HUNG Sepsis/SIRS Flashcards
Why do owners need to wear gloves when giving Chloramphenicol?
May cause idiosyncratic aplastic anemia
Which ampicillin is antipseudomonal penicillin?
Piperacillin-tazobactam
True or False: Most of the NE produced by adrenal glands are converted to epinephrine after being released to the blood stream.
True
About 80% NE are converted to epinephrine
Name a condition when “spillover” of NE can be observed.
Heart failure
where chronically elevated sympathetic tone cause NE “spillover” from the synaptic cleft into the bloodstream.
What are the two major pre-synaptic adrenoreceptors?
𝜶2A/D - inhibitory effect
𝜷2 - stimulatory effect
What are the 9 subtypes adrenoreceptors?
𝜶1A, 𝜶1B, 𝜶1D
𝜶2A/D, 𝜶2B, 𝜶2C
𝜷1, 𝜷2, 𝜷3
True or False: 𝜶1 receptors generally have stronger affinity to epinephrine than NE, while 𝜶2 receptors are the opposite.
False
True or False: 𝜷1 receptors have equal affinity to epinephrine and NE, while 𝜷2 receptors have much stronger affinity to epinephrine than NE.
True
𝜷2 receptors are pretty much exclusively to Epi
True or False: In most tissues, 𝜶1 receptor subtypes are junctional, and 𝜶2 receptor subtypes are extra-junctional.
True
Which 𝜶2 receptor subtypes locate at the pre-synaptic region and endothelium and cause vasodilation?
𝜶2A/D
Which G protein does 𝜶1, 𝜶2 and 𝜷 receptor subtypes usually couple with? are they stimulatory or inhibitory?
𝜶1: Gq/11 protein → activate phospholipase C → release non-mitochondrial intracellular Ca stores
𝜶2: Gi protein → inhibits adenylate cyclase → inhibit conversion of cAMP from ATP → inhibits protein kinase A → inhibit voltage-gated Ca channels
𝜷: Gs protein → activates adenylate cyclase → convert ATP to cAMP → activates protein kinase A → open voltage-gated Ca channels
True or False: 𝜶1A/D receptors are responsible for large arterial vasoconstriction, and 𝜶1B receptors are responsible for smaller arteries and arterioles as well as induces vascular smooth muscle growth and/or hypertrophy.
True
What is the main difference in the 𝜶 receptor subtypes distribution between artery and venous?
Artery: 𝜶1 receptors are junctional and 𝜶2 receptors are extra-junctional
Venous: 𝜶2 receptors are junctional and 𝜶1 receptors are extra-junctional → 𝜶2 receptors is the predominate one managing vasoconstriction
Which adrenoreceptors on the endothelium stimulate NO production and subsequent vasodilation?
𝜶2A/D
What is the density of 𝜶1 receptor subtypes on the myocardium compared to 𝜷?
𝜶1A receptor subtypes 10-15% of 𝜷 receptors
𝜶1A receptor subtypes is responsible for about 25% of inotropy
True or False: 𝜷1 receptors activation at the heart increase inotropy (contractility), chronotropy (HR), lusitropy (relaxation) and dromotropy (AV node conduction).
True
What is the effect of 𝜷 receptors at the vascular system?
Vasodilation
What is the effect of 𝜶 receptors and 𝜷 receptors on the coronary system?
𝜶 receptors - vasoconstriction
𝜷 receptors - vasodilation
What is the predominant 𝜷 receptor subtypes on the endothelium?
𝜷2 receptor
Stimulation of which adrenoreceptors will cause renin release? which one will cause inhibition of renin release?
𝜷1 → renin release
𝜶2 → inhibition of renin release
Both receptors locate at JXA
What is the role of 𝜷-agonist receptor kinase (𝜷-ARK).
When 𝜷 receptors are activated, 𝜷-ARK are activated to catalyze the 𝜷 receptors
Sustained stimulation of 𝜷 receptors → lots of 𝜷-ARK → 𝜷 receptors down regulation (both 1&2)
The remaining 𝜷 receptors will become uncoupled
Uncoupled 𝜷1: mediate myocardial apoptosis
Uncoupled 𝜷2: inhibit apoptosis
Rank the following effects on each receptor
Drug: Dobutamine, Epinephrine, Norepinephrine, Phenylephrine
𝜶1&2
𝜷1
𝜷2
𝜶1&2: Epi = NE = phenylephrine > Dobutamine (weak)
𝜷1: Epi > Dobutamine > NE (weak) > phenylephrine (none)
𝜷2: Epi > Dobutamine (weak)> Epi (none) = phenylephrine (none)
True or False: When 𝜶 agonist is used alone, it can decrease cardiac output.
True
How does vasopressin increase blood pressure (3 mechanisms)?
1) Bind to V1 receptor → increase intracellular Ca level via phosphatidylinositol-bisphosphonate cascade
2) Bind to V1 receptor → inhibit IL-𝜷 induced production of NO and cGMP, as well as iNOS mRNA expression
3) Blocks K+-sensitive ATP channels (normally activated with endotoxemia) → decreasing the amount of K+ flux and subsequently opening the voltage-dependent Ca channels → increase intracellular Ca level
Comparing the dopamine and norepinephrine, what dopamine is not recommended as first-line vasopressor?
Patients on dopamine had higher rate of tachyarrhythmias and mortality rate.
Dopamine also failed to normalize BP in 40% ppl with septic shock.
In the study published by River and colleagues on NEJM in 2001 about the Early goal-directed therapy, what was the time frame and what were the goals they set to achieve?
Within 6 hours
CVP ≥ 8-12 mmHg
MAP ≥ 65 mmHg
SCVO2 ≥ 70%
UOP ≥ 0.5 ml/kg/hr
- Interventions: IV crystalloid bolus (20-30 ml/kg over 30 minutes), vasopressor, dobutamine, RBC transfusion, mechanical ventilation PRN
In the clinical trails associated with EGDT, what were the conclusions for ProCESS, ARISE and ProMISe studies?
- Three nails in the coffin of EGDT
ProCESS
- NEJM 2014
- 1351 patients
- Three groups: EGDT, Protocol-based standard therapy by dedicated team, usual care group (no dedicated team)
- Primary outcome: 60-day mortality → NO difference
- Secondary outcome: 90-day & 1-year mortality → NO difference
ARISE
- NEJM 2014
- 1600 patients
- Two groups: EGDT vs Control
- Primary outcome: 90-day mortality → no difference
- Secondary outcome: higher vasopressor requirement in EGDT group
ProMISE
- NEJM 2015
- 1260 patients
- Two groups: EGDT vs Control
- Primary outcome:
- Secondary outcome: 90-day mortality → no difference
What is the definition of sepsis in 2016 Sepsis-3?
Life-threatening organ dysfunction caused by
dysregulated host response to infection.
NO MORE severe sepsis
According to the 2016 Sepsis-3, how is the organ dysfunction determined?
Acute change in total SOFA score ≥ 2 points
Write down the SOFA scoring system.
Cardiovascular - MAP & vasopressor
Respiratory - PaO2/FiO2
Neurological - MGCS
Renal - creatinine
Hepatic - bilirubin
Hematologic - platelet
0-4 for each category, the higher the worse
What are the components of qSOFA?
Altered mental status (GCS ≤ 15)
SAP ( ≤ 100mg)
Respiratory rate (≥ 22 brpm)
Score of ≥ 2 out of 3 suggests a greater risk or poorer outcome
In 2016 Sepsis-3, what is the definition septic shock?
A subset of sepsis in which underlying circulatory and cellular/metabolic abnormalities are profound enough to substantially increase mortality.
What are the 4 clinical criteria for septic shock in 2016 Sepsis-3?
1) Sepsis
2) Adequate volume resuscitation
3) Vasopressor dependent hypotension (need it to maintain MAP ≥ 65 mmHg)
4) Lactate > 2 mmol/L
a clinical construct of sepsis with persisting hypotension requiring vasopressors to maintain MAP ≥65 mm Hg and having a serum lactate level >2 mmol/L (18 mg/dL) despite adequate volume resuscitation.
According to the 2018 The Surviving Sepsis Campaign Bundle, What are the 5 tasks that need to be accomplished with 1 hour?
1) Measure the Lactate. If lactate > 2 mmol/L, reassess
2) Obtain blood sample for blood culture
3) Administration broad-spectrum antibiotic
4) IV crystalloid 30 ml/kg as fluid resuscitation for hypotension or if lactate > 4 mmol/L
5) Start vasopressor is patient is still hypotensive after fluid resuscitation to maintain MAP ≥ 65 mmHg
According to 2021 Surviving Sepsis Campaign guidelines for sepsis & septic shock management, if a patient is shocky and sepsis is possible, what is the timing to administer antibiotic?
Within an hour of recognization
According to 2021 Surviving Sepsis Campaign guidelines for sepsis & septic shock management, what is their recommendation for using qSOFA as a single tool to screen for sepsis, septic shock?
Against
According to 2016 Surviving Sepsis Campaign guidelines for sepsis & septic shock management, what is the recommended fluid resuscitation plan for hypotensive patient?
30 ml/kg crystalloid within 3 hours of recognization
True or False: According to 2021 Surviving Sepsis Campaign guidelines for sepsis & septic shock management, it is recommended to use procalcitonin plus clinical evaluation to decide when to start antibiotics.
False
Against the use of procalcitonin to decide the starting time, but can be used to decide when to d/c antibiotic when optimal duration is unknown
According to 2016 Surviving Sepsis Campaign guidelines for sepsis & septic shock management, what is the recommendation for 𝜷-lactam administration in septic or septic shock patients?
Prolonged infusion
According to 2021 Surviving Sepsis Campaign guidelines for sepsis & septic shock management, what is their recommendation for restrictive vs liberal fluid strategies in the first 24 hours of resuscitation?
No conclusion - insufficient evidence
According to 2021 Surviving Sepsis Campaign guidelines for sepsis & septic shock management, what is their recommendation for recruitment maneuver?
It is recommended to use the traditional one, but the incremental PEEP/titration strategy is NOT recommended
- “traditional” recruitment maneuver consists of the application of sustained continuous positive airway pressure (e.g., 30–40 cm H2O for 30–40 s),
According to 2021 Surviving Sepsis Campaign guidelines for sepsis & septic shock management, what is their recommendation for restrictive vs liberal transfusion strategies?
Restrictive transfusion strategy is recommended
According to 2021 Surviving Sepsis Campaign guidelines for sepsis & septic shock management, what is their recommendation for pharmacologic venous thromboembolism prophylaxis?
Recommended
According to 2021 Surviving Sepsis Campaign guidelines for sepsis & septic shock management, what is the threshold to start insulin therapy?
When BG ≥ 180 mg/dL
According to 2021 Surviving Sepsis Campaign guidelines for sepsis & septic shock management, what is the indication for sodium bicarbonate administration?
Severe metabolic acidosis (pH ≤ 7.2) and AKI
What are the two structures that mammalian cells have but bacterial cell walls do not?
Cholesterol
Phospholipid
What are the two major classes of antimicrobial peptides (AMPs)?
Defensins
Cathelicidins
- AMPs comprise 3 main groups:
- digestive enzymes and peptides that disrupt the microbial cell membrane
- peptides that bind essential elements
- peptides that act as decoys for microbial attachment
List 5 PAMPs and 5 DAMPs.
PAMPs
- Gram (+): lipotechoic acids, flagellin, peptidoglycan, mannose-rich sugar
- Gram (-): LPS, porin in the outer membrane, peptidoglycan, mannose-rich sugar, flagellin
- Acid-fast bacteria (e.g. Mycobacterium spp): mycolic acid, arabinogalactan, peptidoglycan fragments
- Bacterial and viral genomes (RNA, DNA)
- Fungal chitin
- Parasite: glycophosphatidylinositol (GPI)
- polysaccharides
- lipoprotein
DAMPs
- High mobility group box 1 protein (HMGB-1)
- DNA, RNA
- Histone
- ATP/ADP
- S 100 protein
- Heat shock protein
- Interleukin-1𝜶
- Heparan sulfate
- Hyaluronic acid
- Fibrinogen, Fibronectin
- surfactant A
- Ferritin
- Uric acid crystals
- Amyloid peptide
What are three major families of pattern recognizing receptors (PRRs)?
TLRs
NLRs
RLRs
List 6 cells/places you can find TLRs.
Dendritic cells
Endothelial cells
Macrophages
Lymphocyte B cells
Natural killer cells
Epithelial cells
Fibroblasts
What are the two most important TLRs?
TLR 2 & 4
Because they can recognize diverse PAMPs
What is the one structures from both Gram (+) and Gram (-) that NOD1 and NOD2 can recognize?
Peptidoglycans
True or False: Inflammasomes activate Caspase-1, and lead to the synthesis of IL-1𝜷 and IL-18.
True
What are the two cells that TNF-𝜶 predominately produced by?
Activated macrophage
T-cells
Pro-TNF is expressed on the cell membrane, and the cleaved by TNF-converting enzyme (TACE/ADAM17) → yield soluble and membrane-bound forms
What are the two main transcription factors that are activated by PRRs and subsequently activate transcriptions of various inflammatory mediators?
AP-1
NF-ĸB
What are the functions of TNF receptor 1 and 2, respectively?
TNFR-1: mediate the proinflammatory and apoptotic pathways associated with inflammation
TNFR-2: promotion of tissue repair and angiogenesis
List 4 functions of TNF-𝜶 on the endothelium which leads to the clinical signs of sepsis.
1) Increase production of iNOS and COX-2 → vasodilation
2) Increase expression of endothelial adhesion molecules (e.g. E-selectin, intercellular adhesion molecule 1 (ICAM-1), vascular cell adhesion molecule 1 (VCAM-1)) → facilitate leukocyte transmigration
3) Induce expression of procoagulant proteins (e.g. TF)
4) Down-regulate anticoagulant proteins (e.g. thrombomodulin)
Name 4 pro-inflammatory interleukins that NF-ĸB activates.
IL-1, IL-6, IL-8, IL-12
Which interleukins can induce the production of IL-1 receptor antagonist protein (IRAP-1) and soluble TNFR?
IL-10 (anti-inflammatory)
List 8 characteristics of acute phase response.
Fever
Neutrophilia
Activation of coagulation cascade
Activation of complement cascade
Serum iron and zinc binding
Enhance gluconeogenesis
Increase muscle catabolism
Altered lipid metabolism
Name 4 negative acute phase proteins.
Albumin
Protein C
Protein S
Antithrombin
Adiponectin
Insulin-like growth factor-1
Transferrin
Apolipoprotein A
Retinol-binding protein
Cortisol-binding protein
Transthyretin
True or False: serum CRP concentrations provide a sensitive but nonspecific means of measuring inflammation.
True
What is the key of triggering coagulation cascade in sepsis?
Tissue factor!!!
How do macrophages recognize apoptosis cell?
cell surface appearance of phosphatidylserine (PS)
List 4 positive acute phase proteins in dogs and cats. Which one is the major and which one is minor?
C-Reactive protein
Haptoglobin
Serum amyloid A
𝜶1 acid glycoprotein
Dog: CRP
Cat: SAA
Where is procalcitonin normally produced? What about during sepsis?
Normal: thyroid gland C cells
Sepsis: mononuclear leukocytes
True or False: High-mobility group box 1 (HMGB1) is proinflammatory, can induce TF and inhibit protein C.
True
During sepsis, how will the blood flow to the liver change?
Normal: portal vein 75% hepatic artery 25%
Sepsis: portal vein flow increase, hepatic artery flow decrease
List 3 mechanisms of liver dysfunction during sepsis.
1) Hypoxic injury (decrease flow from hepatic artery)
2) Glutamine deficiency → unhealthy GI tract → GI bacterial translocation to liver
3) GI tract-derived catecholamines arrive liver via portal vein → Kupffer cell adrenoceptor activation → enhances production of TNF-α, IL-6, and NO
True or False: Sepsis-induced AKI is due to renal hypoperfusion.
False
It can also due to increased vasodilation (loss of gradient) or direct nephrotoxicity from the pro-inflammatory cytokines
What is the function of epithelial growth factor angiopoietin-1 (Ang-1) and angiopoietin-2 (Ang-2)?
Ang-1: enhances endothelial cell survival & promotes barrier integrity
Ang-2: promotes endothelial activation and dysfunction
Where is angiopoietin normally stored?
Weibel-Palade Bodies!
What are the three most important fever-producing cytokines?
IL-1
IL-6
TNF-𝜶
True or False: Exogenous pyrogen is the main pyrogens that cause fever.
False
Exogenous pyrogens do not cause fever. They induce endogenous pyrogens and endogenous pyrogens affect the thermoregulatory center.
For every 1 F increase in body temperature above normal range, how much percentage of calories and water intake increases?
7%
True or False: NSAID is used to treat true fever by blocking the endogenous pyrogens.
False
NSAIDs inhibit the chemical mediators of fever production and allow normal thermoregulation.
They DO NOT block endogenous pyrogens
What are the two prostaglandins that are responsible for fever?
PGE2
PGF2𝜶
What is the definition of nosocomial infection?
Infection develops at least 48 hours after hospital admission without proven prior incubation.
List 3 risk factors of developing nosocomial infection.
1) Prolonged hospitalization
2) Mechanical ventilation
3) Indwelling devices
True or False: Zoonoses diseases are more likely to be transmitted via indirect contact than direct contact.
True
How is G-CSF induced in the bone marrow?
Tissue macrophage release IL-23 → specific lymphocyte release IL-17 → G-CSF stimulated from the bone marrow stromal cells
What is the distribution of neutrophils in the circulating pool and marginated pool in dogs and cats, respectively?
Circulating pool: marginated pool
Dog: 1:1
Cat: 1:3
What is the definition of neutropenia in dogs and cats, respectively?
Dog: < 2900/uL
Cat: < 2000/uL
What type of cell does Ehrlichia canis infect?
Monocytes
List 5 drugs that can cause neutropenia.
1) Estrogen
2) Chemo drug (e.g. vincristine)
3) Methimazole
4) Phenobarbital
5) Azathioprine
What is PIRO stand for?
Predisposition
Insult/infection
Response
Organ dysfunction
List 5 anti-inflammatory cytokines.
IL-4
IL-10
IL-13
Transforming growth factor β
Glucocorticoid
What are the common site of Gram (-) bacterial infection? What about Gram (+)?
Gram (-): GI, urogenital
Gram (+): skin, injured soft tissue, IV site
What is the definition of cryptic shock?
Discrepancy between macrocirculation (systemic heomdynamics) and microcirculation
True or False: Normally, ScvO2 is slightly lower than SvO2, but during shock state, ScvO2 can be much higher than SvO2.
True
Due to redistribution of the blood flow and subsequent increased oxygen extraction ratio from the splanchnic circulation.
Does ScvO2 include myocardial perfusion?
No
What are Mycoplasma spp.?
Fastidious bacteria without cell wall
Non-hemotrophic vs Hemotrophic
True or False: Mycoplasmas are pathogenic bacteria and normally do not exist in dogs and cats.
False
They are normal flora in the upper respiratory tract of dogs and cats, and in the urogenital mucosa in dogs.
Why 𝜷-lactam is not effective in treating Mycoplasma?
No cell wall!
What is Actinomyces spp.? What about Nocardia spp.?Which one is normal flora in animals?
Actinomyces spp.: Gram (+), anaerobic/microaerobic bacteria
Nocardia spp.: Gram (+), aerobic bacteria
Actinomyces spp. is normal flora in animals
What is the characteristic cytological findings of Actinomyces and Nocardia infection?
suppurative to pyogranulomatous inflammation
What is the main structural component of gram (+) bacteria?
Peptidoglycan
Which group of Streptococcus causes the most Streptococcal infection in dogs and cats?
Group G (e.g. Streptococcus canis)
- It is also a normal microflora in dogs and cats
True or False: 𝜷 hemolytic streptococcal canis can cause hemolysis in dogs.
False
The definition of hemolytic or non-hemolytic is based on in vitro blood culture
What is the most common bacteria causing Streptococcal toxic shock syndrome and necrotizing fascitis/soft tissue infection in dogs and cats?
Group G 𝜷-hemolytic streptococcal canis
Describe the pathophysiology of STSS.
What is the suggested criteria to diagnose STSS in dogs and cats?
- Isolation of Streptococcus canis
A. From a normally sterile site
B. From a nonsterile site - Clinical signs of severity
A. Hypotension: SAP < 90 mmHg in dogs & < 80 mmHg in cats
B. Two or more of the following signs: - Renal impairment: creatinine above the upper limit of the reference range
- Coagulopathy: thrombocytopenia or DIC (prolonged clo ing times, low serum fibrinogen concentration, and increased fibrin degradation products)
- Liver involvement: serum AST, ALT, or total bilirubin concentrations at least twice the upper limit of the reference range
- Acute respiratory distress syndrome defined as acute onset of diffuse pulmonary infiltrates and hypoxemia in the absence of cardiac failure, or evidence of diffuse capillary leak manifested as acute onset of pulmonary edema, or pleural or peritoneal effusions with hypoalbuminemia
- A generalized erythematous macular rash that may desquamate
- Soft tissue necrosis, including necrotizing fasciitis or myositis, or gangrene
Why enrofloxacin administration in dogs with streptococcal infection is associated with STSS/NFM?
Enrofloxacin administration can induce bacteriophage development and cause subsequent bacterial cell lysis. After bacterial cell lysis, some bacteriophage-encoded lymphocyte mitogens are release, which can induce superantigen-like response of lymphocytes.
What type of bacteria is streptococcus spp.?
Gram (+), facultative anaerobic cocci arranged in chains
What type of bacteria is enterococcus spp.?
Gram (+), facultative anaerobic cocci
True or False: Many enterococci are intrinsically resistant to numerous antibiotics.
True
What is the standard of care for serious enterococcal infections ICU patients?
Gentamicin (but not amikacin) + cell wall–active agent (generally ampicillin)
- it is not appropriate to prescribe amoxicillin-clavulanate or ampicillin-sulbactam for an enterococcal isolate that is reported to be susceptible to ampicillin → they are easy to develop resistance by exposed to β-lactamase–inhibitor drugs
What gene mediates the methicillin resistance of S. pseudintermedius? What does it change?
mecA gene
It encodes the production of modified penicillin binding protein (PBP) → low affinity to 𝜷-lactam
How to determine whether a S. pseudintermedius is MRSP? Which antibiotic is used to test?
based on in vitro resistance to oxacillin
True or False: If staphylococci are resistant to oxacillin, they are inherently resistant to all other β-lactams, including cephalosporins and amoxicillin-clavulanate
True
What is clavulanic acid?
an inhibitor of β-lactamases
True or False: All pathogenic enterococci are inferred to be intrinsically resistant to clindamycin and potentiated sulfonamides.
True
True or False: Enterobacter cloacae strains are inherently resistant to amoxicillin, amoxicillin- clavulanate, narrow-spectrum cephalosporins, and cefoxitin.
True
What bacteria can produce urease and alkalize the urine?
Proteus
It can alkalinize urine by hydrolyzing urea to ammonia
List 6 bacteria that belongs to Enterobacteriaceae.
Escherichia coli
Salmonella
Enterobacter
Proteus
Klebsiella
Serratia
What type of bacteria is Pseudomonas aeruginosa?
Gram (-), obligated aerobic bacteria
List 3 drugs that are anti-pseudomonal β-lactam.
Ceftazidime (3rd generation cephalosporin)
Meropenem (carbapenem)
Imipenem (carbapenem)
Piperacillin
Ticarcillin
- Other class: aminoglycoside
Name three extended- spectrum β-lactamases (ESBL) producing bacteria.
E coli
Proteus mirabilis
Klebsiella pneumoniae
On the bacterial culture and susceptibility test, what findings should you raise concern for extended- spectrum β-lactamases producing bacteria?
Bacteria that shows resistance to aztreonam, cefpodoxime (3rd generation), or ceftazidime
What is extended- spectrum β-lactamases (ESBL)?
ESBLs are β-lactamases capable of conferring bacterial resistance to the penicillins; first-, second-, and third- generation cephalosporins; and aztreonam by hydrolysis of these antibiotics
What color will Gram (+) and (-) be with Direct Gram staining?
Gram (+): purple, violet blue
Gram (-): pink, red
In the third generation cephalosporins, which antibiotic is the only one that is effective for anaerobic infection?
Cefotaxime
Are meropenem and imipenem effective to anaerobic infection?
Yes
What is enrofloxacin partially metabolized to?
ciprofloxacin
Which anti-fungal medication can be excreted in urine, itraconazole or fluconazole?
Fluconazole
What is the main side effect of Amphotericin B?
Nephrotoxicity
Which anti-fungal medication can penetrate CNS and eyes, itraconazole or fluconazole?
Fluconazole
Define 90-60 rule.
For an antibiotic, infections due to susceptible bacteria will respond to the therapy about 90% of the time; whereas infections due to resistant bacteria will respond about 60% of the time
What are three types of bacterial resistance?
1) Intrinsic
- Pseudomonas aeruginosa, which shows resistance to the majority of β-lactam antimicrobials
- all gram (-) organisms are resistant to vancomycin
2) Circumstantial
- drug cannot penetrate to the sites (e.g. CNS, eyes, prostate)
- pH makes the drug ineffective
3) Acquired
How many CFU needs to be reached before spontaneous mutations cause resistance to two drugs?
> 10^14
Name two class of drugs that are concentration-dependent.
Fluoroquinolone
Aminoglycoside
For concentration-dependent antibiotic, what is the target Cmax:MIC and AUC:MIC
Cmax:MIC > 10-12
AUC:MIC > 100-125
- AUC = area under the curve for 24 hours, which is influenced by both dose and interval
For patients who receives aminoglycoside, it is recommended to monitor the serum drug levels. What are the two time points to check and what are they for?
1-2 hr post-administration → peak concentration (check efficacy)
4-6 hr post-administration →trough concentration (check safety)
According to ACVIM Consensus about antibiotics, what are the three approaches to reduce antimicrobial resistance?
1) Prevent disease occurrence
2) Reducing overall antimicrobial drug use
3) Improved antimicrobial drug use
In a study published by Sigal et al in 2017 JAVMA about sepsis in cats, what are the abnormal findings on blood work?
Metarubricytosis
Hypertriglyceridemia
High circulating muscle enzyme activities
Prolonged aPTT
Elevated D-dimer
Decreased total protein C and antithrombin
Non-regenerative anemia
Hyponatremia
Which prostaglandin cause fever in hypothalamus?
Prostaglandin E2
Dogs have how many days of neutrophils supply in bone marrow?
5 days
True or False: Lymphopenia can be seen in both cortisol and epinephrine response.
False
Only cortisol response; epinephrine cause lymphocytosis
What is MOA of aminoglycosides?
Bind to 30s ribosomal subunit → inpair protein synthesis
How does the efficacy of aminoglycoside change when it is in an acidic and low oxygen tension environment?
Decreased efficacy
- Not good for abscess
True or False: Aminoglycoside should not be contained in the syringe with calcium.
True
No calcium, sodium bicarbonate or heparin
Are aminoglycosides effective for anaerobic?
No
Their uptake across bacterial cell membranes depends on energy derived from aerobic metabolism
How is aminoglycoside eliminated?
Excreted in the urine (predominately by glomerular filtration)
What is single daily dosing regime for aminoglycosides?
The total daily dose is administered as a single dose about every 24 hours
Aminoglycosides provide post-antibiotic effect (PAE). What is PAE?
Bacterial replication is impeded even after serum drug conc. have fallen below the MIC
What is the target Cmax for aminoglycosides?
8 - 10 times of MIC
How does aminoglycoside cause kidney injury?
- Renal proximal convoluted tubules
The cationic state of the aminoglycosides facilitates binding to tubular epithelial cells → Intracellular transport → high concentrations of the aminoglycoside within lysosomes → Lysosomes destabilize and rupture → disrupts normal cell structure and function
What is the MOA of fluoroquinolone?
Inhibit DNA gyrase or topoisomerase IV (both are enzyme-bound bacterial DNA complex) → inhibit normal bacterial DNA synthesis → bacterial cell death
What are the primary target for fluoroquinolone in gram (+) and gram (-) bacteria?
Gram (+): topoisomerase IV
Gram (-): DNA gyrase
Which generation is pradofloxacin?
3rd generation
True or False: Approximately 40% of marbofloxacin is excreted unchanged by the kidney.
True
What is the MOA of sulfonamides?
It’s a competitive antagonist of PABA → disrupted bacterial folic acid synthesis → inhibit bacterial DNA synthesis
Why is enterococcus are naturally resistant to sulfonamides?
They can incorporate exogenously produced folate
List 5 adverse effects for sulfonamides.
Anemia
Proteinuria/hematuria
Iatrogenic reversible hypothyroidism
KCS
Sulfonamide hypersensitivity (e.g. fever, polyarthropathy, hepatotoxicity, skin
eruptions, thrombocytopenia, neutropenia)
What is MOA of macrolides?
Binds to 50s ribosomal subunit → inhibit protein synthesis
Among all the antibiotics that inhibit protein synthesis, which one is bactericidal?
Aminoglycosides
What is the target organisms of macrolides?
Gram (+)
Anaerobic
Mycoplasma
- Azithromycin has better coverage to gram (-) compared to other macrolides
What is the target organisms for metronidazole?
Anaerobic gram (+) and gram (-)
List 5 antibiotics that are bactericidal
𝜷-lactam
Aminoglycosides
Fluoroquinolone
Sulfonamides
Metronidazole
What is the MOA of chloramphenicol?
Binds to 50s ribosomal subunits → inhibits protein synthesis
List 1 advantage and 2 disadvantages for chloramphenicol.
Advantages:
1) Very broad-spectrum
Disadvantages:
1) Can cause bone marrow aplasia in human
2) Inhibit cytochrome p- 450 → decreases clearance of other drugs
What is MOA of tetracycline? Is it bactericidal or bateriostatic?
Bind to 30s ribosomal subunit → inhibit protein synthesis
Bacteriostatic
What is the MOA of clindamycin? Is it bacteriostatic or bactericidal?
Bind to 50s ribosomal subunit → inhibit protein synthesis
Bacteriostatic
Name 2 antibiotics that bind to 30s ribosomal subunit and 3 that bind to 50s ribosomal subunit.
30s: aminoglycosides, tetracyclines
50s: chloramphenical, macrolides, clindamycin
True or False: Clindamycin also works for Toxoplasma gondii, Neospora caninum, Hepatozoon, and Babesia spp. but not gram (-) bacteria.
True
What is the MOA of vancomycin?
Glycopeptide
Binds to the peptide precursors in the
bacterial cell wall → preventing cross-linking of peptidoglycan side chains → inhibit cell wall synthesis
How is vancomycin metabolized?
Excreted through kidneys
What is MOA of rifampin?
Block RNA polymerase
Bactericidal
List 5 antibiotics that are time-dependent.
𝜷-lactam
Macrolides
Clindamycin
Tetracycline
Chloramphenical
What is the coverage for vancomycin?
Gram (+) aerobic and anaerobic
What are the two groups of antibiotics which their activity diminished by the presence of cations?
Fluoroquinolone
Aminoglycosides
What are two groups of antibiotics that don’t work well in abscess?
Aminoglycosides
Vancomycin
Name 4 antibiotics that don’t work well in acidic environment.
Aminoglycosides
Clindamycin
Fluoroquinolone
Macrolides
What bacteria produces amphotericin B?
Streptomyces nodosus
What is the MOA of amphotericin B?
Bind to ergosterol in fungal cell membranes → increased permeability → cell death
What is the major adverse effects of amphotericin B?
Nephrotoxicity (binds to cholesterol in the proximal tubular cells → renal vasoconstriction & renal tubular acidosis)
- To reduce nephrotoxicity, AMB usually is infused in 5% dextrose and administered intravenously over 1 to 5 hours
What is the MOA of azole antifungal drugs?
Inhibit the fungal P-450, which is necessary for the development of ergosterol in fungal cell wall
What are the two big group of azole drugs?
Triazole: itraconazole, fluconazole, voriconazole, posaconazole
Imidazole: ketoconazole, clotrimazole, enilconazole, miconazole
What is the peak concentration for azole anti-fungal drugs?
6-14 days
Which group of azole drugs have less effect on mammalian sterol synthesis and longer half life?
Triazole (itraconazole, fluconazole)
Which azole anti-fungal drug is absorbed better with food and acid environment, and can be affected by H2 blocker, itraconazole or fluconazole?
Itraconazole
- And ketoconazole
Which azole anti-fungal drug has better penetration across BBB, blood-eye and blood-prostate barriers, itraconazole or fluconazole?
Fluconazole (water soluble, low protein-bound)
If CNS is involved in a fungal infection, which anti-fungal drug should be used, itraconazole, ketoconazole or fluconazole?
Fluconazole
How is fluconazole, itraconazole and ketoconazole metabolized/excreted, respectively?
fluconazole: minimal metabolism, renal excretion
itraconazole: cytochrome P-450
ketonazole: cytochrome P-450
What is the drug of choice for histoplasmosis and cryptococcosis in the CCM?
Histoplasmosis: Itraconazole
Cryptococcosis: Fluconazole
Mycoplasma spp do not have cell wall, so they are intrinsically resistant to which two types of antibiotics?
𝜷-lactam
Glycopeptides (e.g. vancomycin)
True or False: Enterococcus is intrinsically resistant to aminoglycosides because the polar molecules can hardly penetrate the cell wall.
True
What is the term of the movement of neutrophil across the capillary wall?
Diapedesis
- diapedesis occurs through the interendothelial junctions of postcapillary venules
What do the primary, secondary and tertiary granules contain in neutrophils?
Primary (azurophil): myeloperoxidases, defensins, lysosomal hydroxylase, neutral protease
Secondary (specific): metalloprotease
Tertiary (gelatinase): receptors for enhanced cellular communication
There are two types of macrophages - M1 and M2. What are the function for each one of them?
M1
- Activated by inflammatory cytokines (TNF-𝜶, INF-𝛄)
- Produce pro-inflammatory cytokines (IL-1β, IL-6, TNF-α) and prostaglandins
- Phagocytosis
- Inhibit cell proliferation
M2
- Activated by anti-inflammatory cytokines (IL-4, IL-10, IL-13)
- Secrete growth factors (e.g. PDGF or TGF-β) → stimulate fibroblasts to produce collagen
- Promote cell proliferation and tissue repair
Both M1 and M2 macrophages secrete enzymes like collagenases and elastases to dissolve the extracellular matrix, facilitating phagocytosis and remodeling, respectively
There are two types of T helper cells - TH1 and TH2. What cytokines do they secrete?
TH1
- Stimulated by IFN-γ and IL-12
- Produce IFN-γ and IL-2
- Function: maximize the bacterial killing potential of macrophages and stimulate proliferation of cytotoxic T-cells
TH2
- Stimulated by allergic reaction or helminthic infections
- Produce IL-4, IL-5, IL-10, and IL-13
- Function: increase in IgG1 and IgE production, and eosinophil activation.1
Which two TLRs do LPS bind to?
TLR2, TLR4
Which pattern recognition receptor does HMGB1 bind to?
RAGE
Name 4 functions of TNF-𝜶.
1) Activate natural killer cells
2) Proliferate cytotocix T cells
3) Mediate T cell apoptosis
4) Produce proinflammatory cytokine (e.g. IL-6)
5) Produce oxygen reactive species, chemotaxis, and endothelial adhesion molecules
True or False: IL-1ra, serves a counterregulatory function and is actually an antiinflammatory cytokine that competes with IL-1 for receptor sites.
True
In IL-1 family what are the two substances that need to be complexed with IL-1𝜷 to activate cellular signaling pathway?
IL-1RI (a functional receptor)
IL-1 receptor accessory protein (IL-1RAcP)
Which cytokines play a pivotal role in initiating hepatic synthesis of the acute phase proteins?
IL-6
True or False: IL-6 is a pro-inflammatory cytokine.
True
But it also can initiate compensatory antiinflammatory responses and downregulating proinflammatory cytokine production.
What are the three functions of IL-8?
1) Induce chemotaxis of neutrophils
2) Stimulate phagocytosis
3) Promote angiogenesis
IL-8 is also referred to CXCL8
List 4 functions of IL-10.
1) depresses the production of cytokines (TNF-α, IL-1, IL-6, and IL-8), by inhibiting translocation of NFκB and promoting degradation of messenger RNAs
2) downregulates the production of Th-1 cytokines
3) promotes shedding of TNF receptors into the systemic circulation
4) inhibits antigen presentation by macrophages and dendritic cells
How does steroid affect the arachidonic acid pathway?
Inhibits phospholipase A2
Draw the arachidonic acid pathway.
Which prostaglandin is a potent pyrogenic agent?
PGE2
Which prostaglandin can cause uterus contraction?
PGF2
Are Leukotriene B4, LTC4, LTD4, LTE4 proinflammatory or anti-inflammatory?
Proinflammatory
Does leukotriene cause vasoconstriction or vasodilation?
Vasoconstriction
True or False: The synthesis of platelet-activating factor is primarily modulated by mitogen-activated protein kinase (MAPK) intercellular signaling pathways.
True
Where is platelet-activating factor from?
from cell membrane phospholipids metabolized by phospholipase A2
Where is endogenous carbon monoxide from? Is it considered anti-inflammatory or pro-inflammatory?
Enzymatic breakdown of heme to bilirubin by heme oxygenases
Anti-inflammatory
Where is endogenous hydrogen sulfide from? How does it work on the cells?
It is produced in tissues during cysteine metabolism (cystathionine β-synthase and cystathionine γ-lyase)
It works on ATP-dependent K+ channels, hydrogen sulfide relaxes smooth muscles and induces vasodilation.
True or False: Bradykinin stimulates venous dilation through local nitric oxide release.
True
What class of cytokine does substance-P belong to?
Tachykinin
List 4 causes of hyperlactatemia during sepsis/septic shock.
1) Inadequate whole-body oxygen delivery
2) Impaired tissue oxygen extraction and the microcirculation
3) Increased glycolytic flux and Na,K- ATPase activity Through 𝜷2 stimulation
4) decreased lactate clearance
What are the three main components of endothelial glycocalyx? Which one is the most abundant component?
Proteoglycans (PGs) - syndecans, glypicans
Glycoprotein (GPs) - selectins, immunoglobulins, integrins
Glycosaminoglycans (GAGs) - Heparan sulfate (HS), chondroitin sulfate (CS), dermatan sulfate (DS), keratin sulfate, hyaluronan (HA)
Glycosaminoglycans (GAGs) is the most abundant
Which syndecan does endothelial glycocalyx mainly contain?
Syndecan-1
- Syndecan is a transmembrane protein
What are the two main selectins found in endothelial glycocalyx?
P-selectin (constitutively expressed and stored within Weibel-Palade bodies of the EC and platelets)
E-selectin
Name 5 GAGs in endothelial glycocalyx. Which one is the most abundant on endothelial glycocalyx? Which one is not attached on the core protein and synthesized at difference place different from the rest?
Heparan sulfate (HS)
Chondroitin sulfate (CS)
Dermatan sulfate (DS)
Keratin sulfate
Hyaluronan (HA)
Heparan sulfate (HS) most abundant!
Hyaluronan (HA) → synthesized on the cell membrane
True or False: Fibrinogen is not incorporated into the endothelial surface layer due to its large molecular weight.
False
It is incorporated into the ESL
Does Amoxicillin–clavulanate provide good anaerobic coverage?
Yes
