PC 2 mod 2.2 lec 14-16

fosfomycin is a SMALL/LARGE molecule that easily forms _____ and has HIGH/LOW BA with use limited to ______

- small

- salts

- low

- UTI

______ is a small molecule that easily forms salts and has low BA so limits use to UTI

fosfomycin

fosfomycin MOA

--> enters cell through 2 active transport systems ______ and _____

--> once in, it reversible blocks _____

--> acts as an analog of ______ and inhibits initial ____ synthesis step triggered by _____

--> blocks production of _____

- GLpT

- UhpT

- bacterial cell wall synthesis

- phosphoenolpyruvate

- peptidoglycan

- MurA

- NAM

______ has MOA of entering cell through 2 active transport systems, GLpT and UhpT to reversibly blood cell wall synthesis by acting as an analog of phsophoenolpyruvate inhibiting initial peptidoglycan synthesis step triggered by MurA and blocking NAM

fosfomycin

is Vd of fosfomycin high or low?

low

fosfomycin is eliminated by _____ route and 93% ends up in ______

- renal

- urine

does fosfomycin have good protein binding?

no

is fosfomycin oral or IV? what is the agent called?

oral

fosfomycin tromethamine (dissociates in blood)

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

a. streptococcus spp.

b. s. pneumoniae

c. viridans strep

d. MSSA/MSSE

e. MRSA/MRSE

f. E. faecalis

g. E. faecium

d. MSSA/MSSE

e. MRSA/MRSE

f. E. faecalis

g. E. faecium

which of the following gram- does fosfomycin have activity against? (pt1)

a. neisseria spp.

b. H. influenzae

c. M. catarrhalis

d. e. coli

e. klebsiella

f. p. mirabilis

a. neisseria spp.

d. e. coli

e. klebsiella

f. p. mirabilis

MORE COMMON FOR UTI

which of the following gram- does fosfomycin have activity against? (pt2)

a. morganella spp

b. enterobacter spp

c. citrobacter spp

d. serratia spp

e. p. paeruginosa

f. acinetobacter

b. enterobacter spp

c. citrobacter spp

d. serratia spp

e. p. paeruginosa

NOT AS COMMON

fosfomycin has misc activity against... (5)

- salmonella

- shigella

- listeria

- aerococcus

- h pylori

mechanisms of resistance of fosfomycin...

--> altered bindining due to mutations in _____

--> overexpression of ______ circumventing activity of fosfomycin

--> mutations in ______

--> modifying ______

- murA

- enolypyruvyl transferase

- transport system

- enzymes

fosfomycin has interactions with drugs that stimulate ______, as they decrease _____

- motility

- absorption

3 places in therapy for fosfomycin

- uncomplicated acute cystitis

- complicated cystitis

- prophylaxis

fosfomycin for uncomplicated acute cystitis is administered as ___gm dose ___x and the preparation is _____ that must be ______

3g one time

- power

- mixed with 4 oz water

fosfomycin for complicated cystitis is giving ___gm q___h for up to ___ doses

- 3gm

- q48h

- 3 doses

dose of fosfomycin for prophylaxis of recurrent UTI is give ___gm every ___ days

3gm

10 days

recurrent UTI is defined as at least ____ episodes of COMPLICATED/UNCOMPLICATED infection document by cultures within the past 12 months

- 3 episodes

- uncomplicated

con with fosfomycin is...

cost

MOA of nitrofurantoin

--> nitrofurantoin is activated by ______ to reactive intermediates

--> these intermediates damage ______, ____ and other macromolecules involved in ______ and _______

- bacterial flavoproteins

- ribosomal proteins

- DNA

- metabolism

- cell wall synthesis

______ has MOA of being activated by bacterial flavoproteins to become reactive intermediate

nitrofurantoin

bacteria reduce nitrofurantoin more _______ than mammilian cells, so it is selective for that

rapidly

PK of nitrofurantoin

--> HIGH/LOW BA

--> SHORT/LONG T1/2

--> elimination?

--> conc in urine? serum?

- high

- short

- renal and biliary

- high in urine, low in serum

elimination of nitrofuranoin through kidney leave it ______

unchanged

ACIDIC/ALKALINE urine may reduce antimicrobial activity of nitrofuranoin

alkaline

clinical response of nitrofurantoin is based on _______, so impaired ______ limits use

- urine conc

- renal function

does nitrofurantoin enter tissues well?

no

3 drug of nitrfurantoin class

- macrobid

- macrodantin

- furadantin

should you take nitrofurantoin for pyelonephritis?

no

should you take nitrofurantoin with food?

yes

does nitrofurantoin need renal adjustment? if so, at what CrCL?

yes,

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

a. streptococcus spp.

b. s. pneumoniae

c. viridans strep

d. MSSA/MSSE

e. MRSA/MRSE

f. E. faecalis

g. E. faecium

d. MSSA/MSSE

e. MRSA/MRSE

f. E. faecalis

g. E. faecium

which of the following gram- does nitrofurantoin have activity against? (pt1)

a. neisseria spp.

b. H. influenzae

c. M. catarrhalis

d. e. coli

e. klebsiella

f. p. mirabilis

d. e. coli

e. klebsiella

CAUSE UTI

which of the following gram- do nitrofurantoin have activity against? (pt2)

a. morganella spp

b. enterobacter spp

c. citrobacter spp

d. serratia spp

e. p. aeruginosa

f. acinetobacter

b. enterobacter

c. citrobacter

e. p aeruginosa

hemolytic anemia from nitrofurantoin is more common in patients with _____ deficiency

G6PD

nitrofurantoin can cause rare events, like ______ if used long term or _____ in patients with G6PD deficiency

- pulmonary toxicity

- hemolytic anemia

______ can cause rare events, like pulmonary toxicity if used long term or hemolytic anemia in patients with G6PD deficiency

nitrofurantoin

nitrofurantoin is contraindicated in ______ and ______

- pregnancy

- neonate

(hemolytic anemia)

nitrofurantoin can cause color of urine to be...

brown

nitrofurantoin has drug interactions with ______ and ______

- magnesium based antacids

- probenecid

probenecid INCREASES/DECREASES nitrofurantoin conc

increases

magnesium based antacid INCREASE/DECREASE nitrofurantoin absorption

decrease

nitrofurantoin can cause false positive ______ lab test

glucosuria

nitrofurantoin is ONLY indicated for...

cystitis

treatment duration for nitrofurantoin treating cystitis is typically ____ days for uncomplicated disease

5 days

nitrofurantoin prophylaxis dose for recurrent UTI is ____ mg po ____

50-100mg po daily

can you use nitrofurantoin long for prophylaxis?

no, dangerous

polymyxins are CATION/ANION and HYDROPHILIC/HYDROPHOBIC

cation

amphiphilic

polymyxins have hydrophilic _______ and hydrophobic _______

- peptide ring

- tail

_____ are positively charged amino groups found on polymyxins

L-dab

L-dabs are _____ charged _____ groups on ______

- positively charged

- amino

- polymyxins

MOA of polymyxins

--> _____ align with _____, which is POSITIVE/NEGATIVE charge of gram POSITIVE/NEGATIVE

--> _____ interacts with bacterial cell membrane

--> this causes increase in _____ of cell wall

- L-dab

- LPS

- negatively

- negative

- hydrophobic tail

- permeability

______ has MOA of L-dab (positive amino groups), lining up and binding to LPS causing hydrophobic tail to increase permeability of cell wall

polymyxins

two types of polymyxins

- colistin

- polymyxin B

polymyxin PK

--> HIGH/LOW BA

low

are polymyxins renally eliminated?

colistin (CMS) is

polymyxin b is not

CMS IS/IS NOT renally eliminated

colistin IS/IS NOT renally eliminated

polymyxin b IS/IS NOT renally eliminated

- is

- is not

- is not

which is more protein bound, colistin or polymyxin B?

polymyxin B

colistin has GOOD/POOR penetration into lung, pericardium and CSF?

poor

______ colistin optimizes lung exposure

inhaled

are urine concentrations of colistin HIGH or LOW?

high

urine conc. of colistin are high due to conversion of _____ to _____ in _____

- colistimethate

- colistin

- kidney

polymyxins are CONCENTRATION/TIME dependent?

concentration

colistin is administered as...

inactive prodrug, colistimethate sodium

why is colistin administered as prodrug?

fewer injection site reactions

in patients with good renal function, colistimethate sodium (CMS) clearance is SLOWER/FASTER than conversion to colistin, leading to LOW/HIGH serum conc.

- faster

- low

(20-25%)

variables effect colistin conc. are ____ variability and variability in _____

- batch to batch

- renal function

does polymyxin B or colistin have improved serum conc?

polymyxin B

polymyxin B is _____ in kidney, resulting in LOW/HIGH urinary conc. which is not good for _____

- reabsorbed

- low

- UTI

can colistin be used for systemic infection? can polymyxin?

- no

- yes

do polymyxins have activity against gram-? gram+?

yes

no

which gram+ bacteria do polymyxins have activity against?

none

which of the following gram- do polymyxins have activity against? (pt1)

a. neisseria spp.

b. H. influenzae

c. M. catarrhalis

d. e. coli

e. klebsiella

f. p. mirabilis

b. H. influenzae

c. M. catarrhalis

d. e. coli

e. klebsiella

which of the following gram- do polymyxins have activity against? (pt2)

a. morganella spp

b. enterobacter spp

c. citrobacter spp

d. serratia spp

e. p. aeruginosa

f. acinetobacter

b. enterobacter spp

c. citrobacter spp

e. p. aeruginosa

f. acinetobacter

is colistin adjusted renally?

yes

mechanisms of resistance of polymyxins

--> alterations of ______

--> increased production of _____

--> ______

--> increasing levels of _____ by replacing ____ to stabilize the outer membrane

- LPS

- capsule polysaccharide

- efflux proteins

- H1 outer membrane protein

- Mg

resistance of polymyxin by alteration of LPS is done by INCREASING/DECREASING net charge, limiting binding

increasing

intrinsic resistance of polymyxins is driven by...

alteration of LPS

increased production of capsule polysaccharide reduce polymyxins by limiting their interaction with _______

LPS

increased levels of H1 mechanism of resistance to polymyxins works by replacing _____ in LPS to stabilize outer membrane

Mg

dosing strategy for colistin includes ______ dose, ______ dose, and ______ adjustment

- loading

- maintenance

- renal

dosing weight used for polymyxin B is...

total body weight (NOT IDEAL)

dosing strategy for polymyxin B is use of _____ weight, _____ dose, _____ dose and NO renal adjustment

- total body weight

- loading

- maintenance

2 adverse effects that can occur with polymyxins

- nephrotoxicity

- neuromuscular blockade

onset of nephrotoxicity from polymyxins would be within _____ weeks and it is dependent on ______

- 1 week

- dose

nephrotoxicity of polymyxin is due to mechanism similar to MOA, where polymyxins increase ________ cell membrane permeability resulting in cell ______ and ______

- tubular

- swelling

- lysis

neuromuscular blockade caused by polymyxin is ____ dependent and REVERSIBLE/IRREVERSIBLE and happens due to blocking release of ______

- dose

- reversible

- ACh

is polymyxin or colistin considered more reliable?

polymyxin

______ is preferred polymyxin for systemic and invasive infections

______ is preferred polymysin for lower UTI infections

- polymyxin B

- colistin

polymyxins are ______-line of therapy for ______ and are used in ______ therapy

- last line

- extensively drug resistant (XDR) gram- bacilli

- combination

_______ is last line therapy for XDR gram- bacilli

polymyxins

which of the following have high BA?

a. fosfomycin

b. nitrofurantoin

c. polymyxin

b. nitrofurantoin

which of the following have low BA?

a. fosfomycin

b. nitrofurantoin

c. polymyxin

a. fosfomycin

c. polymyxin

forsfomycin and nitrofurantoin have same coverage of GRAM +/GRAM - which is... (4)

- gram +

- MSSA

- MRSA

- both enterococcus

is polymyxin B good for UTIs?

no, reabsorbing kidney

which drug uses TBW for dosing?

polymyxin B

unique in dosing of polymyxin B and colistin is use of...

loading dose and maintenance dose

which of the following covers neisseria, p.miribalis, and serratia?

a. fosfomycin

b. nitrofurantoin

c. polymyxin

a. fosfomycin

fosfomycin covers _______, _______ and _______ gram- that nitrofurantoin and polymyxins don't cover

- neiserria

- p. miribalis

- serration