Antibiotics in septic patients in the ER
Miquel Ekkelenkamp
University Medical Center Utrecht
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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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Clinical reasoning in infectious diseases
Symptoms Treatment
Pathogen
Disease
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Clinical reasoning in infectious diseases
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
ud
om
on
as
Acin
eto
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
om
on
as
Acin
eto
ba
cte
r
S. aureus Streps
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Gram-negativeAnaerobes
Gr+Gr- Enterobacteriales Non-fermH. infl
Gram-positive
EnterococciCoNS
Pse
ud
om
on
as
Acin
eto
ba
cte
r
S. aureus Streps
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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Gram-negativeAnaerobes
Gr+Gr- Enterobacteriales Non-fermH. infl
Gram-positive
EnterococciCoNS
S. aureus
MRSA MSSA
Pse
ud
om
on
as
Acin
eto
ba
cte
r
S. aureus Streps
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Gram-negativeAnaerobes
Gr+Gr- Enterobacteriales Non-fermH. infl
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-negativeAnaerobes
Gr+Gr- Enterobacteriales Non-fermH. infl
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
om
on
as
Anaerobes
Gr+Gr- Enterobacteriales NFHI
Gram-positive
S. aureus StrepsEnterococciCoNS
MRSA ESBL CREAMP-C
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Gram-negative
Pse
ud
om
on
as
Anaerobes
Gr+Gr- Enterobacteriales NFHI
Gram-positive
S. aureus StrepsEnterococciCoNS
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
Gr+Gr- Enterobacteriales NFHI
Gram-positive
S. aureus StrepsEnterococciCoNS
MRSA ESBL CREAMP-C
Amoxicillin / clavulanate
Ceftriaxone
Gentamicin / tobramycin / amikacin
Cefuroxime
A/C
Meropenem / imipenemM/IMero/imi
Amox/clav
Vancomycin / linezolid / daptomycin
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Gram-negative
Pse
ud
om
on
as
Anaerobes
Gr+Gr- Enterobacteriales NFHI
Gram-positive
S. aureus StrepsEnterococciCoNS
MRSA ESBL CREAMP-C
Amoxicillin / clavulanate
Ceftriaxone
Gentamicin / tobramycin / amikacin
Cefuroxime
A/C
Meropenem / imipenemMero/imi
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
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Gram-negative
Pse
ud
om
on
as
Anaerobes
Gr+Gr- Enterobacteriaceae NFHI
Gram-positive
S. aureus StrepsEnterococciCoNS
MRSA ESBL CREAMP-C
Amoxicillin-clavulanate
Ceftriaxone
Gentamicin / tobramycin / amikacin
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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Gram-negative
Pse
ud
om
on
as
Anaerobes
Gr+Gr- Enterobacteriaceae NFHI
Gram-positive
S. aureus StrepsEnterococciCoNS
MRSA ESBL CREAMP-C
Amoxicillin-clavulanate
Ceftriaxone
Gentamicin / tobramycin / amikacin
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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Gram-negative
Pse
ud
om
on
as
Anaerobes
Gr+Gr- Enterobacteriaceae NFHI
Gram-positive
S. aureus StrepsEnterococciCoNS
MRSA ESBL CREAMP-C
Amoxicillin-clavulanate
Ceftriaxone
Gentamicin / tobramycin / amikacin
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-negativeAnaerobes
Gr+Gr- Enterobacteriales Non-fermH. infl
Gram-positive
Entero-
cocciCoNS
Pse
ud
om
on
as
Acin
eto
ba
cte
r
S. aureus Streps
Penicillin Penicillin
Augm Amoxicillin
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
ListeriaMenigo-
coccus
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Gram-negativeAnaerobes
Gr+Gr- Enterobacteriales Non-fermH. infl
Gram-positive
Entero-
cocciCoNS
Pse
ud
om
on
as
Acin
eto
ba
cte
r
S. aureus Streps
Penicillin Penicillin
Augm Amoxicillin
Piptazo Piperacillin / tazobactam
3rd gen: ceftriaxone
3rd gen: ceftazidime
Meropenem / imipenemMero/imi
Ciprofloxacin
ClindamycinClinda
Gentamicin / tobramycin
Metronida-
zole
Vancomycin / daptomycin / linezolid
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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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?
Mild pneumonia: focus on
S. pneumoniae
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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?
No reaction: add coverage
for atypical pathogens /
H. influenzae
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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?
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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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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