Sepsis/SIRS/MODS Flashcards
Which molecule brought by albumin is protective of the endothelial glycocalyx?
Erythrocyte-derived sphingosine-1-phosphate (Suppress matrix metalloproteinase)
What are components of the immunosuppression during sepsis?
Dysregulated compensatory anti-inflammatory response, lymphocyte exhaustion, increased tolerance to endotoxins, dyregulated expansion of T-regulatory cells
Name determinants of immunoparalysis in sepsis (6)
Macrophage deactivation Negative regulatory mediators Increased apoptosis Increased anti-inflammatory mediators Altered energy uptake Suppression of immune cells
Name risk factors for antimicrobial resistance (6)
Antibiotic within the past 3 months
Environment with high frequency of resistance (Hospital, community)
Immunosuppressive therapy or disease
Bacterial translocation from GI tract
Invasive procedures
Placement of foreign material with surface conductive to bacterial colonization
Name the two bacteria that are the major part of GI microflora
Enterococcus (Gram +) and E.coli (Gram -)
Define MDR, XDR and PDR
MDR: Resistance to 3 or more antibiotic families to which the antibiotic is naturally susceptible
XDR: Sensitivity to only 1 or 2 antibiotics
PDR (Pandrug resistance): Resistance to all antibiotic families
Define a nosocomial infection
Infection that the patient acquired in the hospital, arising more than 48 hours after hospital admission, within a week of discharge or within a month of surgery
What is the decline in survival per hour of antibiotic delay in septic shock (people)?
7.6%
Which type of antibiotics can have antagonistic effects in combination therapy?
Combination of a drug that inhibits ribosomes (chloramphenicol, tetracycline, erythromycin) with a drug that relies on protein synthesis for the bactericidal activity (Beta-lactam, fluoroquinolone)
Give an example of a synergic antibiotic combination therapy
Ampicillin with gentamicin (Cell wall agent promote entry of gentamicin into cell) for enterococcus, enterobacter, pseudomonas and MRSA
What are three major factor to consider in the dosing regimen of antibiotics?
MIC of the infecting microbe
Plasma and tissue drug concentration and the site of infection
Impact of microbial and host factors impacting the drug concentration at site of infection
Time dependent antibiotic have a ___________ (reversible/irreversible) action on their target?
Reversible (Cell wall inhibitors, folic acid inhibitors, bacteriostatic atbs)
What is the appropriate magnitude of Cmax/MIC in concentration-dependent antibiotics?
10-12
What is the best measurement of effectiveness for concentration-dependent antibiotic? What value is associated with bacteria killing and decreased resistance?
Area under the inhibitory curve. AUIC >100-125 generally associated with bacterial killing and decreased resistance
What are the three levels (Blood vessel barrier) of drug penetration in normal tissues?
1) Sinusoidal capillaries; No barrier to bound or unbound drugs (Adrenal cortex, pituitary gland, liver and spleen)
2) Fenestrated capillaries; Pore permeable to unbound drugs (Kidneys, endocrine glands). **Protein bound drugs will not diffuse as well, and MIC might be underestimated (Doxycycline)
3) Continuous (Non-fenestrated); Tight junction prevent drug movement (Brain, CSF, testes, prostate, muscles)
____________ (lipid/water) soluble antibiotics penetrate better in organs with continuous capillaries?
Lipid (30-80% penetration vs 2-30% in bronchial secretion)
What are the two main causes of expansion of volume of distribution in critical patients?
Septic shock and trauma (Third spacing/edema)
What is the inoculum effect?
Larger inocula have a higher bacterial load/target, this require more drug molecules
Larger inocula have a greater risk of spontaneous mutation and produce more destructive enzumes
How can nephrotoxicity to aminoglycoside be prevented?
1) Once daily administration with trough <1.2mg/ml
2) Hydration of patient
3) Morning administration (to promote drinking)
4) Avoid nephroactive drugs
What are the benefit of antimicrobial de-escalation?
Cost minimization, reduction in adverse events, reduced risk of antimicrobial resistance, decreased incidence of infections related to antimicrobial use (C. difficile diarrhea, superinfection, fungal/Candida)
Which families of antibiotics are included in beta-lactam antimicrobials?
Penicillin, cephalosporin, carbapenem
What are two types of resistance against beta-lactam antibiotics?
Beta-lactamase produciton
Change in cell wall permeability (mecA gene modifies PBP2a in methicillin resistance)
What are the benefits of meropenem over imipenem?
More soluble, less nephrotoxic, can be administered quicker
What is the adaptive resistance of bacteria?
Capacity to decrease the update of an antibiotic after the first dose, more likely if low Cmax after administration (e.g. aminoglycoside and pseudomonas)
What is the inhibitory quotient?
Cmax/MIC; Must be > 8-12 for effective bacterial killing of concentration dependent antibiotics
What conditions can alter the volume of distribution?
Vascular leak syndrome, edematous states, hypoalbuminemia, SIRS, mechanical ventilation, extensive burns, severe trauma, aggressive intravenous fluid therapy, parenteral nutrition
Name risk factors for aminoglycoside-induced nephrotoxicity?
Advanced age, duration of therapy, fever, volume depletion, dehydration, nephroactive drugs, preexisting kidney disease, potassium/magnesium depletion
Name adverse events related to aminoglycoside administration
Neuromuscular paralysis- Interference with release and uptake of ACh in the NMJ and inhibition of calcium movement into the nerve terminal. Can be treated with calcium infusion or cholinesterase
Ototoxicity/vestibulocochlear toxicity
Nephrotoxicity: Uptake by proximal tubular cells and high concentration in lysosomes cause cell disruption. Single-daily-dosing and monitor for granular/cellular cast and proteinuria/glucosuria recommended
What are strategies to avoid nephrotoxicity with aminoglycoside
1) Single daily dosing (In the morning)
2) Hydration of patient
3) Therapeutic drug monitoring with drug free interval of 2-4 hrs
4) Discontinuation of nephroactive drugs
5) Cautious use in patients with variable volume of distribution (Sepsis, edema, burns,…)
What is the target of action for fluoroquinolone?
DNA gyrase (primary target) and topoisomerase IV
Define postantibiotic effect.
Period of time after serum drug concentration falls below the MIC that bacterial growth continues to be inhibited
(E.g. fluoroquinolones, aminoglycosides)
What are the mechanisms of resistance against fluoroquinolones
1) Mutation of the target- Gene mutation of DNA gyrase (Gram -) and topoisomerase IV (Gram +)
2) Increased expression of efflux pump (E. Coli and Salmonella)
3) Altering outer membrane porins to prevent passive diffusion of the drug into cytoplasm
4) Plasmid
Fluoroquinolones have ___________ (higher/lower) concentration in lungs, bile, prostate and urine compared to serum.
Higher
Fluoroquinolones are ________ (Ineffective/effective) against intracellular organisms,
Effective- Accumulation in neutrophils and macrophages, activity against mycoplasma, mycobacteria, chlamydia and brucella
Administration of oral antiacids ________ (Increase/decrease/does not affect) absorption of fluoroquinolones and food ________ (Increase/decrease/does not affect) its absoprtion.
1) Decrease
2) Does not affect (but delays peak serum)
How do fluoroquinolones cause seizures?
Inhibition of GABA receptors and stimulation of NDMA receptors
How do fluoroquinolone cause cartilage damage in juvenile animals?
Inhibition of proteoglycans synthesis, chelation of magnesium, inhibition of mitochondrial dehydrogenase activity
Name three major adverse events associated with fluoroquinolone use.
- Seizures and neurological abnormalities
- Cartilage defect in juvenile patients
- Retinal degeneration and blindness in cats
Name three major adverse events associated with fluoroquinolone use.
- Seizures and neurological abnormalities
- Cartilage defect in juvenile patients
- Retinal degeneration and blindness in cats
Which parameters are used for SIRS criteria?
Temperature
Heart rate
Respiratory rate
WBC count
What are the parameters for SIRS criteria in dogs?
T <100.6 or > 102.6
HR >120
RR>20
WBC >16K, <6K or band >3%
What are the parameters for SIRS criteria in cats?
T <100, > 104
HR <140, > 225
RR >40
WBC <5K or >19K
What is the definition of sepsis based on Sepsis-3?
Life-threatening organ dysfunction secondary to an infectious process
What is the definition of septic shock based on sepsis-3?
Life-threatening circulatory, metabolic and cellular dysfunction secondary to an infectious agent.
Clinically, requirement for vasopressor or lactate >2mmol/L despite normovolemia
