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If oral dose is a lot higher than IV dose, what could this mean?
it means the drug goes through high 1st pass metabolism
Which two bugs make biofilm that it is hard for abx to penetrate?
What are some reasons why impaired abx distribution occur?
- physicochemical property (partition coefficient, pKa)
- extent of perfusion
- presence of destructive enzymes
- size of junction between cells
- active transport system
- efflux pump
Where is meningitis inflammation located?
describe the anatomy
- meninges are composed of three layers: pia, archnoid, dura (in the order from deep to outer)
- inflammation is between arachnoic and dura
How much CSF do adults have?
What happen to protein, glucose and WBC during meningitis?
- protein goes up due to bug's byproducts
- glucose goes down because bugs eat them
- WBC goes up a little bit but brain does not have much WBC in general. so 5-10 WBC is indicative of infection.
What are the factors that increase the penetration and concentration of antibiotic in the CSF?
- low protein binding (except ceftriaxone)
- low ionization
What is BBB?
specialized barrier system of endothelial cells that separates the blood from the underlying brain cells
What are the factors that reduce the activity of the abx?
- low pH of fluid (acidic fluid)
- too much protein in fluid
- high temperature fluid
Does cefazolin penetrate BBB?
- 1st generations do not
Does cefprozil penetrate BBB?
- 2nd generations do not
Does cefotetan cross BBB?
- 2nd generations do not
Does cefuroxime penetrate BBB?
- it is the only 2nd generation that penetrates BBB
What is the only 2nd generation cephalo that penetrate BBB?
Which 3rd generation cephalo cross BBB?
Does ceftazidime cross BBB?
Does cefdinir cross BBB?
Which cephalosporin would you use to cover pseudomonas that will cross BBB?
what is the cephalosporin of choice for meningitis?
do carbapenem cross BBB?
What may be a downside for drugs that cross BBB?
may have potential to cause seizure
can FQ cross BBB? what should you do?
- yes: levo, moxi, cipro
- may need a higher dose (off label)
do aminoglycoside cross BBB?
not really: water loving
do metronidazole cross BBB?
does rifampin cross BBB?
do vancomycin cross BBB?
yes but unpredictable because it is a large molecule.
can abx get metabolized in CSF?
how is the antibiotic t/2 in brain compared to systemic t/2?
antibiotics stay in brain for awhile so t/2 is longer in brain than systemic
which antiretrovirals are metabolized by CYP450?
Non-nuc and PI
Most of the antibiotics are eliminated ___ (renally or hepatically)
Drugs concentrations in CSF are dependent on ____ and ____.
In CSF, beta-lactams are ___.
(time, concentration dependent or both?)
Explain the details behind the mechanism.
- concentration dependent: exceed MBC by 10-30
- and also
- time dependent: levels in CSF need to exceed the MBC for more than 50% of dosing interval to exhibit maximal bacterial killing
Vancomycin should be ____ fold higher than MBC for bacterial killing.
5 to 10 fold
In CSF, aminoglycosides are ____.
(time, concentration or both dependent?)
AG is concentration dependent for both systemic and CSF.
When is AG typically only used in CSF?
typically only used in shunt infections where there can be direct installation of antibiotic into CNS
AG can be used in synergy with ___ for ____.
- listeria meningitis
- (listeria's drug of choice is ampicillin. gentamicin is used as synergy to help enter BBB)
In CSF, FQ are _____.
(time, concentration or both dependent?)
- both time and concentration
- need high peak but also keep above the MIC for the dosing interval
Is FQ FDA-indicated for antimicrobial activity in CSF? what dosing is usually used?
- no, it is off label
- once daily is not enough so more dosing.
- (Levaquin BID for meningitis)
What are examples of synergy medications for antimicrobial activity in CSF?
- ceftriaxone + vanco
- ampicillin + gent (for listeria)
- b-lactams + b-lactamase inhibitor
What is shunt used for?
for hydrocephalus to drain the fluid out to perritoneal cavity
What two organisms cause CSF shunt infection?
- staph aureus
- staph epi
- (gram positives love plastic)
What is the empiric therapy for CSF shunt infection?
What do you do in CSF shunt infection?
- remove infected shunt
- external drainage
- always treat systemic and use intraventricular as adjunct
What are signs and symptoms of CSF shunt infection?
- + CSF culture
What is the length of therapy for CSF shunt infection?
- 10 days after sterilization of fluids
- so this means at least 2 weeks or more total
when is intraventricular abx useful?
- failure of parenteral therapy to sterilize CSF
- highly resistant organisms sensitive only to abx with poor CSF penetration
- when shunt devices cannot be removed
- this is so-called "salvage therapy".
Which abx is FDA approved for intraventricular use?
- this is a trick question.
- NO antibiotic is FDA approved for this.
- just case reports
What is inhibitory quotient formula? what is the target quotient?
- trough CSF concentration / MIC
- so higher the MIC, the harder it is to achieve the target
- target is 10-20
Would systemic dose be smaller than CSF dose?
- that doesnt make sense
when would you use Q/D abx?
when there is resistance to vancomycin
Intrathecal antibiotic therapy administered through a needle in the ____.
What are two very important issues to consider during intrathecal therapy preparation? why?
- because could have a lot of inflammation
What kind of solution is intrathecal solution?
parenteral solution of preservative free normal saline
Some case reports of intrathecal administration are available with which abx?
- amphotericin B
When do you use aerosolization?
- VAP: ventilation associated pneumonia
- cystic fibrosis
What beneficial effect does aerosolization have?
uses higher concentration adn maximized concentration dependent killing effects
Which four drugs have been examined for aerosolization?
- amphotericin B
Which 4 bugs are prevalent in your lungs when you have cystic fibrosis?
- Pseudomonas aeruginosa (early, later)
- staphylococcus aureus (early)
- H. influenza (early)
- brukholderia cepacia (cousin of pseudo)
Why is it beneficial to use aerosolization for CF patients?
- even though the lungs are always colonized, we want to prevent any chronic infections
- reduced bacterial density in sputum
- improve lungh functino
What are some risks of aerosolization?
- resistance to abx
- bronchospasm due to excipients
- cough bad taste
What is Tobi and how do you use it?
- tobramycin aerosolized
- for CF patients
- 21 days on and 21 days off
When is aerosolization used as a treatment option?
- VAP: ventilation associated pna
- make sure to sue with systemic
Which drugs are used as a prevention option for aerosolization?
- but this is not really a great option
what is the drug of choice for pneumocystis pneumonia (PCP)?
what are the alternatives?
- alternatives: Mepron, Dapson, pentamidine
What are some pentamidine side effects?
- renal toxicity
- QTc prolongation (must do EKG)
- electrolyte imbalance
- glucose imbalance
With which two drugs do you see more side effects when you use aerosolization?
Which amphotericin B form will have less bronchospasm side effect during aerosolization?
How do you use outpatient aerosolized pentamidine for prophylaxis for PCP?
- 300mg once q 4 weeks
- administer via Respirgard II nebulizer
- administer until the nebulizer chamber is empty (~30-45 min)
- flow rate 5-7 L per min from a 40-50 lbs per sq in (PSI) air or oxygen source
What does PVC stand for?
Where is it located?
How long can you have it for?
- peripheral venous catheter
- inserted into the veins of the forearm or the hand
- PVC cannot stay in the body long. approx 2 days
What is PAC?
What is it used for?
- peripheral arterial catheter
- used to monitor hemodynamic status and determine blood gas level to critically ill patient
What is CVC?
when is it used?
- central venous catheter
- used in onco patient because they cannot get peripheral
What are the examples of long term CVC?
- CVC = central venous cather
- Hickman, Broviac: more common
- Groshong, Midline, PICC
What does PICC stand for?
peripherally inserted central catheter
What are two examples of totally implantable device catheter? when are these used? What would be an advantage of these devices?
- Mediport, Port-a-cath
- for chemotherapy
- because it is under your skin, you are not much exposed and thus less infection potential
How long is the IV therapy for endocarditis?
When is antibiotic lock therapy and catheter used? (what patient population?)
- CVC for chemotherapy
- parenteral nutrition
Which short term CVC would you not use often, why?
- femoral., intrajugular, right subclavian
- central venous catheter = CVC
- femoral is not used because this gets infected FAST
When are Broviac (CVC) double and triple lumen catheter used?
- for very sick patients
- these catheters, however, get infected easily because they are hanging out.
How do you detect catheter infection?
Where do majority of infections in tunneled catheters originate?
What is an antibiotic lock therapy?
- instillation of highly concentrated antibiotic solution into a catheter lumen
- this allows for abx to dwell for a specified amount of time
How do you diagnose if you are infected by a catheter?
- draw 2 sets of blood samples: peripheral and catheter then compare
- cultures of removed catheter (tip) for suspected CRBSI
- catheter exit site exudate: send for gram stain and culture
What is the definition CRBSI?
- catheter related bloodstream infection
- >15 CFU (roll plate) ST
- >102 CFU (quantitative broth culture) LT
what are the likely organisms for catheter related infection?
- mostly gram positive
- some gram negative
- candida for immunocompromised patients (super sick)
How do you manage catheter related infection?
- remove catheter (but may not always be an option)
- systemic antibiotic
- replace catheter at an alternate site
- salvage therapy: systemic abx + abx lock therapy
What is a salvage thearpy?
systemic antibiotic + antibiotic lock therapy
What systemic antibiotic do you use for catheter infection if you have MSSA and MSSE?
What systemic antibiotic do you use for catheter infection if you have MRSA and MRSE?
What systemic antibiotic do you use for catheter infection if you have enterococcus?
- ampicillin +/ gentamycin
What systemic antibiotic do you use for catheter infection if you have E.coli or klebsiella?
What systemic antibiotic do you use for catheter infection if you have enterobacter or serratia?
What systemic antibiotic do you use for catheter infection if you have acinetobacter?
- ampicillin/sulbactam (Unasyn)
- NO ampicillin alone
Can you treat acinetobacter with ampicillin, if you have catheter infection?
- Yes but it has to be Unasyn
- not ampicillin alone
What systemic antibiotic do you use for catheter infection if you have pseudomonas?
- pip/taz (Zosyn) +/ aminoglycoside
What systemic antibiotic do you use for catheter infection if you have candida or albican or non-albican spp?
- echinocandin (i.e. micafungin)
- lipid AmB
When is it contraindicated for remove catheter?
- no alternative venous access
- patient has significant bleeding diathesis
- QoL is a priority compared to reinserting a new catheter at another site.
When is the abx lock therapy recommended?
for patients with CRBSI involving long term catethers when no signs of exit site or tunnel infection for whom catheter salvage ist he goal
How are you supposed to use antibiotic lock therapy?
- Should NOT be used alone.
- use with IV therapy for 7-14 days
How long should the antibiotic lock therapy dwell time be? what is the preference time?
- should not exceed 48 hours
- preference is every 24 hour
How should you use antibiotic lock therapy in HD patients?
renew the lock solution after every dialysis session
When is catheter removal recommended?
- for CRBSI due to S. aureus and candida spp, instead of treatment with abx lock and catheter retention
- however, s.aureus and candida have biofilms so hard to clear
How do you treat patients with multiple positive catheter drawn blood cultures that grow coagulase negative staphylococci or gram-negative bacilli and concurrent negative peripheral blood cultures?
antibiotic lock therapy can be given without systemic therapy for 10-14 days
Antibiotic lock therapy is most effective if ___ drug concentration is maintained for _____ period of time to maximize killing activity
What are two important factors for abx lock therapy?
- stability: stable within the lumen for the dosing interval or dwell time
- compatibility: with cathether type, with other antimicrobial used, with heparin
How do you treat coagulase negative staph catheter infection and for how long?
sytemic antibiotic + lock for 10-14 days
How do you treat long term catheter s. aureus infection and for how long?
systemic abx + lock for 4 weeks (Because this is a tough bug)
How do you treat enterococcus LTC and for how long?
systemic abx + lock for 7-14 days
How do you treat gram negative bacilli LTC and for how long?
systemic abx + lock for 10-14 days
what should you do if the catheter infection is gram positive?
check TEE or TTE to rule out endocarditis
What is the advantage of ethanol for catheter infection?
- broad spectrum antibacterial based on denaturization
- resistance is unlikely
- could be synergistic with other abx
How is the treatment success for catheter infection based?
- according to site of infection: exit site infection is more successful (lumen), tunnel or pocket infectino is less likely
- according to microbe: CoNS more successful than s.aur or pseudo. candida and biofilm organisms fail
What course of the treatment do you have to change for catheter infection if endocarditis is involved?
- the abx regimen remains the same
- however as opposed to 7-14 days, it will be 4-6 weeks of treatment.
- could be done in home care
How do you treat candida during catheter infection? how long are you supposed to treat?
- document the first time the culture comes out negative
- then treat two more weeks from this point on