abx concept Flashcards
empiric vs directed therapy
empiric = founded on practical experience but not proven scientifically (initiation of treatment prior to determination of firm diagnosis)
directed = based on MICs from culture
how to choose an antibiotic empirically
- guidelines
- knowledge of what bugs cause what infections
- knowledge of susceptibilities of bugs in different settings
pros and cons of using broad spectrum drugs
pros: improve odds of favorable outcome, reduce odds of bad outcome, lessen suffering
cons: cost, toxicity, stewardship
MIC
lowest concentration that inhibits growth after 18-24 hrs
methods for determining MIC
- microbroth dilution
- automated susceptibility testing
- disk diffusion + ZOI
- E-test
MIC breakpoint
concentration of an antibiotic that determines whether a species of bacteria is susceptible or resistant (MIC <= breakpoint is susceptible)
pharmacokinetics vs pharmacodynamics
what the body does to the drug (ADME) vs what the drug does to the body
PK/PD principles to consider in antibiotic selection
- oral bioavailability
- distribution to different compartments (central vs peripheral)
- clearance
- Vd
what are “protected” sites in the body?
- csf
- eye
- prostate
- biofilm
concentration dependent killing
- aminoglycosides, fluoroquinolones, metronidazole
- rate of bactericidal killing maximized at Cmax in serum
- when [drug] < MIC, persistent growth suppression due to post-abx effect (PAE)
- high, extended interval dosing to maximize peak [drug]
time dependent killing
- B-lactams
- bacterial killing based on amount of time where serum [drug] > MIC…must be > 40-50% of the time for effective killing
- peak serum concentration irrelevant and no PAE
- increased frequency with lower dosing to maximize time > MIC
concentration and time dependent killing
- AUC/MIC
- vanco, dapto, tetracyclines, macrolides
which antibiotics require therapeutic drug monitoring and why?
- vancomycin and gentamicin
- direct relationship between [drug] and efficacy/toxicity
- inter-patient variability in serum [drug] with standard dosing
- low TI
- efficacy/toxicity delayed or hard to measure
- available assay
cidal vs static
cidal kill bugs
static inhibit growth but depend on host defense to kill organism
when are cidal drugs necessary?
- can’t rely on host immune response (immunocompromised)
- septic shock, meningitis, endocarditis
pros and cons of double coverage
pros: synergy, anticipate resistance and presence of multiple organisms, prevent emergence of resistance
cons: more adverse effects, increased risk of colonization with resistant bugs, antagonism, cost
adverse consequences of abx use
- antibiotic associated diahrea
- c diff colitis
- damage to microbiome
common mechanisms of antimicrobial resistance
- reduced entry of abx into cell
- efflux pumps (esp in gram negatives)
- production of microbial enzymes that destroy the drug
- modification of target
- decoy binding sites
- alteration of microbial proteins needed to activate prodrugs
- alternative pathways
how is resistance spread?
horizontal gene transfer via transformation, transduction, and conjugation
most urgent threats by resistant bugs
CRE, C. diff, resistant neisseria gonorrhoeae
B-lactam ADE
allergic reactions and anaphylaxis
aminoglycoside ADE
nephrotoxicity
vancomycin ADE
red man’s syndrome
fluoroquinolone ADE
achilles’ tendon rupture
linezolid ADE
bone marrow suppression (leukopenia, thromocytopenia)
daptomycin ADE
myopathy
TMP-SMX ADE
stevens-johnson syndrome
type I hypersensitivity to drug
- immediate
- IgE mediated
- urticaria, angioedema, anaphylaxis
type II hypersensitivity to drug
- cytotoxic; IgG mediated
- immune hemolytic anemia, thromocytopenia
type III hypersensitivity to drug
- immune complex mediated (IgG bound drug)
- serum sickness, drug fever, vasculitis
type IV hypersensitivity to drug
- delayed (days)
- T cell mediated
- maculopapular rash, contact dermatitis, fixed rug eruption, stevens-johnson, toxic epidermal necrolysis
B-lactam cross-reactivity
- more likely with similar side chains
- type I reaction to penicillin => 5-10% with cephalosporin
- azetreonam is not cross reactive (unique side chain)
- if reaction to one B-lactam is a rash, likely to be reaction to all (unlikely that a different one will cause anaphylaxis)
death toll and $ cost of antibiotic resistance
- 2 million infections with 23,000 deaths annually in US
- $20 billion in healthcare costs + $35 billion in lost productivity
