PC 2 mod 2.2 lec 11 & 13 (FQ and sulfonamides)

substitution on the main quinolone core can alter _______ and ______

- PK properties

- microbiologic activity

_____ modification on position ______ of quinilone was one of earliest modifications, leading to 10x increase in DNA gyrase inhibition

- flourine

- 6

bacteria replicate DNA by...

--> separating the double helix

--> ______ is responsible for breaking the hydrogen bonds, unwinding the stands, and stabilizing them for replication

--> ______ is responsible for synthesizing complementary DNA

--> the _____ pulls strands apart, causing supercoiling

--> _____ removes supercoiling to relieve torsional stress

- DNA helicase

- DNA polymerase

- helicase

- DNA gyrase

following complete replication, bacterial cells needs to be separated, and this is done by _______

topoisomerase IV

DNA gyrase is made of ____ subunits ____ and ____

topoirimase IV is made of ____ subunits ____ and ____

- 4 --> gyrA and gyrB

- 4 --> ParC and ParE

FQ MOA is to interfere with ______ and _____ to disrupt DNA development and daughter cell formation

- DNA gyrase

- topoisomerase IV

______ is primary target for FQ in gram -

DNA gyrase

______ is primary target for FQ in gram +

topoisomerase IV

4 FQ antibiotics

- ciprofloxacin

- levofloxacin

- moxifloxacin

- delafloxacin

______ and _____ FQ both have high BA, so IV and PO are equal

- levofloxacin

- moxifloxacin

____ and _____ FQ both have 2x daily dose due to SHORTER/LONGER halflife

- ciprofloxacin

- delafloxacin

- shorter

_____ and _____ FQ both have 1x daily dose due to SHORTER/LONGER halflife

- levofloxacin

- moxifloxacin

- longer

which FQ abx has most renal elimination?

levofloxacin

which FQ abx is primarily metabolized by liver NOT renal so does not need renal dose adjustment

moxifloxacin

do FQ distribute into CSF?

yes

are most FQ renally eliminated and need renal adjustment?

yes, except moxifloxacin

which FQ have no activity against gram +?

ciprofloxacin

ciprofloxacin has no activity against gram+, so no ______

respiratory indication

ciprofloxacin, levofloxacin, and delofloxacin have activity against ALL GRAM- except...

acinetobacter

______, _______ and _____ FQ have activity against all gram- except acinetobacter

- ciprofloxacin

- levofloxacin

- delafloxacin

what are the 2 respiratory FQs?

- levofloxacin

- moxifloxacin

which of the following gram + does levofloxacin have activity against?

a. streptococcus spp.

b. s. pneumoniae

c. viridans strep

d. MSSA/MSSE

e. MRSA/MRSE

f. E. faecalis

g. E. faecium

a. streptococcus spp.

b. s. pneumoniae

c. viridans strep

d. MSSA/MSSE

which of the following gram + does moxifloxacin have activity against?

a. streptococcus spp.

b. s. pneumoniae

c. viridans strep

d. MSSA/MSSE

e. MRSA/MRSE

f. E. faecalis

g. E. faecium

a. streptococcus spp.

b. s. pneumoniae

c. viridans strep

d. MSSA/MSSE

e. MRSA/MRSE

which of the following gram + does delafloxacin have activity against?

a. streptococcus spp.

b. s. pneumoniae

c. viridans strep

d. MSSA/MSSE

e. MRSA/MRSE

f. E. faecalis

g. E. faecium

a. streptococcus spp.

b. s. pneumoniae

c. viridans strep

d. MSSA/MSSE

e. MRSA/MRSE

f. E. faecalis

which 2 FQ does not have action against MRSA?

- ciprofloxacin

- levofloxacin

which 2 FQ have activity against anaerobes?

- moxifloxacin

- delfloxacin

high frequency of FQ resistance in _________- gram POSITIVE/NEGATIVE bacteria

- ESBL

- negative

atypical susceptibilities of FQ (3)

- chlamydia

- mycoplasma

- legionella pneumonphilia

renal adjustment for ciprofloxacin if CrCL is...

renal adjustment for levofloxacin if CrCL is...

renal adjustment for moxifloxacin if CrCL is..

NO RENAL ADJ

renal adjustment for delafloxacin if CrCL is...

mechanisms of resistance for FQ are...

--> alterations to ______

--> reduction in ________ by ______

--> reduction in ______

--> FQ/AG modifying ______

- target site

- intracellular conc --> efflux pumps

- porin channels

- enzymes

alterations to target site causing FQ resistance are usually _____ on DNA gyrase or topoisomerase IV

- point amino acid substitutions

restrict use for _____, _____ and _____ due to many side effects of FQ

- sinusitis

- bronchitis

- uncomplicated UTI

FQ can induce ______ disorders

musculoskeletal

FQ can induce musculoskeletal disorders like ________ in cartilage and joints in pediatric patients and ______ in adult patients

- development concerns

- tendonitis and tendon rupture

FQ have been associated with _____ and rupture of ______

aortic aneurysms

aortic aneurysms with FQ are more common in age ___ and course > ___ days

- >70

- >14 days

FQ can cause _____, a form of ventricular fib

QTc prolongation

avoid FQ with multiple _____ medications

QTC prolonging

FQ can cause higher risk of ______ infection

C. diff

FQ can cause disturbance of ______

--> risk of ______ in diabetic patients

--> risk of ______ more often

- blood glucose

- hypoglycemia

- hyperglycemia

5 drug-drug interaction of all FQ

- warfarin

- antidiabetic agents

- chelation agents

- QT prolonging

- NSAID

NSAID + FQ may cause increased risk of _____ due to antagonism of ______

- seizure

- GABAa

which FQ has little activity on QT interval

delafloxacin

chelation agent decrease ______ of FQ and need to be separated by 2hr

gastric absorption

ciprofloxacin is a _____ inhibitor, so can increase levels of ______ and _____ and inhibit transport of ______

- CYP1A2

- theophylline

- cyclosporine

- methotrexate

FQ are one of the only _____ options for pseudomonas

ORAL

FQ are one of the only oral options for _______

pseudomonas

FQ are primary agents for management of _______

anthrax

which 3 FQ are used for community acquired pneumonia?

- levo

- moxi

- dela

delfloxacin is used in the treatment of _____ infection by _____

- acute bacterial skin/skin structure

- MSSA or MRSA

two sulfonamides used today

- sulfamethoxazole/trimethoprim

- sulfadiazine

3 brand names for sulfa/trim

- bactrim

- septra

- sulfatrim

base of sulfonamide is _____ nucleus, with substituents to the ____ group or _____ group

- sulfanilamide

- amido

- amino

bacteria synthesize their own folic acid using ______

PABA

bacteria synthesize ______ using PABA

folic acid

MOA of sulfonamides

sulfonamides are structural analogues of ______ with inhibits ________ that is used to incorporate it to dihydropteroate acid, the precursor to ______

- PABA

- dihydropteroate synthase

- folic acid

synergistic effect of trimethoprim to sulfa is it is a potent inhibitor of ________

dihydrofolate reductase

trimethoprim is potent inhibitor of dihydrofolate reductase, which reduces _______, a derivative of folic acid, results in decrease folate synthesis and bacterial nucleotides, so less _______

- tetrafolic acid

- growth

sulfonamide PK

--> HIGH/LOW BA

--> elimination?

- high

- renal

can sulfa/trim and sulfadiazine enter CSF?

yes

sulfadiazine has reduced entry into ______ and ______ (must be topical) compared to sulfa/trim

- prostate

- eye

dosing of trim/sulfa for pneuomystis jiroveci is ____mg/kg/day divided q___h as an IV or PO?

- 15-20mg/kg/day

- q8h

- IV

dosing of trim/sulfa for cystitis is ____ SS/DS PO q___h

- 1 DS

- q12h

dosing of trim/sulfa for s. aureus ABSSSI is ____ SS/DS PO q___h

- 1-2 DS

- q12h

dosing of trim/sulfa is based on ______ component

trimethoprim

single strength (SS) sulfa/trim is ____mg/_____mg

double strength (DS) sulfa/trim is _____mg/_____mg

- 400mg/80mg

- 800mg/160mg

dosing strategy for sulfadiazine is to give ____g _____ due to HIGHER/LOWER Vd

- 2-4g

- loading dose

- lower Vd

is sulfadiazine available oral or IV?

is sulf/trim available oral or IV?

oral

both

which of the following gram + does trim/sulfa have activity against?

a. streptococcus spp.

b. s. pneumoniae

c. viridans strep

d. MSSA/MSSE

e. MRSA/MRSE

f. E. faecalis

g. E. faecium

a. streptococcus spp.

b. s. pneumoniae

d. MSSA/MSSE

e. MRSA/MRSE

which of the following gram- do sulfa/trim have activity against? (pt1)

a. neisseria spp.

b. H. influenzae

c. M. catarrhalis

d. e. coli

e. klebsiella

f. p. mirabilis

g. morganella spp

all

trim/sulfa has miscellanous activity against ______, _______, ______ and ______

-pneumocystis jiroveci

- stenotrophomonas

- nocardia

- burkholderia

does trim/sulfa cover any gram- nosocomial?

no

common gram + indications trim/sulfa cover... (3)

MRSA, MSSA, pneumonia

common indication trim/sulfa covers is _____

UTI

resistance mechanisms for trim/sulfa are _____ targets

insensitive

for trim, insensitive target resistance mechanism would be altered binding to _______

dihydrofolate reductase

for sulfa, intensive target resistance mechanism would be altered binding to

dihydropteroate synthase

severe hypersensitivity reaction trim/sulfa can sometimes cause

steven-johnson syndrome

trim has _____ sparing effects, causing _______

- potassium

- hyperkalemia

trim inhibits tubular secretion of _______, so may increase _____ but this is not true kidney injury

- creatinine

- SCr

sulfa/trim is in pregnancy category ____

--> can cause _____ during first trimester

--> can cause ______, _____ or _____ if near term due to crossing of placenta

- D

- congenital abnormalities

- jaundice, hemolytic anemia, kernicterus

_____ is more likely to cause interstitial nephritis or crystalluria and this is due to crystals being precipitated by acidic pH

sulfadiazine

sulfadiazine may cause _______ or ______ due to crystals from _____ pH

- interstitial nephritis

- crystalluria

- acidic

risk of hemolytic anemia from sulfonamides increases in those with ____ deficiency

G6PD

trim is inhibitor of _____ and _____ (pharmacogenomics)

sulfa is inhibitor and substrate of _____

- CYP2C8 and OCT2

- CYP2C9

sulfonamides can interact with what drug?

warfarin

trim/sulfa is first line agent for what organisms....

--> _______ (treatment AND prevention)

--> ______

--> _______

--> _______

- pneumocystis jirovecii

- nocardia

- stenotrophononas maltophilia

- burkholderia cepacia

is trim/sulfa inferior or superior to anti-staph beta-lactams for MSSA?

inferior

sulfadiazine is used primarily for treatment of ______

toxoplasmosis

______ is used for treatment of toxoplasmosis

sulfadiazine

______ target dihydropteroate synthase

_____ targets dihydrofolate reductase

- sulfonamides

- trimethoprim

which FQ has no activity against psuedomonas and acinetobacter?

moxifloxacin

which FQ is the only one with no activity against pseudomonas?

moxifloxacin

SULFA-TRIM/SULFADIAZINE has reduced entry into prostate and eye

sulfadiazine

which of the gram+ do trim/sulfa not have activity against ...

- viridan

- enterococcus

_____ is inhibitor of CYP2C8 and OCT2

_____ is an inhibitor of CYP2C9

- trim

- sulfa

do sulfonamides or FQ have high BA?

sulfonamides