic classes”

• Sanford Guide (no distinction HA-sepsis):– Vancomycin + meropenem or imipenem or piperacillin-tazobactam

– Alternative: daptomycin + cefepime or piperacillin-tazobactam


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Basically

• Preferably treat with a beta-lactam antibiotic

– I.e.: penicillins, cephalosporins, carbapenems or monobactams

• Bactericidal

• Usually well-known safety profile

• Usually inexpensive

• If necessary: add additional antibiotic

– To cover gaps in the desired antibiotic spectrum

– Some people say “for synergy” (limited indications)

• Always take into account:

– Likely focus, risk factors for certain pathogens (antibiotic use,

comorbidity, etc)

– PRIOR CULTURES (positive and negative)


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Beta-lactams: 60% of total antibiotic use

Beta-lactams


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Gram-negativeAnaerobes

Gr+Gr- Enterobacteriales Non-fermH. infl

Gram-positive

EnterococciCoNS

Community-acquired sepsis:-Enterobacteriaceae: E. coli, Klebsiella

-Streptococci (incl pneumococci)

-S. aureus

Pse

ud

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as

Acin

eto

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cte

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S. aureus Streps


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Gram-positive

EnterococciCoNS

Pse

ud

om

on

as

Acin

eto

ba

cte

r

S. aureus Streps

Penicillin Peni

Augm Amoxicillin / clavulanic acid


1st gen: cefazolin

2nd gen: cefuroxime




Ciprofloxacin

ClindamycinClinda


Metronida-

zole


Aztreonam

Colistin

4th gen: cefepime


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Gram-positive

EnterococciCoNS

S. aureus

MRSA MSSA

Pse

ud

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on

as

Acin

eto

ba

cte

r

S. aureus Streps


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Gram-positive

EnterococciCoNS

S. aureus

MRSA MSSA

Enterobacteriales

ESBL Carba-RAMP-C

Pse

ud

om

on

as

Acin

eto

ba

cte

r

S. aureus Streps


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Gram-positive

EnterococciCoNS

S. aureus

MRSA MSSA

Enterobacteriales

ESBL Carba-RAMP-C

Pse

ud

om

on

as

Acin

eto

ba

cte

r

S. aureus Streps

Laupland CMR 2014

EARS-Net data 2015

MRSA outpatients:

<0.1-18 / 100,000 pt yearsESBL outpatients:

2.6%-40% E.coli

Talan, 2014

Castillo 2015


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Gram-negative

Pse

ud

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on

as

Anaerobes

Gr+Gr- Enterobacteriales NFHI

Gram-positive

S. aureus StrepsEnterococciCoNS

MRSA ESBL CREAMP-C


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Gram-negative

Pse

ud

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on

as

Anaerobes


Gram-positive


MRSA ESBL CREAMP-C

Amoxicillin / clavulanate

Ceftriaxone

Gentamicin / tobramycin / amikacin

Cefuroxime

A/CAmox/clav

Meropenem / imipenemMero/imi M/I

Colistin


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Gram-negative

Pse

ud

om

on

as

Anaerobes


Gram-positive


MRSA ESBL CREAMP-C


Ceftriaxone


Cefuroxime

A/C

Meropenem / imipenemM/IMero/imi

Amox/clav

Vancomycin / linezolid / daptomycin


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Gram-negative

Pse

ud

om

on

as

Anaerobes


Gram-positive


MRSA ESBL CREAMP-C


Ceftriaxone


Cefuroxime

A/C


Amox/clav

Metronida-

zole

Or should we consider an

intra-abdominal focus?

ClindamycinClinda

Ciprofloxacin


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Healthcare-associated sepsis

• Circulating hospital-specific pathogens

– Same micro-organism but more resistant (MRSA, ESBL, CRE)

– Different micro-organism: P. aeruginosa, A. baumannii,

Enterobacters, Serratia’s, etc.

• Immunocompromized population

– Underlying illness, post-operative status, intravascular access,

immunosuppressant medication

– Susceptible to wider range of (opportunistic) pathogens:

Pseudomonas aeruginosa and other non-fermenters, yeast and

fungi© ESCMID eLibrary by a

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Gram-negative

Pse

ud

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on

as

Anaerobes

Gr+Gr- Enterobacteriaceae NFHI

Gram-positive


MRSA ESBL CREAMP-C

Amoxicillin-clavulanate

Ceftriaxone


Cefuroxime

A-C

Meropenem / imipenemM/I M/IMero/imi

Amox-clv

Vancomycin / linezolid / daptomycin

Piperacillin-tazobactamP-TPip-tzb

ErtapenemEErtapen

Acin

eto

ba

cte

r

P

Ceftazidime Ct

Cefepime CpCp

Colistin


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Sepsis e.c.i.: choice of antibiotics (1)

• Choice dependent on:– Patient group: e.g. community-acquired vs healthcare-associated

– Local epidemiology: general resistance rates, outbreaks

– Severity of illness (can you afford to miss something?)

– Prior culture results

• Empiric therapy: in principle a beta-lactam– Where necessary antibiotics are added for coverage of resistant micro-

organisms or anaerobes

– Prior culture results always have to be considered


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Sepsis e.c.i.: choice of antibiotics (2)

• Gram-positives: – Cover MRSA?

• Gram-negatives:– Cover ESBL?

– Cover AMP-C?

– Cover carbapenem-resistance?

– Cover P. aeruginosa? Acinetobacter?

• Anaerobes: cover at all?

• Fungi (yeasts): cover at all?

Empiric additional aminoglycoside sufficient?


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Empiric therapy tailored to apparent / diagnosed focus

• Guidelines empirical R/ (should be) available per diagnosis– Pneumonia

– Urinary tract infection

– Intra-abdominal infection

– Skin and soft tissue infection (osteomyelitis, arthritis)

– Meningitis

– Endocarditis

– Et cetera

• Specific pathogens (not) considered

• Outcomes of specific tests can be taken into consideration

• Anamnesis to be taken into consideration


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For instance: community-acquired bacterial meningitis in adults

• Main pathogens– 1: Streptococcus pneumoniaea

– 2: Neisseria meningitidis

– 3: Haemophilus influenzae

– 4: Listeria monocytogenes

• Additional requirement: antibiotic must have good penetration in cerebrospinal fluid– (No clavulanic acid, no 1st or 2nd generation cephalosporins)

Elderly / immunocompromized


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Gram-positive

Entero-

cocciCoNS

Pse

ud

om

on

as

Acin

eto

ba

cte

r

S. aureus Streps

Penicillin Penicillin

Augm Amoxicillin


1st gen: cefazolin

2nd gen: cefuroxime




Ciprofloxacin

ClindamycinClinda


Metronida-

zole


Aztreonam

Colistin

4th gen: cefepime

ListeriaMenigo-

coccus


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Gram-positive

Entero-

cocciCoNS

Pse

ud

om

on

as

Acin

eto

ba

cte

r

S. aureus Streps

Penicillin Penicillin

Augm Amoxicillin





Ciprofloxacin

ClindamycinClinda


Metronida-

zole


Aztreonam

Colistin

4th gen: cefepime

ListeriaMenigo-

coccus

Empiric treatments

(dependent on center / patient):

-Penicillin / amoxicillin monotherapy

-Ceftriaxone / cefotaxime monotherapy

-Amoxicillin + ceftriaxone/cefotaxime


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For instance community-acquired pneumonia

• Main pathogens:– 1: Viruses

– 2: Streptococcus pneumoniae

– 3: Haemophilus influenzae

– 4: Legionella pneumophila

– 5: Mycoplasma pneumoniae

– 6: Chlamydia pneumoniae / psittaci

– 7: Enterobacteriales

– 8: Staphylococcos aureus

• Risk factors for specific pathogens:– Travel, contact with animals, abscesses, aspiration…

www.who.int

Pre-conditions, severe disease(and often colonizers)

Usually mild disease, self-limiting


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Pathogens in CAP

• 1: S. pneumoniae (pneumococcus)

– Main pathogen, probably more than half of infections

– Very susceptible to beta-lactam antibiotics, often not cultured

• 2: Viruses

– In particular in mild pneumonia

• 3: “Atypical” bacteria

– Legionella, Mycoplasma, Chlamydia, (Coxiella)

– Do not respond to beta-lactam therapy

– Mycoplasma more frequent in children; usually self-limiting, occurs in epidemics

– Legionella most severe infections, but relatively rare

• 4: H. influenzae, S. aureus, Gram-negatives

– Often colonizers, overestimation based on culture results

– S. aureus, Gram-negatives particularly severe disease / pre-existing conditions


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Considerations in antibiotics for CAP

• Main pathogen: S. pneumoniae. – Always to be covered, preferably with penicillin / amoxicillin

• In case of severe CAP: broad coverage, in particular include Legionella pneumophila– Some guidelines: include coverage Enterobacteriales and S. aureus

• H. influenzae in practice (far) less common cause of typical CAP

• In studies no advantage empirical therapy for atypical pathogens– Severe infections with Mycoplasma or Chlamydia very rare

• Different classifications of severity– CURB-65, PSI, bedside evaluation


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Gram-positive Gram-negative

E. Coli

KlebsiellaS. aureusS. pneumoniae

Penicill / amoxi

Amoxicillin-clavulanic acid

2nd-3rd gen cephalosporins

Ciprofloxacin

H.influenzae

Viral

Pseudo-

monas

“Atypical”

Legio

nella

Myco

pla

sm

a

Ch

lam

yd

ia

Co

xie

lla

Levofloxacin / moxifloxacin

Doxycycline / tetracycline Doxy/ tetra

Macrolides Macrolides

Very limited

resistance

Pen/amox

4-33% R

7-10% R?

0.1-27% R?

Usually treatable

with (high) iv R/

1-2% R?© ESCMID eLibrary by a

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E. Coli


Penicill / amoxi



Ciprofloxacin

H.influenzae

Viral

Pseudo-

monas

“Atypical”

Legio

nella

Myco

pla

sm

a

Ch

lam

yd

ia

Co

xie

lla




Very limited

resistance

Pen/amox

4-33% R

7-10% R?

0.1-27% R?

Usually treatable

with (high) iv R/

1-2% R?

Mild pneumonia: focus on

S. pneumoniae


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E. Coli


Penicill / amoxi



Ciprofloxacin

H.influenzae

Viral

Pseudo-

monas

“Atypical”

Legio

nella

Myco

pla

sm

a

Ch

lam

yd

ia

Co

xie

lla




Very limited

resistance

Pen/amox

4-33% R

7-10% R?

0.1-27% R?

Usually treatable

with (high) iv R/

1-2% R?

No reaction: add coverage

for atypical pathogens /

H. influenzae


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E. Coli


Penicill / amoxi



Ciprofloxacin

H.influenzae

Viral

Pseudo-

monas

“Atypical”

Legio

nella

Myco

pla

sm

a

Ch

lam

yd

ia

Co

xie

lla




Very limited

resistance

Pen/amox

4-33% R

7-10% R?

0.1-27% R?

Usually treatable

with (high) iv R/

1-2% R?

Severe pneumonia: cover full

spectrum of lung pathogens,

in particular Legionella


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Guideline CAPBritish Thoracic Society 2009, updated 2015

• Treated in community (CRB-65 of 0-1)– Amoxicillin (oral)

• Hospitalized, low severity– Amoxicillin (oral)

• Hospitalized, moderate severity – Amoxicillin + macrolide (oral, if possible)

• Hospitalized, high severity (CURB ≥ 3)– Iv. broad-spectrum beta-lactam + iv. macrolide

British Thoracic Society 2009, annotated to NICE recommendations 2015


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Guideline CAPDutch SWAB guideline 2015

• Treated in community (CRB-65 of 0-1)– Amoxicillin (oral), alternative doxycycline

• Hospitalized, moderate severity– Amoxicillin (oral or iv.)

• Hospitalized, high severity – Broad-spectrum beta-lactam (iv.) (pending Legionella-results)

• Hospitalized, ICU (CURB ≥ 3)– Broad-spectrum beta-lactam + fluoroquinolone

www.swab.nl


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http://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 susceptibility

• Severity disease, co-morbidity or age may be indication for more extensive therapy– For instance meningitis, depending on co-morbidity and age:

• Narrow spectrum (meningococcus/pneumococcus) to broad coverage

– For instance pneumonia, depending on severity: • Narrow spectrum (pneumococcus) to iv. broad spectrum


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Thank you for your attention


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antibiotics in sepsis: the basics - escmid

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