PHARM Flashcards
Which genes are responsible for the structure of DNA topoisomerase II? Why is this important evolutionarily for the bug?
GyrA and GyrB, they code for proteins with the same name. Point mutations can confer resistance to fluoroquinolones
Which two fluoroquinolones are used in serious situations such as nosocomial pneumonia and inhalation anthrax? Why?
Ciprofloxacin and Levofloxacin; these are used because these serious situations require high doses and these two drugs have the best safety profiles. Gemifloxacin and Moxifloxacin do not have well established safety profiles
Which gene increases efflux of macrolides?
mef = macrolide efflux gene
By what two mechansims do macrolide antibiotics increase digoxin levels?
They inhbibit the P-glycoprotein mediated renal SECRETION of digoxin and they kill the normal flora of the gut that metabolize digoxin
T/F: Linezolid is a bacteriostatic drug
True but at high doses it may become bactericidal
A patient being treated for leukemia should probably not receive what inhibitor of the 50 S? Why?
Linezolid, it causes thrombocytopenia, anemia, and neutropenia, in patients with underlying bone marrow suppression (i.e. the chemotherapeutics this guy would get)
Which gene modifies domain V of the 23 S portion of the 50 S ribosome leading to macrolide resistance?
erm gene = erythromycin ribosome meythylase
Which 3 fluoroquinolones can be used for bacterial sinusitis?
All but Gemifloxacin? So moxifloxacin, ciprofloxacin, and levofloxacin
Why does erythromycin require enteric coating with stearates? Which ones have greater oral bioavailability and why?
Because it is a base that is destroyed by stomach acid; clarithromycyin, azithromycin and telithromycin are more acid stable
What is the most serious side effect of linezolid? What effect does it have on CYP3A4? It shares a neuro side effect with what other class of antibiotics?
Thrombocytopenia, neutropenia and anemia in pts with underlying bone marrow suppression? It has no effect on 3A4; it causes peripheral neuropathy like fluoroquinolones albeit much less often
What are the functions of the A, P, and E sites on the ribosome?
A site = entry of aminoacyl tRNA; P site is where the peptidly tRNA is formed and E is where the uncharged tRNA exits
Which drug is a lincosamide?
Clindamycin
Which genes are responsible for the structure of DNA topoisomerase IV? Why is this important evolutionarily for the bug?
ParC and ParE, make up subunits of topo IV, point mutations confer resistance against fluoroquinolones
Which gene for resistance against fluoroquinolones can be transmitted via a sex pilus?
The plasmid: quinolone resistance gene, this is exchanged between two bacteria via conjugation (use of a sex pilus)
Regarding the macrolides what are the adverse effects on the following 1) Cardiovascular 2) Musculoskeletal and 3) Hepatic
1) CV = QT prolongation 2) MSK = precipitate myasthenia gravis and 3) Hepatic = can cause cholecystitis and drug-induced hepatitis BUT telithromycin can cause FULMINANT LIVER FAILURE
This fluoroquinolone has good activity against anaerobes but overall activity on gram negatives not yet established:
Moxifloxacin (most anaerobes are gram negative, but whatever)
Which fluoroquinolones are used for community acquired pneumonia?
All but Cipro (recall: cipro is not very good against S. pneumo which is the major cause of CAP)
Which gene codes for a protein that hydrolyzes the lactone ring of macrolides?
ere which is the erythromycin esterase gene
Which macrolides are indicated for MAC pneumonia? What about syphilis?
MAC= clarithromycin and azithromycin; syphilis is erythromycin which is weird b/c most STI’s are Tx’d with azithromycin
A man who suffers from intermittent heart burn is taking fluroquinolones for an infection and isn’t getting better, why might that be?
He may be taking antacids. Antacids decrease the oral bioavailability of fluoroquinolones (as do ALL divalent and trivalent cations such as Ca and Zn)
What is indicated for Legionairre’s disease and Pertussis?
Erythromycin
Which 4 drugs can interact with the macrolides metabolized by CYP 3A4?
Theophylline, CCB’s, Warfarin, and Cyclosporine
A person with Haemophilus ducreyi is best treated with what macrolide? What should a person with H. pylori receive (macrolide-wise)?
Chancroid = Azithromycin b/c it is STI and azithromycin has good tissue penetrance and long half-life; Clarithromycin for H. pylori
What are the 3 general types of mechanisms of resistance to fluoroquinolones?
1) Mutation in the drug target via (GyrA/GyrB or ParE/ParC) 2) Mutations that affect drug accumulation (efflux pumps and porins) and 3) Plasmid mediated resistance (either/both quinolone resistance gene or variant aminoglycoside acetyltransferase)
Overall, what 5 drugs may be increased in the serum with concomittant use of macrolides (no azithromycin)?
CYP 3A4 drugs: theophylline, cyclosporine, CCB’s, and Warfarin? Also, Digoxin but not bc of 3A4 (azithromycin would only increase digoxin not the others)
Which macrolides are best for URT infections (pharyngitis, otitis media, and sinusitis)
Clarithromycin and Azithromycin
T/F: Fluoroquinolones are bacteriostatic
False. They are bactericidal
What kind of bugs is moxifloxacin best against? How is it metabolized?
Anaerobes, metabolized by the liver
If a bacterium is resistant to fluoroquinolones because it is able to modify the drug enzymatically then 1) How is it doing this? 2) How did it receive the capability to do this?
It is acetylating it with a variant of aminoglycoside acetyltransferase and it was received by conjugation (plasmid-mediated)
Where do tetracyclines and Aminoglycosides act?
30 S ribosome
Compare and Contrast the side effects of fluoroquinolones and macrolides on the cardiovascular and musculoskeletal systems:
1) CV = both cause QT prolongation leading to Torsades and maybe vent tachy 2) Quinolones cause MSK Sx of tendonitis and rupture w/ arthropathy whereas Macrolides can precipitate myasthenia gravis
Which fluoroquinolone is the only one to be metabolized by the liver?
Moxifloxacin
Ciprofloxacin is best against what kinds of microbes?
Gram negative
Which fluroquinolones are best for skin infections? Intra-abdominal infections?
Skin = levo and moxi and Intra-abdominal = cipro
Where do the oxazolidinones act? What drug is in this class?
50 S ribosome but they prevent association of the ribosome, mRNA and the f-met tRNA that initiates transcription; linezolid
How long should an acute sinusitis be Tx’d for? Chronic?
Acute = 10 days; Chronic = 2-3 weeks
Name all of the ketolides. Where do “they” act?
There is only one: Telithromycin? Act at domain V and II on the 23 S portion of the 50 S ribosome? Thus a mutation of domain V would confer resistance to macrolides but not to the one and only one ketolide
Which macrolide is best for UTI’s and why?
Azithromycin because of its good tissue penetration and long half life
What effect will the presence/expression of mef and erm genes have on macrolide activity?
1) mef is the macrolide efflux gene and it will increase efflux/decrease influx of macrolides 2) The erm gene is the erythromycin ribosome methylase gene that methylates a residue on domain V of 23 S of 50 S = macrolide resitance; however, domain II not affected so telithromycin can still be used
What was the first macrolide? Which drug is a ketolide?
Erythromycin; Telithromycin
Which macrolide will most likely need to be renally dosed if a patient has renal impairment?
Clarithromycin as 30-40% is excreted renally
Which mutations can bacteria undergo that reduce drug accumulation (of fluoroquinolones)?
mutations in porins and efflux pumps
Which drug acts on RNA polymerase (not on test)
Rifampin
What are the functions of DNA topoisomerase II and IV? Which are present in gram neg/pos bacteria?
DNA topoisomerase II (aka DNA gyrase) is responsible for relieving positive supercoiling during DNA replication. DNA topoisomerase IV is responsible for cleaving the two daughter strands of DNA after DNA replication is complete. BOTH are present in BOTH gram pos/neg bacteria
Which drug may be used to treat VRE?
Linezolid
T/F: Macrolides are bacteriostatic
True but at high doses they may become bactericidal
Which 3 fluoroquinolones are metabolized by the kidneys? Which is only given in an oral formulation?
Ciprofloxacin, gemifloxacin, and levofloxacin? Gemifloxacin is ORAL ONLY
Which macrolides would be affected by drinking grapefruit juice? Why?
Erythromycin, telithromycin, and clarithromycin because they are metabolized by CYP450 3A4 which is affected by grapefruit juice. Azithromycin can be taken with grapefruit juice
Which fluoroquinolones can be used for bacterial bronchitis?
ALL OF EM, cipro, gemi, moxi, and levofloxacin
What is the mechanism of the musculoskeletal side effects of fluoroquinolones? What is the minimum age of a person to receive fluoroquinolones?
They act directly on collagens and break them down = tendonitis/rupture and arthropathy; 18 y/o
What are the 3 mechanisms of peripheral neuropathy in fluoroquinolones?
1 +2) Via the CNS they act on NMDA and GABA receptors and 3) they can decrease blood flow to peripheral nerves (vasa nervorum)
Mutations in ParC and Par E would be most beneficial for which type of organism?
Gram positive, as these would mutate topoisomerase IV which is the enzyme most affected by fluoroquinolones in gram positives
What are the big four fluoroquinolones used? How are they metabolized?
1) Moxifloxacin (liver) 2) Ciprofloxacin (renal) 3) Levofloxacin (renal) and 4) Gemifloxacin (mostly renal)
Where do macrolides act, SPECIFICALLY?
50 S ribosome; at domain V of the 23 S RNA that makes up the 50 S
Fluoroquinolones were discovered as a by product of this drug
Chloroquine, and anti-malarial. The byproduct was Naldixic acid
What part of bacterial translation, specifically, is inhibited by macrolides?
It basically binds to the E site and stops transpeptidation and translocation of the ribosome
A patient with fulminant hepatitis should not receive which fluoroquinolone?
Moxifloxacin
What effect does the presence of the ere gene have on macrolide activity?
macrolide resistance because the ere gene is the erythromycin esterase gene and cleaves the LACTONE ring of macrolides
Are fluoroquinolones safe in pregnant women? Nursing mothers? Why or why not?
No and No (excreted in breast milk), though their safety profiles have not been elucidated in humans, they have been shown to be teratogenic in animal models
Which fluoroquinolones are best for genitourinary tract infections?
Cipro and Levofloxacin
Fluoroquinolones most strongly inhibit this enzyme in gram-negative bacteria
DNA gyrase (topoisomerase II); Topoisomerase IV is more strongly inhibited in gram positives
Fluoroquinolones most strongly inhibit this enzyme in gram-positive bacteria
Topoisomerase IV; Top II is more strongly inhibited in gram negatives
Why wouldn’t you give moxifloxacin to a patient with a UTI?
Because moxifloxacin is metabolized in the liver
Which fluoroquinolone has good activity against both gram negative and postive organisms?
Levofloxacin
Fluoroquinolones all end in -
oxacin
In an area with low incidence beta-lactamase producing H. flu and M. cattarhalis the DOC is? But if there is a high incidence you can give what?
Ampicillin, TMP-SMX
Which inhibitor of the 50 S ribosome is often reserved for last-resort MDR infections?
Linezolid
Which macrolide has the longest half life?
Azithromycin by far
What kinds of bugs is ciprofloxacin most effective against? Given that, what enzyme must it be affecting? Why isn’t it considered a respiratory fluoroquinolone?
Gram negatives, so it must inhibit Topoisomerase II the best. It takes a high minimal inhibitory concentration (MIC) to inhibit S. pneumo, and therefore is not considered a “respiratory fluoroquinolone” big deal.
Plasmid mediated resistance to fluoroquinolones via conjugation protects which enzymes?
The quinolone resistance gene protects BOTH topoisomerase II and IV against fluoroquinolones
Describe the distribution of clari, azi, and telithromycin in the following 1) Lungs 2) Serum and 3) CSF
Very high in the lungs, good in serum but most goes to lungs, and CSF distribution is MINIMAL (no good for meningitis)
Fluoroquinolones are most likely to prevent separation of replicated DNA strands in this kind of organism:
Gram positive, as this is the function of DNA topoisomerase IV which is most strongly inhibited in gram positives
Which fluoroquinolone is NOT a respiratory fluoroquinolone?
Ciprofloxacin
Fluoroquinolones are most likely tro prevent positive supercoiling in which kind of bug?
Gram negative (this is the function of topoisomerase II which is more strongly inhibited in gram negatives)
What is the mechanism of resistance to linezolid, would the bug also be resistant to macrolides?
A mutation of the linezolid binding site on 23S rRNA, NO there is no cross-resistance because the two sites are totally different
What are the adverse effects of fluoroquinolones on 1) Cardiovascular 2) Skin 3) MSK and 4) Neuro
1) QT prolongation predispose to Torsades –> vent tachy 2) photosensitivity and Steven’s Johnsons 3) tendonitis and rupture and arthropathy 4) peripheral neuropathy
Which sinuses are most commonly involved in acute rhinosinusitis?
Maxillaries followed by frontal
Which 3 macrolides are metabolized by CYP 3A4?
Clarithromycin, Erythromycin, and Telithromycin (ketolide)
Macrolides all have this suffix
thromycin
What is the general spectrum of activity for macrolides in treating bacterial pneumonias?
They can treat gram positive, gram negative and atypical bacterial pneumonias
Which fluoroquinolones are best for chronic bacterial prostatitis?
Ciprofloxacin and Levofloxacin
Which macrolide has the most intense GI complications and why?
Erythromycin b/c it structurally similar to motilin and thus increases gastric activity, and it is actually used for the Tx of gastroparesis
What is the most severe side effect of telithromycin?
Fulminant hepatic failure
