30. Intro to antimicrobials Flashcards
do you want drugs with a high or a low therapeutic index?
high (ie toxic concentration is much higher than the concentration necessary to kill the bug)
properties of good antimicrobials?
high therapeutic index
desirable spectrum of activity
low potential for resistance
favorable Rx properties
low cost
why are all antimicrobials considered toxic?
decimate microbiota, select for resistant microorganisms, and can have adverse effects on other patients (global rise of antimicrobial resistance) EVERY TIME YOU USE ONE
what class of drugs target RNA pol?
rifamycins
what class of drugs target cell wall?
penicillins, cephalosporins, glycopeptides
what class of drugs are 30S ribosome inhibitors?
aminoglycosides, tetracyclines
what class of drugs are 50S ribosome inhibitors?
macrolides, oxazolidonones
what class of drugs inhibit intermediary metabolism?
trimethoprim, sulfonamides
what class of drugs target cell membrane?
lipopeptides
what class of drugs target topoisomerase?
quinolones
when to use broad vs narrow spectrum abx?
broad if don’t know organism or for polymicrobial infections
narrow if know causative agent via cultures
bacteriostatic vs bacteriocidal?
bacteriostatic:
- stops growth
- MBC»_space;> MIC
bactericidal:
- results in 99.9% reduction in number of organisms
- MBC achievable
often unnecess to kill bug completely, because once you slow it down, the adaptive and innate immune systs will take care of it. Endocarditis is an exception because it is in a privilaged site, or ppl taking bactericidal antibiodics when have no neutrophils (chemo) or for treating meningitis
intrinsic vs acquired resistance?
intrinsic: drug was never effective vs bug
- can’t get in
- target different or absent
acquired: most isolates formerly susceptible
- may no longer be true
- genetic change
- selected by time
- theoretically reversible
steps in folate synthesis?
PABA (bacteria only)
dihydropteroic acid (thanks to dihydropteroate synthetase, inhib by sulfonamides)
dihydrofolic acid
tetrahydrofolic acid (thanks to dihydrofolate reductase, inhibi by trimethoprim)
sulfonamides are usually used in combo with what? why?
sulfamethoxazole (TMP - SMX, co-trimoxazole)
enhances activity (synergy), bactericidal vs many microbes, decreases emergence of resistance
TMP-SMX use?
broad activity
- vs gram negatives
- increasingly used vs S. aureus
- active vs some protozoa and fungi
- (pseudomonas, most enterococci resistant)
excellent bioavailability (gets into prostate and CSF no problemo)
excellent tissue penetration
- excreted unchanged in urine (so used for UTIs)
- penetrates prostate, CSF
used for infections of urinary, respiratory (esp sinusitis and otitis media) and GI tracts
increasing use for skin and soft tissue infections due to increasing resistance of S.aureus to other agents
inexpensive
TMP-SMX resistance?
TMP:
- acquisition of plasmid encoding alternate dhfr gene
- often transposon (Tn7) or part of integrons
(resistance in E.coli is now common, resistance in S. aureus is uncommon)
sulfonamides
- can be due to chromosomal mutation
- acquistion of a plasmid encoding alternative alleles of gene encoding dihydropteroate synthetase
TMP-SMX adverse effects
common
- rash
- nausea, vomiting, diarrhea
less common
- hyperkalemia (high doses or renal insufficiency)
- hepatitis, pancreatitis
severe (rare)
- stevens-johnson syndrome and TEN (toxic epidermal necrolysis)
- aplastic anemia, thrombocytopenia, anemia
- hyemolytic anemia (G6PD deficiency)
pregnancy
- kernicterus (late in pregnancy due to SMX)
- early in pregnancy TMP is teratogenic
drug interactions
- displaces warfarin, phentoin, others from albumin
TMP-SMX route of admin
PO or IV BID or qD
DNA gyrase?
topoisomerase II (gyrA and gyrB) creates supercoils
forms transient covalent bond to DNA via phospho-tyrosine
topoisomerase IV?
(parC and parE) - de concatenates intertwined chromosomes
form transient covalent bond to DNA via phospho-tyrosine
quinolones mechanism?
stabilize the enzyme(topoisomerase)-DNA complex w/dsDNA breaks
interferes w/ DNA rep and RNA txn
eventual chromosome fragmentation results in lethality
all quinolones have broad activity vs what?
gram- bacteria (gyrase/Topo II inhibition impt) and atypicals (mycoplasma, chlamydia, legionella) and mycobacteria
ciprofloxacin has relatively poor activity vs what? (making it apoor drug for respiratory infections)
streptococci
gram+ activity of quinolones requires what?
Tpop IV inhibiiton
bioavailability of quinolones?
good orally, but poor absorption in presence of divalent cations (antacids, Fe, Zn)
most excreted in urine except for moxifloxacin
long half-lives for BID or qD dosage
ciprofloxacin targets what?
DNA gyrase, concetrated in urine so used for UTIs
moxifloxacin targets what?
gram+ and anaerobic activity - pneumonia, mycobacterial infectoins, polymicrobial (anaerobic) infections
fluoroquinolone resistance?
across class, can develop during therapy
mutations in taget enzyme
- gyrA or parC near active site tyrosine
- differ by org (single mutation in S. aureus, double in E.coli, global E.coli clone now!)
efflux pumps
- derepression of MDR transporters (evolved to have high level expression)
Fluoroquinolone adverse effects?
safe
nausea, vomiting, abd pain, headache, dizziness
can prolong QT interval in combo w/other drugs
tendon rupture
potential for arthropathy in children?
mechanism of Nitrofurantoin action?
DNA inhibitor
nitrofurantoin spectrum of activity?
active vs gram+ and gram- uropathogens including Staph saprophyticus, strep agalactiae, enterococcus faecalis, E. faecium, E.coli, Klebsiella pneumoniae
NOT vs proteus spp,, pseudomonas spp., or serratia marcescens
pharma properties of nitrofurantoin?
admin PO, does not reach adequate serum levels, but concentrated in urine
use for nitrofurantoin?
UTI
adverse effects of nitrofurantoin?
nausea is common
pulmonary fibrosis rare (occurs w/chronic use)
rifamycins mechanism?
bind to B subunit of RNA polymerase and block txn
bacteriostatic
resistance of rifamycins?
evolves rapidly due to mutations in binding pocket super frequently
frequently preexist in the population, which limits effectivenes
rifampin specific side effects?
turns urine/secretions orange
potent inducer of P450 3A4, so increases metabolism of many drugs
rifabutin specific side effects?
levels can rise in presence of inhibitors of p450 3A4 (like macrolide antibiotics)
rifaximin use?
GI only (not absorbed)
rifamycins use?
for prophylaxis:
- eradicate carriage of Neisseria meningitidis, S. aureus
in combo w/other antimicrobials
- mycobacterial infections
- for synergy in serious bacterial infections
for GI infections (rifaximin only)
rifamycins adverse effects?
GI (pain, nausea, vomiting, diarrhea)
hematological (mild thrombocytopenia, leukopenia, anemia)
hepatitis (w/other drugs or pre-existing liver disease)
fidaxomicin mechanism
blocks RNA pol by preventing formation of open DNA complex
fidaxomicin side effects?
none reported
fidaxomicin use?
poor activity vs Gram- enteric flora including gram- anaerobes
approved only for C.diff infections (w/ fewer relapses than vancomycin)
but super expensive
