Download Approach to the patient with sepsis

Approach to the patient with sepsis:
infectious causes and antimicrobial
management
Morgan Hakki
August 11, 2016
Infection as a cause of sepsis
• ~50% of patients meeting criteria for sepsis
are found to have an infectious cause
– ~95% of patients with bacteremia meet criteria for
sepsis, severe sepsis, or septic shock
• Pneumonia and GU sources most common in
persons presenting to the ER with sepsis:
In hospitalized patients, think of:
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•
•
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Line-associated (CLABSI) bacteremias
Catheter-associated UTI (CAUTI)
Pneumonia
Gut – neutropenic hosts
Microbiologic epidemiology of healthcare
associated infections (HAIs) in the US 2009-2010
CLABSIs #1 source of HAIs
Staph aureus single most common pathogen in HAIs
Predominance of gram positives in CLABSIs
Predominance of gram negatives in CAUTIs, VAP
Epidemiology of Gram Negative bacteremia at OHSU
E. Coli,
Klebsiella Pneumoniae
Pseudomonas aeruginosa
Enterobacter cloacae
Decreasing
incidence
Acinetobacter spp
Serratia marcescens
Proteus Mirabilis
Stenotrophomonas maltiphilia
Fusobacterium
Klebsiella oxytoca
Bacteroides fragilis
Citrobacter Freundii
Leptotrichia spp
Capnocytophaga
Sphingomonas paucimobilis
Moraxella Spp
Pantoea spp
Enterobacter gergoviae
Ralstonia mannitolitylica
Morganella Morganii
Citrobacter youngae
Raoultella planticola
Kluyvera intermedia
Leclercia adecarboxylate
Serratia liquefaciens
Campylobacter spp
Ochrobactrum anthropi
Pseudomonas fluorescans
Raoultella ornithinolytica
Achromobacter spp
Courtesy of Rob Zimmerman
Proteus vulgaris
Unable to be identified
Why does the source of infection
matter?
– Determines empiric coverage based on expected
pathogens
– Source control is critical to successful outcome
• Drain abscesses
• Pull CVCs
• Debride necrotizing fasciitis
– Association with mortality
• GI, Pulmonary: 50-55%
• Urinary tract: 30%
Outcome according to source of sepsis
Antibiotic therapy
• The administration of effective intravenous
antimicrobials, ideally within the first hour and at
most w/in 6 hours, should be the goal of therapy.
– Each hour delay in achieving administration of
effective antibiotics is associated with a measurable
increase in mortality in a number of studies
– Time To Administration of appropriate antimicrobial
therapy one of the strongest predictors of outcome
Time to antibiotic administration and outcome
Which antibiotics to use?
It’s important to get it right the first time! Inappropriate empiric
therapy associated with worse outcome
Who gets inappropriate therapy?
Lots of people: up to 40% in studies; 15-30% at OHSU
MRSA
MRSA and VRE often not covered in
empiric regimen when indicated
E coli covered appropriately more
VRE often than other organisms
Which antibiotics to use?
• Consider:
– the most likely source/clinical syndrome
– drug allergies
– recent receipt of antibiotics
• Especially important in heavily abx exposed
Heme/Onc/BMT
– underlying diseases
– susceptibility patterns of pathogens at OHSU
– documented prior colonizers or infections
Which antibiotics to use?
• Initial selection of antimicrobial therapy should
be broad enough to cover all likely pathogens.
• It is generally not an appropriate strategy to
restrict antibiotic administration in the initial
therapy for this patient population.
• As soon as the causative pathogen has been
identified and susceptibilities known, de-escalate
by selecting the most appropriate antimicrobial
agent that covers the pathogen, is safe and costeffective.
Resistance of select pathogens in the US 2009-2010
40-50% of Staph aureus = MRSA
Note relatively high rate of MDROs
among certain GNs – implications
for empiric therapy in the septic
patient
Resistance among common GNs in US,
2009-2012
Note high rates of P aeruginosa resistance to imipenem
E coli very sensitive to carbapenems
Will vary from institution to institution: appropriate empiric
therapy requires knowledge of institution’s antibiogram
OHSU Antibiograms
https://o2.ohsu.edu/pharmacyservices/antibiograms.cfm
A word about extended-spectrum
beta-lactamase (ESBL) gram negatives
• Enzymes that confer resistance to most betalactam antibiotics, including penicillins,
cephalosporins, and aztreonam
• Found exclusively in gram negative organisms
– Klebsiella spp (K pneumoniae, K oxytoca)
– E coli
– Others:
• Enterobacter
• Proteus
• Acinetobacter
Rates vary widely across US
Highest on East Coast
Relatively low in Northwest US
Management of ESBL gram negatives
• The only current proven empiric therapeutic option
for severe infections caused by ESBLs are
carbapenems
– No clear difference between imipenem and meropenem
• Empiric therapy with cefepime or
piperacillin/tazobactam associated with higher
mortality than empiric therapy with carbapenem
(Chopra et al, AAC, 2012; Tamma et al, CID, 2015)
• OK to change coverage once susceptibilities known
Pharmacology considerations
Bacteriostatic vs bactericidal
“static” = prevents growth; “cidal” = kills bacteria
Some can be both:
At high concentrations, static agents can be cidal
Macrolides generally static but cidal vs Strep pneumoniae
Linezolid cidal against Strep spp; static against Staph and ECOC
Historically, cidal agents have been preferred
in acutely life-threatening diseases:
meningitis, endocarditis, bacteremia
(daptomycin)
(tigecycline)
(clindamycin)
(linezolid)
Not all bactericidal agents are created equally!
Superiority of beta-lactams over vancomycin for MSSA infections
No efficacy difference cefazolin vs
nafcillin for MSSA bacteremia
Although cefazolin better tolerated!
Pharmacology considerations
Time vs concentration dependent killing: basis for
prolonged/extended beta-lactam infusion
concentration dependent
time dependent
Prolonged infusion beta-lactam
antibacterial therapy
• Rationale:
– beta-lactam antibiotics demonstrate time-dependent
killing
– prolonged infusion may improve microbiologic and
clinical cure by increasing the time spent over the
MIC of the organism compared to intermittent dosing
– Intuitively useful when pathogens demonstrate higher
MICs
– Can be done as 24 hour continuous infusion or
extended infusion over 3-4 hours
– Hey, yeah, that’s really interesting but does it work in
real life?
Not powered to
detect survival
effect
Prolonged infusion of beta-lactams:
• No clear answers yet
– Studies limited by small size, heterogeneous patient
populations, mixed microbiology, endpoints
• If benefit, likely limited to
– certain organisms: P aeruginosa or organisms with high MICs, or
– particularly vulnerable populations (immunocompromised
hosts)
• No obvious toxicities noted
• Currently being done routinely in ICU for
piperacillin/tazobactam only
– Not yet cefepime, carbapenems
What about combination therapy?
• Why use combination therapy:
– Delay emergence of resistance: TB, HIV
– Synergistic activity -> better outcome : amp+gent
for enterococcal endocarditis
– Improve likelihood of picking the right agent: if
you have a high rate of Multi Drug Resistant
Organisms
What about combination therapy?
• Combination therapy for suspected or known Pseudomonas
aeruginosa or other multidrug-resistant Gram negative pathogens,
pending susceptibility results, increases the likelihood that at least
one drug is effective against that strain and positively affects
outcome
– Overall benefit depends on local rate of resistance
• At OHSU, relatively low rates so utility of combination therapy is limited
– Overall benefit may also depend on the host: neutropenic patients
with overwhelming gram negative sepsis
– Addition of tobramycin should be considered in neutropenic hosts
with suspected or proven gram negative sepsis
• Once sensitivities are known, clinical trials indicate that there is no
reason to continue combination therapy for GNRs - monotherapy
with appropriate antibiotic is fine (Cochrane Review 2014; Lancet Inf Dis August
2004)
– Exception: aminoglycoside monotherapy generally not recommended
So what’s doing in the Micro lab? A word
about Verigene
• Background
– Brought to OHSU May 2014
– An automated rapid nucleic acid test
– Run after blood culture trips +
• Run on either gram positive or gram negative machine
depending on gram stain
• Turn-around time of ~1-2 hours
Verigene – Gram negatives
Detectable Organisms
Acinetobacter spp.
Enterobacter spp.
E. Coli
Klebsiella oxytoca
Klebsiella pneumoniae
Citrobacter spp.
Proteus spp.
Pseudomonas aeruginosa
• Gram negatives not
detected:
– Stenotrophomonas
– Serratia
– Anaerobes
• Fusobacterium
• Bacteroides
Verigene – Gram negative resistance
markers
1. CTX-M (ESBL)
2. Carbapenemases
• Due to variety of resistance mechanisms present in gram
negatives, absence of molecular resistance marker in
Verigene report does not necessarily predict sensitivities
by traditional phenotyping so generally advisable to wait
for sensitivity report before changing therapy if your
patient is doing well
– Presence of resistance marker should influence choice of
antibacterial agent while awaiting phenotypic sensitivity
report
Verigene – Gram positivies
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•
•
•
•
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• Not detected:
Detected:
– Misc enterococcus spp
Listeria
– Misc Strep spp
Staph aureus
– Micrococcus
Coag Neg Staph
Resistance markers:
E faecalis, E faecium
1. mecA (methicillin resistance Staph)
2. vanA, vanB (vancomycin resistance
Strep:
Enterococcus)
– Pneumoniae
Limited number of resistance
mechanisms in gram positives so
– Pyogenes (GAS)
absence of these in molecular testing is
– Agalactiae, anginosus
more reliable predictor of final
susceptibilities compared to gram
negatives
GRAT question 1
• Which of the following statements pertaining
to healthcare associated infections (HAIs) is
true?
A. The majority (>50%) of bacteremic episodes
are caused by gram negative bacilli
B. Coagulase negative staphylococci are the
single most common cause of CLABSIs
C. Klebsiella pneumoniae is the organism most
commonly isolated in the setting of a CAUTI
D. Candida species are a common cause of VAP
GRAT question 2
• Which of the following bug/drug
combinations is most appropriate before
having results of formal susceptibility testing
when treating a bacteremic patient?
A.
B.
C.
D.
E.
Staph aureus: nafcillin
E coli: levofloxacin
Enterococcus faecalis: ampicillin
Enterobacter cloacae: piperacillin/tazobactam
Enterococcus faecium: ampicillin
GRAT question 3
• Which of the following is true?
A. A microbiologic diagnosis will be definitively made in the
vast majority (80-90%) of patients with clinical sepsis
B. Skin/soft tissue infections are the most common source of
sepsis in patients presenting to ERs from the community
C. Urosepsis is associated with mortality rates of 50-60%
D. Sepsis of GI tract/abdominal sources is associated with
the highest mortality rates compared to other sources
E. Delaying initiation of appropriate antibiotic therapy is not
a factor in overall outcome since our supportive care
measures are so good
GRAT question 4
• You are taking care of a patient whose blood
cultures are growing an aerobic gram negative
rod that was not identified by Verigene. Which is
the most likely?
A. Pseudomonas aeruginosa
B. E coli
C. Bacteroides fragilis
D. Fusobacterium
E. Stenotrophomonas maltophilia
GRAT 5
• Which of the following statements regarding therapy of
gram negative rod bacteremia is true?
A.
Combination beta lactam + aminoglycoside therapy improves
mortality compared to beta lactam monotherapy when treating
sepsis due to infection with a beta lactam susceptible organism
B. Prolonged/extended infusion of beta lactams has been
conclusively demonstrated to improve survival compared to
standard intermittent dosing
C. Empiric therapy with either cefepime or piperacillin/tazobactam
for an isolate identified as an ESBL by molecular testing is
appropriate pending susceptibility testing
D. Prolonged/extended infusion of beta lactams has demonstrated
improved rates of microbiologic and clinical cure of infection
compared to standard intermittent dosing