DNA/RNA inhibitors

fluoroquinolones end in ____

inhibit ____

act in _____

floxacin

inhibit DNA gyrase

act in nucleus

what kind of coverage do fluoroquinolones have?

broad spectrum gram-negative and gram-positive

fluoroquinolones MOA

inhibit DNA gyrase

prevents relaxation of supercoiled dna

are fluoroquinolones bacteriostatic or bactericidal?

time, concentration, or AUC dependent?

bactericidal

concentration-dependent

fluoroquinolones

R1 determines:

potency and dosing profiles

hydrophobic: penetrate more

hydrophilic: increases systemic circulation and half life

fluoroquinolones

R5 determines:

cell wall penetration in different types of anaerobes

fluoroquinolones

R7 determines:

gram+ or gram- bacterial susceptibility

fluoroquinolones

pharmacophore is essential for _____ and acts as a ______

gyrase binding

competitive inhibitor

fluoroquinolones

warnings and precautions

QTc prolongation

glucose regulation

photosensitivity

superinfection: c. diff

hepatotoxicity

teratogenic

AMS

fluoroquinolones

black box warning

tendinitis, tendon rupture

may exacerbate myasthenia gravis

only use for certain things if no other alternatives; don’t use for less severe infections

fluoroquinolones

FDA safety alert

aortic dissections or ruptures

avoid in pts with heart stuff, including HTN

fluoroquinolones

drug interactions

separate?

QTc prolonging meds

multi-valent cations

chelation between carboxylic acid and keto groups

decreased absorption

separate: give FQ 2 hours before or 4-8 hours after

fluoroquinolones

resistance

point mutations:

-Qnr proteins

-variant form of aminoglycoside acetyltransferase (modify cipro)

efflux pump over expression

decrease in permeability of bacteria cells

T/F

all fluoroquinolones are available IV and PO

true

functional groups of ciprofloxacin and what they do

R1: 3 C ring

R7: piperazine ring with basic N

-oral efficacy

-gram positive activity

-half life

X8: carbon only

-limits scope of anaerobe activity

cipro spectrum of coverage

pseudomonas!!!!!

T/F cipro is used for CAP and ABSSSI

FALSE

only FQ NOT used for CAP

only FQ NOT used for ABSSSI (no good gram+ coverage)

cipro clinical indications

pseudomonas inection

levofloxacin R groups and what they do

R7: piperazine ring with methyl group

-increased half-life

-CNS penetration

X8: ring with an O

-enhances gram-negative activity

-reduces photosensitivity

levo spectrum of activity (hint: think anything respiratory)

pseudomonas

MSSA

strep pneumoniae

atypicals

h. influenzae

what are the respiratory fluoroquinolones?

levofloxacin

moxifloxacin

what fluoroquinolones cover pseudomonas?

cipro

levo

dela

moxifloxacin R groups and what they do

R7: two rings

-increased lipophilic character

X8: OCH3

-second most therapeutically effective group

what is the only FQ without pseudomonas coverage?

moxi

what is the only FQ with anaerobe coverage?

moxi

why is moxifloxacin not used for UTIs?

doesn’t concentrate well in urine because it doesn’t get eliminated through kidneys…therefore doesn’t need renal dose adjustment

what is the only FQ that does NOT need renal dose adjustment?

moxi

what FQ can be used as monotherapy for intra-abdominal infections?

moxi

delafloxacin R groups and what they do

X8: Cl

-halogen

-most therapeutically effective substitution

-increases polarity

-increases binding

-increases absorption profile

T/F delafloxacin has a very broad spectrum of activity but is only approved for ABSSSI

TRUE

because it’s new

what is the only FQ with MRSA coverage?

dela

what is the ONLY antibiotic on the market with pseudomonas and MRSA coverage?

delafloxacin

per kearns: what fluoroquinolone has a BBW for tendon rupture and peripheral neuropathy

note sing has BBW for tendon rupture for all FQs

delafloxacin

is metronidazole bacteriostatic or bactericidal?

bactericidal

metronidazole requires activation which only occurs in _____

anaerobes and protozoa

metronidazole takes advantage of nonenzymatic reaction, what protein reduces it to its toxic metabolites?

ferredoxin

metronidazole spectrum of activity

broad anaerobic activity

-gram + and -

protozoa

h. pylori

T/F metronidazole has activity against aerobes and anaerobes

FALSE

only anaerobes

clinical uses for metronidazole

intraabdominal infections (combo)

h. pylori eradication when PCN allergy

what drug has a disulfiram-like reaction, so you need to avoid alcohol during therapy and for 3 days after discontinuation?

metronidazole

ADRs of metronidazole

disulfiram like reaction

severe hepatotoxicity

metallic taste

nausea (take with food)

BBW for metronidazole

carcinogenic

based on animal data

drug interactions with metronidazole

warfarin

-enhance anticoagulant effects (incr. INR)

what is the difference in structure between metronidazole and tinidazole?

tinidazole has a sulfur group: longer half life

bactrim always has a ______ ratio (SMZ:TMP)

5:1 ratio

sulfonamides are _________ inhibitors

folic acid synthesis

single strength (SS) bactrim

80 mg TMP

400 mg SMZ

double strength (DS) bactrim

160 mg TMP

800 mg SMZ

T/F the drugs in bactrim (sulfamethoxazole/trimethoprim) are bacteriostatic alone, but bactericidal together

TRUE

sulfonamide targets the _____, inhibiting conversion to ____

targets the DHPS enzyme

inhibits conversion to DHF

only in prokaryotes

trimethoprim targets _______, inhibiting conversion to _____

targets DHFR enzyme

inhibits conversion to THF

prokaryotes and eukaryotes

sulfonamides resistance

bacteria can utilize salvage pathway

SAR of sulfonamides

sulfonyl group connected to amino group

-aromatic SO2

overall charge of sulfonamides is _______ and is a _______ analogue

positive —> acidic

PABA analogue

sulfonamides are soluble at ____________

alkaline pH

bactrim spectrum of activity

broad

staph aureus (including MRSA)

enteric gram-negative rods (resistance increasing)

parasites and fungi

what is first-line for uncomplicated cystitis (UTIs)?

bactrim

bactrim clinical uses

UTIs

tx and prophylaxis of PCP

skin and soft tissue infection (staph)

-monotherapy: purulent infection

toxoplasma gondii encephalitis

infectious diarrhea: traveler’s diarrhea, shigellosis

what medication should you NEVER challenge if allergy exists?

bactrim

-sulfa allergy

bactrim ADRs

rash

blood dyscrasias: CBC

hyperkalemia

crystalluria: HYDRATE

what concerns do we have for bactrim with neonates and pregnancy?

kernicterus (neonates)

neural tube defects (pregnant)

-don’t use in 1st trimester

-caution near time of delivery —> kernicterus

bactrim drug interactions

warfarin: enhance anticoagulant effect (increased INR)

sulfonylureas: enhance hypoglycemic effect

meds that incr. risk of hyperkalemia: spironolactone, ACEs

rifamycins are ______ inhibitors

RNA synthesis (transcription)

what is the MOA of rifamycins?

binds to DDRP (DNA dependent RNA pol) at the ZBD to prevent RNA transcription

what rifamycin is available IV?

rifampin

T/F rifamycins are NOT effective for systemic infections

TRUE

<1% absorption due to aromatic groups

what has less penetration: rifampin or rifapentine?

rifampin

because of substitution with cyclopentane ring: lipophilic

rifamycins are bacteriostatic or bactericidal?

bactericidal

should rifamycins be taken with food or on an empty stomach? why?

empty stomach

increased food in gut can lead to decreased absorption

rifamycins MOA

naphthlene ring on rifamycins form pi-pi bonds with the ZBD of DDRP

RNA pol can’t interact properly

how does resistance to rifamycins happen?

mutation occurs on the RNA pol gene (rpoB)

spectrum of activity of rifamycins

mycobacteria (including TB)

staph aureus

clinical uses of rifampin

multi-drug regimen for TB

meningococcal prophylaxis

device-related osteoarticular infections caused by MSSA/MRSA (used with antistaph antibiotic)

clinical uses of rifabutin

add on treatment with macrolide for MAC

what rifamycins are not absorbed, therefore only useful for GI conditions like traveler’s diarrhea and hepatic encephalopathy?

rifaximin

rifamycin

do rifamycins need renal dosing?

NO

all are eliminated via liver —> hepatotoxicity

ADRs of rifampin

discoloration of body fluids

-remove soft contact lenses to prevent staining

rifamycins are potent inducers of __________

CYP450

do NOT use with protease inhibitors