Download summary of guidelines for traditional broth and instrument systems

Sepsis
C604
1-28-2015
Bryan H. Schmitt D.O.
E-mail: [email protected]
Robbins sections for review
• Systemic effects of inflammation
(Chapter 3): 99-100
• Shock
(Chapter 4): 131-134
CLINICAL AND PATHOLOGIC ASPECTS OF BLOOD
STREAM INFECTIONS
Bacteremia = presence of bacteria in blood
Clinical patterns of bacteremia
• Transient
• Intermittent
• Continuous
Fungemia, candidemia, viremia,
parasitemia etc.
Old terms
• Septicemia = bacteremia and clinical
manifestations of infection
• “Blood poisoning”
Sepsis Definitions:
• Sepsis
Implies presence of pathogenic microorganisms in the
bloodstream (usually bacteremia) with signs and
symptoms of infection, such as fever, chills, and
tachycardia
• Septic shock
Indicates the presence of hypotension with sepsis
• Severe sepsis
Characterized by septic shock with organ system failure (or
dysfunction) -- associated with 20% to > 50% mortality
SYSTEMIC INFLAMMATORY RESPONSE
SYNDROME (SIRS)*
• Not all patients who appear to have sepsis are infected
• Manifestations same as for sepsis
• Non-infectious causes include: pancreatitis, ischemia,
multiple trauma and tissue injury, administration of tumor
necrosis factor & other mediators of inflammation.
• When due to infection, the terms sepsis & SIRS are
synonymous.
(*Bone et al., 1998. Definitions for sepsis and organ failure. Chest. 101:1644-1655
[consensus conference recommendations]; see also Mandel et al 2005, p 906)
Sepsis/SIRS
Bacteremia
Other
SIRS
Infection Fungal
Trauma
Sepsis
Parasit.
Vir.
Other
Burns
Pancreatitis
*Severe Sepsis/SIRS includes some evidence of organ failure
Septic shock
•
•
•
•
•
•
Overwhelming Systemic infection
“ENDOTOXINS”, i.e., LPS (Usually Gram-)
Gram+ (Listeria)
FUNGAL
Viral (rarely)
“SUPERANTIGENS”, (Superantigens are polyclonal Tlymphocyte activators that induce systemic inflammatory cytokine
cascades; “toxic shock” superantigens by S. aureus are the prime
example.)
ENDOTOXINS
• Usually Gram(-) Rods
• Major component of cell membrane
• Also called “LPS”, because they are Lipo-Poly-
Saccharides
• Elicits strong immune response, LIPID-A is major
component involved
• Enters bloodstream through secretion and through
destruction of cell membrane
FACTORS THAT MEDIATE THE SEPSIS
SYNDROME
Microbial factors (e.g., endotoxin or lipopolysaccharide of
GNR’s; peptidoglycan of GPC cell walls, toxins, fungal
antigens and others)
Chemical mediators of inflammation and other host factors
(Robbins, Chap. 2) - Examples:
• Cytokines
– Tumor necrosis factor (TNF-) in particular
– Interleukin (IL)-1; IL-6, IL-12
• Chemokines
– IL-8
– Macrophage inflammatory protein (MIP)-1
• Lipid mediators
– Prostaglandins
– Leukotrienes
SEPTIC shock events
(linear sequence)
• SYSTEMIC VASODILATION (hypotension)
• ↓ MYOCARDIAL CONTRACTILITY
•
•
•
•
•
DIFFUSE ENDOTHELIAL ACTIVATION
LEUKOCYTE ADHESION
ALVEOLAR DAMAGE (ARDS)
DIC
VITAL ORGAN FAILURE CNS
MULTIPLE ORGAN DYSFUNCTION
SYNDROME (MODS)
Organ failure or dysfunction, a frequent complication of SIRS (occurs in
~ 30% of patients with sepsis).
Manifestations may include:
Brain:
Confusion, delirium, stupor, coma
Heart:
Depressed myocardial contractility; heart compensates by
dilating and beating faster to increase output; Actual cardiac
output drops
Clotting: Endothelium damaged with widespread microvascular
thromboses, or disseminated intravascular coagulation (DIC).
(Consumption of platelets and clotting factors).
Lungs: Pulmonary congestion and edema (acute
respiratory distress syndrome (ARDS) “shock lung”
Acute pulmonary edema (& congestion) in a
patient with ARDS who died of sepsis.
Acute pulmonary edema in a patient with ARDS
who died of sepsis.
H&E of lung of patient with ARDS who died of
sepsis. Note diffuse alveolar damage with
hyaline membranes --
Multiple Organ Dysfunction Syndrome
(Continued)
Kidney:
Liver:
G.I.tract:
Endocrine
Skin
lesions:
Acute renal failure (acute tubular necrosis)
Bile stasis, focal necrosis and jaundice
Hemorrhagic necrosis of mucosa probably due to
ischemia (at least in part) poor
perfusion, clot formation.
Stress hormones (eg. cortisol, catecholamines,
glucagon circulate at high levels)
Petechiae, purpura
Kidney with acute, tubular necrosis
(H&E)
Liver with acute passive congestion
Small intestine with full-thickness necrosis
Waterhouse-Friderichsen Syndrome
SOURCES OF ORGANISMS
IN BACTEREMIA
• Most common sources
– IV catheters 25%
– Genitourinary tract (UTI) 25%
– Respiratory tract (pnemonia) 20%
– Intraabdominal foci 10%
• Source not apparent in 20-25% of
patients
Microorganisms in Bacteremia
• ≥ 660,000 episodes of bacteremia in US/year
• ~ 10% of all blood cultures drawn in many hospitals are
positive
• Gram-positive bacteria in 52% of cases
• Gram-negative bacteria in 38% of cases
• Fungi in ~ 5% of cases (mostly Candida species)
• Frequency of anaerobes declined in 1990’s to ~ 1% but
increased slightly recently
• ~ 5% of bloodstream infections are polymicrobial
Refs: Martin 2003. NEJM 348:1546, & Llewelyn 2007. CID
44:1343
ORGANISMS COMMONLY INVOLVED
IN BACTERMIA: OUR EXPERIENCE
• Staphylococci including MRSA; we are also
seeing increasing frequency of enterococci
and streptococci
• Gram- negative rods; esp. E.coli, Klebsiella,
Pseudomonas, and Enterobacter – Serratia
• Anaerobes: esp. species of Bacteroides
fragilis group
• Fungemia: Candida most common
Bacterial Blood Isolates
Eskenazi 2011 (1609)
• GNRs
1.
2.
3.
4.
5.
6.
E. coli (98)
K. pneumoniae (51)
P. aeruginosa (35)
E. cloacae (24)
P. mirabilis (18)
K. oxytoca (18)
• GPCs
1.
2.
3.
4.
5.
6.
7.
CNS (619)
S. aureus (135)
MRSA (158)
E. faecalis (76)
Corynebacterium. (44)
S. pneumoniae (25)
S. agalactiae (19)
Yeast Isolates
Eskenazi 2009 (75)
1.
2.
3.
4.
Candida albicans (40)
Candida glabrata (37)
Candida tropicalis (9)
Cryptococcus neoformans (7)
Blood Culture Time to Detection
( 569 positives in 2011 )
•
•
•
•
•
24 hours (503)
48 hours (36)
72 hours (20)
96 hours (5)
120 hours (5)
88 % positive on Day 1
2 % positive on Day 4/5
Common “Contaminants”
•
•
•
•
•
1.
2.
3.
4.
5.
CNS (coagulase negative staphylococci)
Propionibacterium
Corynebacterium
Bacillus
alpha-hemolytic streptococci
COMMON “CONTAMINANTS”
Coagulase-negative staphylococci , Propionibacterium
acnes, Corynebacterium spp., and Bacillus spp.
• In general, single cultures positive for these bacteria
represent contamination. **one blood culture is one
venipuncture**
• Mutiple, separate cultures growing one of these
isolates are more likely to indicate clinically significant
bacteremia.
• But, all contaminants are capable of causing disease;
coag- neg. staphylococci especially important in
patients with indwelling vascular and CNS catheters
*And neonates
PROGNOSIS IN PATIENTS WITH BACTERMIA
• Higher mortality for Pseudomonas or fungal sepsis than
for E. coli or Klebsiella infections
• Mortality 25 – 50% with aerobic Gram-negative rods
• Gram-positive bacteria; fewer mortalities with certain
exceptions (VRE, MRSA)
• Mortality 25 – 50% in Bacteroides bacteremia
• C. septicum bacteremia; >50% mortality reported but
(underlying malignancy often present [e.g., colon ca.])
• Fungi; rates of fungemia increasing; mortality with
Candida is high
PATHOGENESIS
• Most bacteremic infections are endogenous
• Patients at higher risk for bacteremia
– Neonates
– Older individuals
– Patients with malignancy and/or neutropenia; antibiotic
Rx may predispose to GPC’s; fungemia
– Intravenous drug abusers
– AIDS patients, and patients with:
– Liver or splenic dysfunction
– Transplant; immunosuppressive Rx
– Intensive care units; long-term care facilities
– Foreign bodies; instrumentation; various kinds of
catheters
ICU patient with intravascular & urinary catheters
Hand-washing: most important in prevention of
nosocomial infections
DIAGNOSIS OF BACTEREMIA
Diagnostic importance of blood cultures
– High mortality if patient untreated or inappropriate
antibiotics
– Blood cultures needed to establish an etiology
– Obtain pathogen for identification, antimicrobial
susceptibility testing, optimization of antimicrobial
therapy
Recommendations/Indications
• Draw blood cultures before antibiotics are
administered
•
•
•
•
Fever >38 C
Or hypothermia (<36 C)
Leukocytosis (>10,000 WBC)
Granulocytopenia (<1000 neutrophils)
Timing of Blood Cultures
• Just before fever spike is best
• At fever spike is 2nd best
• Peripheral vein if possible- heparin is
inhibitory and “lines” are colonized
• Draw at least 1 hour apart if possible
What is a Blood Culture?
• Blood obtained from a SINGLE VENIPUNCTURE
and inoculated into media
• 1 bottle, 2 bottles or multiple bottles/plates
etc.
• 1 venipuncture = 1 blood culture
Bactec 9240 Blood Culture Instrument
Door Opened -- Bottles in
Incubator/Fluorescence
Detection System
Blood Culture Media
• Example: BACTEC FX System
• Bacteria present metabolize nutrients and produce
carbon dioxide
• A sensor dye in the bottle reacts with CO2
• BACTEC photodetectors measure fluorescence
• Measurements occur every 10 minutes
• Detection in 5 days or less
Some Technical Variables Affecting
Blood Cultures
• Resins in broth bind antibiotics & can increase
detection of some microorganisms.
• Agitation of media (during incubation) increases
yield & speed of detection
• Anticoagulant: sodium polyanetholsulfonate (SPS)
in media -- SPS interferes with phagocytosis,
inhibits complement & lysozyme, inactivates
aminoglycosides, & inhibits N. gonorrhoeae, & P.
anerobius
Resins
• At IU Hospital the introduction of resins
resulted in 18 % increased recovery of isolates
receiving antibiotics
• There is a similar increase in recovery for
patients not on antibiotics
Most Common
Blood Culture
Adult Aerobic
Adult Lytic
Contamination is Controlled by Proper Skin
Antisepsis Before Venipuncture.
Skin Preparation -Scrub with 70% alcohol,
then
1-2% tincture of iodine
Venipuncture -Gloves must be
sterile when vein
palpated
VOLUME OF BLOOD CULTURED
This is the single most important variable in
recovering microorganisms from blood of
bacteremic or fungemic patients!
• Adults: 20 - 30 ml optimal
• Infants and small children; > 1 ml needed
NUMBER OF BLOOD CULTURES
Not more than 2
to 3 per 24
hours!
Of cases ultimately
proven to have
positive cultures:
• 80% positive with
the 1st set
• 89% with the 2nd set
• 99% positive with
the 3rd
Number of Blood Cultures
• 2 or 3 blood cultures per 24-hour period
separated by time
• If endocarditis or severe sepsis suspected- do
2 or 3 blood cultures (venipunctures)
immediately and start antibiotics
SPECIAL Blood Culture PROCEDURES REQUIRED:
EXAMPLES
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Brucellosis
Leptospirosis
Tularemia (Francisella tularensis)
Nutritionally variant streptococci
Cell wall deficient forms
Cat scratch disease (Bartonella henselae)
Mycobacterium spp.
PATHOGENESIS OF INFECTIVE
ENDOCARDITIS
• Bacteremia a prerequisite - e.g., from gut, oropharynx,
or skin; or dental/surgical procedures, IV drug abuse,
catheters
• Factors associated with I.E. include mitral valve
prolapse, or congenital heart disease; rheumatic heart
disease is now less common than in past.
• Prosthetic heart valves are prominent predisposing
factors.
INFECTIVE ENDOCARDITIS
• Colonization of heart valves with bacteria, fungi,
rickettsia, chlamydia or possibly viruses with
• Formation of friable, infected vegetations leading to
valve injury
• Two types:
• Acute - highly virulent organisms, e.g., S. aureus
• previously normal valve; acute onset; >50% die
• Subacute - organisms of low virulence, e.g. viridans
strep, enterococci, GNRs, anaerobes, GPRs, fungi
• slower onset, diffuse clinical findings, fewer die
MORPHOLOGIC FINDINGS
• Acute infective endocarditis - leaflet perforation;
myocardial abscess
• Above findings rare with subacute infective
endocarditis
• With IV drug abuse, vegetations often acute and on
right-sided heart valves
• Morphologic findings in body sites other than heart:
• Janeway lesions, Osler nodes, Roth spots, splinter
hemorrhages
Staphylococcus aureus endocarditis involving mitral
valve
Staphylococci in Gram-Stained Smear
DIAGNOSIS OF INFECTIVE ENDOCARDITIS
AND OUTCOME
• Clinical diagnosis confirmed by blood cultures
– 3 sets of blood cultures per 24 hrs should suffice
– 20-30 ml of blood per draw (i.e., per blood culture
set)
• Blood cultures should be positive in > 95% of cases if
the recommendations followed.
• Antimicrobial treatment aided by I.D. & susceptibility
testing of specific microorganism involved
• Five-year survival with early diagnosis and appropriate
Rx = 50% - 90%.
POSITIVE BLOOD CULTURES:
Processing Positive Bottles
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•
•
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Visual inspection of bottles
Gram-stain
Other stains (e.g., Acridine Orange)
Preliminary results called to clinician ( Gram+ coccus vs
Gram – rod)
• Subculture onto aerobic & anaerobic solid plating media
• Rapid susceptibility testing & identification
• Molecular methods (e.g., peptide nucleic acidfluorescence in-situ hybridization (PNA-FISH) for GPCs
and yeast; RT-PCR for MRSA; and others
Current Laboratory Detection
Methods of BSIs
Blood Draw from Patient
After 12-14 h incubation
(24-48 h from time of draw),
bacteria grow, lab begins ID
Incubation on Blood
Culture Monitoring
System (6-18 h)
After 2-24 h
(48 h total) ID is
reported to physician
via chart
Slide from Dr. Nate Ledeboer, MCW/DynaCare/Milwakee, WI
Notify ordering
physician
of positive culture and
plate for ID and
susceptibility
48-72 h from time of draw,
full ID and susceptibility
reported to physician
PNA probes target ribosomal
RNA inside cells
PNA FISH = Peptide Nucleic Acid
Fluorescence In Situ Hybridization
PN1870A
S. aureus/CNS PNA FISH
S. aureus
S. aureus
CNS
C-N S
Non-staphylococci
C. albicans (green), C. tropicalis (yellow); C glabrata/krusei (red)
Gram-Positive BSI
Rapid Diagnostic Tests
FDA Cleared Tests:
AdvanDx (PNA FISH): S. aureus/CNS, E. faecalis/OE
Nanosphere’s Gram-Positive Blood Culture Test (BC-GP)
BioFire/Film Array GP/GR/Yeast blood culture test
Verigene Gram-Positive Blood Culture Nucleic Acid Test (BC-GP)
Staphylococcus aureus
Staphylococcus epidermidis
Staphylococcus lugdunensis
Staphylococcus spp.
Genus
Streptococcus spp.
Listeria spp.
mecA
Resistance
vanA
vanB
Species
Streptococcus pneumoniae
Streptococcus anginosus Group
Streptococcus agalactiae (GBS)
Streptococcus pyogenes (GAS)
Enterococcus faecalis
Enterococcus faecium
Gram-Negative BSI
Rapid Diagnostics Tests
FDA Cleared Tests: AdvanDx (E. coli/P. aeruginosa, GNR Traffic Light)
Tests in Development: Nanosphere Verigene BC-GN, BioFire BCID
Verigene Gram-Negative Blood Culture Nucleic Acid Test (BC-GN)—In Development
Genus
Acinetobacter spp.
Escherichia coli
Proteus spp.
Klebsiella pneumoniae
Citrobacter spp.
Enterobacter spp.
KPC
NDM
Resistanc
e
CTX-M
VIM
IMP
OXA
Specie
s
Klebsiella oxytoca
Pseudomonas aeruginosa
Serratia marcescens
EFFECTS ON HEALTH CARE COST (Rapid BC IDs
Available 24/7)
Hospitalization cost
reduction of
$19,547/patient
Estimated cost savings of
~ $18 million annually
theoretical
64
Perez KK, et al. Arch Pathol Lab Med. 2012
•
•
•
•
Issues
1. Molecular Testing is expensive but rapid
2. Lab cost go up (thousands)
3. Overall, patient cost go down (millions)
4. Length of Stay, morbidity and mortality go
down
• 5. The “system” saves money (millions) and
patient outcomes improve
• 6. “Silos” must come down: it is one lab and it
is one health care delivery system
• 7. Thousands spent in the lab budget can save
millions for the hospital system