Nucleic Acid Synthesis Inhibitors Flashcards
What is the mechanism of Rifampin?
A bactericidal drug that binds bacterial RNA polymerase at the active center, blocking the elongation of mRNA
What is the spectrium of Rifampin?
Broad: GRam + and - plus Mycobacteria tuberculosis
WHat do intrinsic resistance and acquired resistance to rifampin occur?
Intrinsic resistance- in some bacterial strains the drug is unable to bind to the β subunit of RNA polymerase
Acquired resistance- the strain acquires mutations in rpoB gene preventing drug binding (alteration of the target)
What are the side effects and toxicities of rifampin?
Side effectis: GI side effects (nausea diarrhea)
Hypersensitivity reaction is a FEVER, which is unusual
Toxicity: Hepatotoxic, so use caution when administering to patients with chronic liver disease
It causes the induction of cytochrome p450 enzymes, which will increase the metabolism of other medicines leading to organ rejection (if on immunosuppresssant) and loss of seizure control (if on AEDs)
TURNS BODY FLUIDS ORANGE!!!
What modificiation must occur to rifampin for it to be excreted in the feces? What happes to it if the modificaiton doesn’t occur?
Deacetylation of rifampin in th liver will place the drug into bile which will go to the GI tract and be excreted as feces.
If the deacytelation doesn’t occur in the liver, the drug will still be brought into the bile thorugh the GI tract, but instead of being excreted it will be reabsorbed back into the blood.
So impairmed liver function leads to highe rblood serum levels
What is the mech of ocation for fidaxomicin?
What is its spectrum?
Its a bactericidal drug that inhibits RNA polymerase by binding to sigma subunit of RNA polymerase.
It has a narrow spectrum and targets gram positive anaerobes. This makes it a good treatment for C diff.
How does resistance develop to Fidaxomicin?
Would you expect rifampin and fidaxomicin to exhibit cross resistance?
Resistance arises from point mutations in RNA polymerase (but this has only been observed in vitro–probably because the drug is so new still)
You would not expect rifampin and fidaxomicin to exhibit cross resistance because they have different tarets.
What are the side effects of fidaxomicin?
Low absoprtion, nausea, vomiting
WHat are the 3 fluoroqinolones we need to remember?
Ciprofloxacin
levofloxacin
moxifloxacin
What is the mechanism of the fluoroquinolones?
What is the spectrum?
Bacteridical drugs that inhibit DNA replication by binding bacterial DNA topoisomerase.
Spectrum: Broad coverage for Gram + and -, plus atypicaly organisms like mycoplasma
How did resistance develop to the fluoroquinolones?
First of all, they were heavily overprescribed because they have such a broad spectrum.
Resistance has developed due to inceased efflux pumps
and
mutation in topoisomerases
Specifically what two topoisomerases do the fluoroquinolones bind to?
Which topoisomerase is a better target for gram + and which is a better target for gram -?
Topo II (gyrase) and Topo IV
Inhibition ot toto2 prevents relaxation of positivley supercoiled DNA that is required for normal transcription and replication —–best for gram -
Inhibition of topo4 interferes wtih the separation of replicated chromosomal DNA (decatenation) intot he respective daughter cells during cell diviison —–gram +
Ultimately, what happens to the DNA when fluoroquinolones bind to the topoisomerases?
you get double stranded DNA breaks that cause cell death
What drug is used to treat and prevent illnesses that are deliberately spread thoruhg biological warfare like plaue, anthrax or tularemia?
ciprofoxacin
What are the side effects for the fluoroquinolones?
GI side effects
confusion
photosensitivity
tendon rupture
prolongation of the QT itnerval
DO NOT USE IN PREGNANT WOMEN
What is important NOT to take with fluoroquinolones?
Don’t take calcium, iron, aluminum, or zinc and avoid dairy products/calcium-fortified juice
bcause the chelate cations decrease the amount of absorption of the drug
You would need to adjust dosage for renal dysfunction for all the fluoroquinolones EXCEPT….
moxifloxacin–it’s not excreted intot he urine
Why are fluoroquinolones good for UTIs?
They have good bioavailability and willeffectively reaches the urine.
What are the two folate antagonists we learned about?
sulfonamides
trimethoprim
How do sulfonamides work?
What will they work against?
WHy do they not affect humnans?
Sulfonamides indirectly block DNA synthesis by blocking the folate synthesis pathway
Specifically, sulfonamides are PABA analogs that act as competitive inhibitors of dihydropteroate synthetase
Bacteria and fungi that syntheisze thier own dihydrofolic acid are sensitive to sulfonamides.
Mammals gets dihydrofolic acid in their diets, so this doesn’t affect them.
What bacteria will be resistant to sulfonamides?
How does resistance develop?
Bacteria that uptake dihydrofolic acid
are resistant to Sulfonamides as long as there is
enough dihydrofolic acid around.
Acquire resistance through changes in the dehydropteroate synthetase, increased efflux, or increased production of PABA (so it could outcompete the drug)
What is the sulfonamide we need to remember?
sulfamethoxazole
Are sulfonamides bacteriocidal or static?
Sulfonamides themselves are bacteriostatic, but if given with trimethoprime, they become bacteriocidal
What are the adverse effets of sulfonamides?
Hypersensitivity is SUPER common: rash, stevens-johnson syndrom
They will cross react with any other drugs containing sulfonamid moieties, which causes crystalluria leading to acute renal failure
If given to someone with glucose 6-phospahte dehydrogenase deficiency, there will be hemolysis of RBCs
Sulfonamides can also compete for binding to albumnin, leading to an increase in bilirubin which can accumulate in the brain anc cause kernicterus in infants and complications with drugs like warfarin
What is the mechanism of action for trimethoprim?
Is it bacteriostatic or cidal?
Trimethoprim inhibits bacterial dihydrofolate reductase (DHFR) so you don’t get conversion from FH2 to FH4
This is bacteroststic on it’s own, but cidal if given with sulfonamides
How does resistanc edevelop to trimethoprim?
Alterations in DHFR
Increased amounts of DHFR
THe use of alternative metabolic pathways (rarer)
What are some adverse effects of trimethoprim?
Bone marrow suppression (becausei t can block folate synthesis in humans as well)
Hyperkalemia
What is bactrim?
What is its spectrum?
It is the combo drug of trimethoprim and sulfamethoxazole!
It has a braod spectrum for treatmen tof UTIs, Shigella, Salmonella, and Pneumocystit (so it covers fugi as well!)
What is the mechanism for metronidazole?
Bactericidal—metronidazole acts like an electron sink which when activated will generate free radicals leading to DNA strand breaks and cell death.
What is the spectrum for metronidazole?
Protozoa
anaerobic bacteria including C diff
What are the adverse side effects of metronidazole?
nausea, diarrhea, headache, and METALLIC TASTE
avoid during pregnancy!!!!!
Causes a disulfiram-like reaciton with alcohol
WHy is metronidazole only metabolized to the active form in anaerobes, not aerobes?
It requires ferredoxin to reduce the drug into the active form.
In aerobes most of the ferredoxin is in the oxidized form already, so its unablel to metabolize the drug to its active form
What happens in the disulfiram-ethanol reaction?
Metronidazole blocks aldehyde dehydrogenase, inhibitin the oxidation of acetaldehyde and causing a marked icnrease in acetaldehye concentrations after ethanol consumption
THe symptoms of this arejust severe hangover symptoms
Besides metronidazole, which other antibiotic class that can cause disulfiram reactions and should therefore not be consumed with alcohol?
2nd gneration cephalosporins
What is the most likely organism causing UTIs?
E. coli
What is the preferred treatment for E. coli UTI?
Nitrofurantoin!
Most e coli are resistant to beta lactams and are developing resistance to the bactrin (TMP-SMX combo)
What is the mechanism of nitrofurantoin?
It’s bactericidal– the drug is reduced by bacterial flavoproteins to produce reactive intermediates that can inactivate or alter bacterial ribosomal proteins and other macromolecules, leading to inhibition of DNA synthesis, RNA, cell wall, and protein synthesis
What is nitrofurantoin’s spectrum?
What is the only type of infection its used for?
It has a very broad spectrum, but it’s rapidly excreted in the urine and doesn’t reach high concentrations anywhere else, so it’s used specifically for UTIs
What is there no resistance to nitrofurantoin?
Because the drug interferes with a variety of processes
What are the acverse effects of nitrofurantoin?
vomiting and pulmonary toxicity
Upregulation of PABA synthesis is associated with the development of drug resistance twoard which antibiotic?
Sulfamethoxazole
Which drug is most likely to cause anemia in individuals with glucose-6 phosphate dehydrogenase deficiency?
Sulfonamides
Resistance to which drug occurs following the acquisition of mutations in DNA topoisomerase
fluoroquinolones
What drug would you use for empiric therapy in a patient with signs and symptoms of a UTI with a positive urinalysis?
Nitrofurantoin
