Antimicrobials Flashcards
Criteria for TDM
- narrow therapeutic window
- large inter patient variability (or intra)
- method to use measure level (timely)
- does not replace patient assessment and monitoring
Why do we monitor anti microbial drug levels?
- Optimize serum levels
- too low conctn = more susceptible organisms will be killed off while organisms with increased likelihood of resistance will survive => resistance and treatment failure - Minimize toxicity
- sustained high drug conctns put the pt at increased risk of experiencing adverse effects - Research
Vancomycin therapeutic window
Narrow!
<10mg/L = lacks effectiveness
> 20mg/L = toxic
Streptomyces orientalis
Vancomycin
What does vanc do?
Inhibits bacterial cell wall synthesis
- used to treat resistant GPB = CNS, S.aureus, Enterococcus
Very large molecule so makes it hard to pass across membranes = difficult to penetrate to site of infection
Pharmacodynamics of vanc
- slow kill = may even be bacteriostatic against some
- inoculum dependent = less effective w larger inoculum
- time dependent bacterial kill (AUC/MIC)
> requires multiple blood draws
> infusion would provide consistent AUC/MIC
> maintaining trough levels 4-6x MIC appears ideal
Red neck syndrome
- vancomycin
- more frequent with older prep
- hypotension, flushing, upper body rash
- minimize risk by increasing vol of infusion, slowing infusion rates
Vancomycin nephrotoxciity
- when it was impure = more prevalent
- increased toxicity when combined with aminoglycoside
T or F. The higher the trough of vanc, the greater type chance of nephrotoxicity
T
Ototoxicity
Vancomycin
- auditory nerve damage and hearing loss
- 80-100 mg/L
- current literature refutes the existence of this
Monitoring vancomycin
- routine levels no recommended
- consider levels in select patients
> deteriorating or unstable kidney functions
> morbidly obese
> therapy greater than 2 was
> infants and children w serious infection
> CSF infections
> CF, burns (rapid clearance)
> dialysis patients
draw trough level when pt is t steady state - before 5th dose usually
When do we collect specimen for vanc trough level
30 mins or less before next dose
- first level at steady state and after at lest 2 MDs
dont rush= closer u wait, closer to steady state
**some pts may need level sooner = obes, high Rena function (peds)
Subsequent levels once/week
Vancomycin at <10 mg/L trough
Decrease interval or increase dose
Vancomycin at 10-20 mg/L trough
Target troughs
Vancomycin at > 20 mg/L trough
Increase interval or decrease dose
When do we order random vanc levels?
- pts with unstable kidney function
- do not get regular doses of Van but rather get doses based on levels
(Random levels until desired level then give another dose)
Aminoglycosides
Gentamicin
Tobramycin
Alika in
What do aminoglycosides target?
Gram negative active agents
Dosing aminoglycoside
- concentration dependent killing
> more bacteria killed w high conctn
> measure peak levels to assess efficacy - narrow therapeutic index
> drug saturates in kidneys and auditory system
> requires low drum level to diffuse back out an avoid toxicity (accumulation)
> measure trough levels to minimize toxicity - optimize dosing w high doses and time to recover
> conventional and extended interval
Adverse effects of aminoglycosides
Nephrotoxicity - usually reversible
Ototoxicity - may be irreversible
> hearing loss, loss of balance
Risk factors:
- unadjusted doses, duration of treatment, hypovolemia, hypotension, other nephrotoxic/Ototoxic drugs
T or F. AG nephrotoxicity is generally reversible
T
- usually occurs 5-7 days into treatment
- can even occur after D/C
Risk factors: duration of therapy, baseline renal function, other kidney insults, elevated trough leve;s
T or F. Auditory Ototoxicity in AG is reversible
F! May be irreversible
- congenital mitochondrial dysfunction notable (avoid AG if toxicity reported on maternal side)
- warning: tinnitus, sense of fullness in ears
Vestibular totoxicity
- usually occurs 5-14 days after initiation of AG therapy
- has occurred with IP, inhaled AG therapy
- symptoms can happen independently of drug levels
Symptoms of vestibular ototoxicity
- disequilibrium: vertigo, nausea/vomiting, headache
- oscillopsia: objects appear to move back and forth esp. with head movement
- nystagmus: involuntary rapid eye movements
When should patients on AG be told to watch and report signs and symptoms of ototoxicity
After seven days of therapy
What is extended interval dosing
- employs principles of concentration dependent kill and drug-free intervals
- takes advantage of post-antibiotic effect
- contraindicated = endocarditis, dialysis patient, cystic fibrosis
- precautions: liver disease, pregnancy, severe renal dysfunction
3 general classes of anti fungal (systemic)
- Polynesian = amphotericin B
- echinocandins= caspofungin, micafungin, anidulafungin
- new triazoles = flucoazole, viconazole, etc.
Invasive fungal infections mostly an issue in ….
Immunocompromised pts
antifungal that may require TDM
amphotericin
- toxic; may qualify
- BUT cannot be monitored with blood/serum levels
Voriconzole TDM?
nonlinear
evidence of association of effect and toxicity with levels
therapeutic range for efficacy: antifungals
trough blood level more than 1 mg/L for clinical outcomes
therapeutic range for toxicity of antifungals
trough blood level less than 5.5 mg/L for safety
Voriconazole properties
- active against lots of yeast and several mold infections
- narrow ther index: 2-5.5 mcg/mL
- well absorbed = 96% bioavail
- highly metabolized by CYP2C19, CYP2C9, CYP3A4 = 8 metabolites
- extensive tissue distribution
- 80% of metabolites eliminated in urine
- half-life = 6 to 12 hours
other azoles where TDM applies:
itraconazole
posaconazole
isavuconazole
voriconazole TDM recommendations
- target range = 1.0 to 5.5 mg/L
- level after 5-7 days on same dose
- assay performed at UAH twice weekly on tandem MS
T or F. Linear PK is much easier to manage for pts on antimicrobial therapy
T!
