Principles of Antibiotic Use - Walworth 4/25/16 Flashcards
what features of microbes allow for selective toxicity?
unique targets:
- bacterial cell wall
- unique fts of fungal plasma membrane
- biosynthetic pathways unique to microbes
preferential targets:
- bacterial ribosome
- dihidrofolate reductase (DHFR)
classification of antimicrobial agents
target…
- cell wall synthesis
- penicillin, cephalosporin, vancomycin
- cell membrane
- antifungals, daptomycin (G+ bacteria)
- protein synthesis
- 50S inhibitors, 30S inhibitors
- DNA replication (DNA gyrase)
- quinolones
- transcription
- rifampin
- folic acid productin (DHFR)
susceptible vs resistant
susceptible: possible to achieve a concentration of the drug at the site of infection such that…
- it inhibits organism
- it isn’t toxic to human cell
resistant: concentration that is inhibitory/bactericidal is greater than what can be achieved safely
therapeutic index
ratio of toxic dose/effective dose
antibiotics? typically large
susceptibility and resistance:
bacteriostatic vs. bacteriocidal
bacteriostatic: pop doesn’t increase/decrease → stays constant
- ex. protein synthesis inhibitors (except aminoglycosides - bacteriocidal)
bacteriocidal: drop bacterial pop
- ex. cell wall-active agents, rifampin, quinolone
empirical definitions! have their limits
MIC/MBC
how do you determine whether an agent is bacteriostatic or bacteriocidal?
MIC: minimal inhibitory conc
- take dilutions of a drug, add bacteria in a dilution test → MIC is lowest dilution at which bacteria does not grow
MBC: minimal bacteriocidal conc
- take all dilutions at which bacteria did not grow (MIC and higher) and plate them in an Agar test → MBC is lowest concentration at which there is no growth
- there’s no drug in the agar, just growth medium → any dilution at which bacteria were inhibited but not killed will show growth
if MBC is within therapeutic range: bacteriocidal
if MIC is within therapeutic range, but MBC is not: bacteriostatic
limitations
- static/cidal can vary based on growth medium
- static/cidal can vary based on organism
factors that influence susceptibility
site of infection
- concentration that can be achieved in serum, CSF, vitreous humor, urine etc varies!!!
local factors
- low pH, high protein conc, anaerobic conditions
general uses of antimicrobial therapy
disease-therapy timeline
- prophylactic
- empiric
- definitive
disease-therapy timeline
no infection → prophylaxis
infection →
preemptive
symptoms →
empiric
pathogen isolation → definitive
resolution → suppressive
uses of antimicrobial therapy
definitions
examples (if applicable)
1. prophylactic therapy
- preventative therapy - usually targeted towards likely infectants
ex. prevent wound infection after surgery
2. empiric therapy
- aims to cover all likely pathogens (since specific infecting org not yet identified) based on etiology or site of infection
- should use cultures from site of infection and blood before starting therapy
- ideally single broad-spectrum agent, but can also use combo therapy
3. definitive therapy
- aims are identified pathogen via specific, narrow-spectrum agent
- duration? depends on pathogen, site of infection, host factors
- monitor therapeutic response microbiologically/clinically
combination therapy
should be the exception, not the rule!
epirical therapy of severe infection when causative agent is unknown
why might you do it?
- polymicrobial infection
- enhance antimicrobial activity against a specific infection
- prevent emergence of resistance
- reduce tox to host
ex. TB, esp MDR-TB
drug-drug effects of combinatorial therapy
often use drugs with diff mechs of action
synergistic : one drug makes bug more sensitive to inhibitory action of another drug
- bactericidals tend to be either synergistic or additive (cell wall synth inhibitor + aminoglycoside)
additive : drugs work indep of each other
- bactericidals tend to be either synergistic or additive (cell wall synth inhibitor + aminoglycoside)
indifferent : combo works same as each individually
antagonistic : combo less effective than individuals
- bacteriostatics antagonize activity of bactericidals (tetracyclines + beta-lactams)
*
antibiotic misuse
overprescription driven by…
- patient demand
- time constraints on physicians
- diagnostic uncertainty
major consequence: emergence of resistant organisms!!!
can arise from…
- failure to document causative organism (not able to narrow) or to narrow once definitive therapy possible
- treating nonresponsive infection, fevers of unknown origin
- wrong dosage
- improper reliance on chemo alone
- lack of adequate bacteriological info (compensated for by multiple broad spectrum agents)
antibiotics
natural products produced by microorgs that suppress the growth of other microorganisms, may eventually destroy them
- today, also includes synthetic antibacterial agents
