Week 6: Pharmacotherapy (Septic Shock ID + SE - Blue)

What types of infections can cause sepsis?

bacterial, viral, fungal, or parasitic infections

Does sepsis require bacteria in the bloodstream?

No, sepsis is an inflammatory response to infection, not necessarily bacteremia

What are examples of infections that can cause sepsis?

UTI, pneumonia, skin/soft tissue infection, and viral infections such as COVID-19

What is the general sepsis management timeline?

recognition → fluids → labs → antibiotics → source control

When may antivirals or antifungals be included in initial sepsis treatment?

when a viral or fungal cause is reasonably suspected

When should cultures be obtained in suspected sepsis?

before antibiotics, as long as this does not substantially delay treatment

How should blood cultures be collected?

2 sets from 2 sites; each set has 1 aerobic + 1 anaerobic bottle

Why are blood cultures drawn from 2 different sites?

to help distinguish true infection from contamination

Why should cultures ideally be obtained before antibiotics?

antibiotics may kill organisms and prevent culture growth

What is source control in sepsis?

rapidly identifying and removing/draining the infection source when practical

What are examples of source control?

remove/change infected lines or Foley catheters; drain or wash out infected sites

When should antibiotics be given when septic shock is present?

immediately, ideally within 1 hour

What if shock is absent and sepsis is possible but uncertain?

rapidly assess; if infection remains likely, give antibiotics within 3 hours

What does Code Sepsis do?

activates rapid response and makes sepsis-related orders STAT

What is the goal of Code Sepsis?

early goal-directed therapy and faster sepsis care

What 5 questions guide infectious disease treatment?

Infection? → Site? → Likely organisms? → Antibiotics? → Patient/disease factors?

What findings can help determine whether an infection is present?

WBC, procalcitonin, imaging, UA, cultures, and clinical findings

What factors guide selection of an empiric antibiotic regimen?

site, pathogens/resistance, immunity, age/comorbidities, MDRO risk, allergies, and organ function

What immune defects can change expected pathogens?

HIV, splenectomy, neutropenia, and immunosuppressive therapy

What past information is especially useful for assessing MDRO risk?

previous cultures showing resistant organisms

What must be balanced when choosing broad empiric therapy?

adequate coverage vs. antibiotic stewardship and resistance

How did the 2021 sepsis guidelines change empiric antibiotic selection?

use patient-specific resistance risk instead of automatically covering all pathogens

When should empiric MRSA or broader gram-negative coverage be used?

when the patient has risk factors for those resistant organisms

When should empiric antifungal therapy be used?

when fungal infection risk is high

What organisms should raise concern for resistance in nosocomial infections?

pseudomonas and resistant enterobacterales

Why are certain Enterobacterales concerning?

they may have inducible AmpC production and beta-lactam resistance

SPACE

Serratia spp., Pseudomonas aeruginosa/

Providencia, Acinetobacter spp., Citrobacter spp.,

and Enterobacter spp

HECK-Yes

Hafnia alvei, Enterobacter cloacae, Citrobacter

freundii, Klebsiella aerogenes, and Yersinia enterocolitica

What are major MDRO risk factors?

immunocompromise, ARDS, recent IV antibiotics, RRT, long hospitalization, structural lung disease, MRSA, ventilation, or prior resistant infection

What recent antibiotic exposure increases MDRO risk?

IV antibiotics within 90 days

What 4 broad organism groups should you consider for empiric coverage?

gram-positive, gram-negative, anaerobes, and atypicals

What resistant organisms require special consideration within these groups?

MRSA for gram-positive and Pseudomonas/resistant Enterobacterales for gram-negative

What coverage is commonly considered for skin, diabetic foot, and respiratory infections?

Skin: GP/MRSA

Diabetic foot: GP/GN ± MRSA/Pseudomonas/anaerobes

Respiratory: GP/GN ± MRSA/Pseudomonas/atypicals

What coverage is common for urinary, abdominal, and surgical infections?

Urinary: mainly GN

Abdominal: GN + anaerobes

Surgical: GP/MRSA ± GN/anaerobes by site

What does piperacillin/tazobactam cover?

P, GN, Pseudomonas, and anaerobes; NOT MRSA

What does cefepime cover?

GP, GN, and Pseudomonas; NOT MRSA or reliable anaerobes

What are ceftriaxone, metronidazole, and vancomycin mainly used to cover?

ceftriaxone: mainly GN; metronidazole: anaerobes; vancomycin: GP/MRSA

How are concentration-dependent antibiotics optimized?

maximize concentration/exposure relative to MIC; loading or higher doses may help

How are time-dependent antibiotics optimized?

maximize time above MIC with frequent, extended, or continuous dosing

Why use an extended infusion instead of a short intermittent infusion?

ncreases time above MIC

Which antibiotics especially benefit from extended infusions?

time-dependent beta-lactams

How should prolonged beta-lactam infusion generally be initiated?

initial bolus/loading dose followed by prolonged maintenance infusion

How does treatment progress from suspected infection to definitive therapy?

culture → empiric therapy → gram stain → identification → susceptibilities → definitive therapy → monitor response

When should empiric antibiotics be de-escalated?

assess daily and narrow when cultures, susceptibilities, and clinical response allow

How can pharmacists help de-escalate antibiotics?

review cultures/MRSA testing, stop unnecessary coverage, act on susceptibilities, and recommend duration

What duration strategy is recommended when a septic patient is improving?

prefer shorter rather than longer antibiotic courses

When might antibiotic therapy need to be extended?

when the patient has not adequately improved

What are the 6 links in the chain of infection?

agent → reservoir → portal of exit → transmission → portal of entry → susceptible host

What major HAIs should pharmacists help prevent, and how can they help?

CAUTI, VAP, SSI, CLABSI, and C. diff; optimize antibiotics, stewardship, infection control, and MDRO risk assessment

What is a seizure?

a sudden episode caused by abnormal electrical activity/conductivity in the brain

Status Epilepticus (SE)

≥5 minutes of continuous clinical/electrographic seizure activity OR recurrent seizures without returning to baseline between seizures

What causes the prolonged seizure activity in status epilepticus?

failure of normal mechanisms that terminate seizures or initiation of mechanisms that cause prolonged seizures

VITAMIN ED (major causes of status epilepticus)

Vascular, Infection, Trauma, Autoimmune, Metabolic, Idiopathic, Neoplasia, Eclampsia, Drugs

Example of a metabolic abnormality that can cause seizures?

hyponatremia or other electrolyte disturbances

What medication is the go-to treatment for seizures due to eclampsia?

magnesium

What medications/substances can precipitate seizures or status epilepticus?

AED nonadherence, amphetamines, aspirin overdose, TCAs, benzodiazepine/EtOH withdrawal, bupropion, carbapenems/cefepime, cocaine, and tramadol

How does convulsive status epilepticus (GCSE) typically present?

rhythmic motor activity, impaired mental status, and post-ictal neurologic deficits

How does nonconvulsive status epilepticus (NCSE) differ from GCSE?

seizure activity occurs on EEG without obvious convulsive findings; patients may appear confused, stare, or have altered mental status

Why is convulsive SE treated immediately?

it is a medical and neurologic emergency; medications should be administered ASAP

2 major neurotransmitters in seizure pharmacotherapy?

Glutamate = excitatory ("gas pedal")

GABA = inhibitory ("brake pedal")

How can decreasing glutamate signaling help stop seizures?

blocking Na⁺ channels or presynaptic vesicle release decreases excitatory neurotransmission

How does increasing GABA activity help stop seizures?

increased GABA-A activity increases Cl⁻ influx → hyperpolarization → decreased neuronal firing

What is the general treatment sequence for status epilepticus?

emergent initial therapy → urgent second-line therapy → refractory therapy if seizures continue

What is first-line emergent drug therapy for status epilepticus?

a benzodiazepine

What happens if seizures continue despite a benzodiazepine?

give an urgent second-line antiepileptic drug (AED); persistent seizures then require refractory therapy

ABC(DEFG)

Airway, breathing, circulation, and Don't Ever Forget the Glucose

Why should glucose be checked immediately in a patient with seizures?

hypoglycemia can cause seizures and is rapidly reversible with glucose

MOA of benzodiazepines in status epilepticus?

GABA-A agonism, increasing inhibitory activity, the "brakes"

What benzodiazepine doses are used for emergent SE treatment?

diazepam 10 mg IV/PR

lorazepam 4 mg IV (0.1 mg/kg)

midazolam 10 mg IV/IM (0.2-0.3 mg/kg)

**doses may be repeated

What are major adverse effects of benzodiazepines in SE?

respiratory depression and hypotension

Should hypotension prevent adequate benzodiazepine treatment of SE?

No, stop the seizure first, then manage hypotension/respiratory effects

Key characteristics of phenytoin for SE?

Na⁺ channel blocker; 20 mg/kg ×1, with an additional 5-10 mg/kg after 10 min if needed; max infusion 50 mg/min

What major adverse effects are associated with IV phenytoin?

hypotension, arrhythmias, and purple glove syndrome

What important drug interaction and contraindications does phenytoin have?

CYP450 inducer; avoid with severe heart block or bradycardia

Why is fosphenytoin generally preferred over IV phenytoin?

it has a more physiologic pH, can be administered faster (max 150 PE/min), and causes fewer adverse effects

How is fosphenytoin dosing expressed?

phenytoin equivalents (PE); 1 mg PE fosphenytoin = 1 mg phenytoin

MOA and SE dose of valproic acid?

Na⁺ channel blockade + GABA transaminase inhibition

40 mg/kg IV (max 3000 mg) with an additional 20 mg/kg after 10 min if needed

What major adverse effects and interactions occur with valproic acid?

hepatotoxicity, pancreatitis, hyperammonemia, thrombocytopenia; CYP450 inhibitor and avoid with carbapenems/phenytoin

When should valproic acid be avoided?

pregnancy and liver failure

MOA and SE dose of levetiracetam?

SV2A blocker; 60 mg/kg IV ×1 (max 4500 mg)

What are the major advantages of levetiracetam for SE?

few adverse effects, no significant drug interactions, no major contraindications, and preferred in pregnancy

What adverse effects may occur with levetiracetam?

agitation and irritability

How can newer buffered levetiracetam be administered in acute SE?

100 mg/mL buffered product may be given undiluted IV push over ~5 minutes, despite the package insert listing a 15-minute infusion

What are advantages of IV-push levetiracetam?

faster administration and potential time/cost savings

What drugs enhance GABA activity in acute/refractory SE?

benzodiazepines initially and barbiturates in refractory cases

Key characteristics of propofol for refractory SE?

GABA-A agonist/general CNS depressant + NMDA blockade; given as a bolus followed by continuous infusion

What major adverse effects/limitations occur with propofol?

hypotension, respiratory depression, PRIS, and hypertriglyceridemia; continuous infusion requires an intubated patient

Key characteristics of midazolam infusion for refractory SE?

GABA-A agonist given as a bolus then infusion; can cause hypotension, respiratory depression, and tachyphylaxis and is hepatically cleared

Why must patients receiving continuous midazolam for refractory SE be intubated?

continuous benzodiazepine sedation can cause significant respiratory depression

Key characteristics of ketamine for refractory SE?

NMDA receptor antagonist given as a bolus followed by infusion; may cause dissociation/psychosis, hypertension, tachyarrhythmias, and hypersalivation

When might ketamine be a poor choice?

cardiac decompensation or when increases in BP, HR, or ICP would be detrimental

What therapies may be considered for super-refractory SE?

barbiturates, clobazam, perampanel, inhaled anesthetics, ECT, steroids/immunotherapy, neurosurgery, or hypothermia

Key characteristics of pentobarbital in super-refractory SE?

barbiturate that enhances GABA activity; given as bolus then infusion and may cause hypotension, respiratory depression, and coma; CYP450 inducer

What should happen after acute seizure control is achieved?

identify/treat the underlying cause, determine maintenance AED needs, slowly wean continuous infusions, and use EEG monitoring when available

How can pharmacists contribute to SE management beyond selecting medications?

rapid drug procurement, medication-list review, therapeutic drug monitoring, and identifying/treating potential causes

Overall treatment approach to convulsive status epilepticus?