PC 2 mod 2.2 lec 8 & 9 (aminoglycosides)

aminoglycoside nomenclature...

--> derived from _______ --> synthetic derivative ____

- streptomyces (mycin)

- icin

aminoglycoside structure is a _____ between 2 _____

- 2-deoxystreptamine

- sugars

aminoglycosides are ______, so the DONATE/ACCEPT electrons so can be susceptible to modifications

- nucleophiles

- donate

MOA of aminoglycosides...

--> aminoglycosides self promote uptake process involved drug-induced disruption of ______ between adjacent _____ of gram POSITIVE/NEGATIVE, creating _____

--> they then transport across cytoplasmic membrane which is dependent on ______ and termed _____

- Mg2+ bridges

- LPS

- negative

- porins

- electron transport

- energy dependent phase 1

MOA aminoglycosides cont...

--> bind to ____ of ribosomal subunit

--> block initiation of ______

--> block further _____ and elicit premature _____

--> incorporate incorrect ______

- 30s

- protein synthesis

- translation

- premature termination

- amino acids

aminoglycosides do not function well in BASIC/ACIDIC pH and in AEROBIC/ANAEROBIC conditions

- acidic

- anaerobic

aminoglycoside PK

--> GOOD/POOR BA

--> ORAL/IV

--> SHORT/LONG T1/2

--> LOW/HIGH protein binding

--> LOW/HIGH adipose distribution

--> elimination?

- poor

- IV

- short

- low

- low

- renal

do aminoglycosides penetrate well into purine fluids in abscesses?

no, acidic and aerobic

do aminoglycosides penetrate well into lungs?

no, bad for pneumonia

penetration of aminoglycoside...

--> CSF ?

--> sputum ?

--> prostate ?

--> bladder ?

--> eye ?

--> bone ?

- CSF- no

- sputum- poor

- prostate- good

- bladder- good

- eye- only topical formulation

- bone- good

aminoglycosides have ____ phases of elimination

3

_____ phase of aminoglycoside elimination is distribution of drug from blood to tissues

alpha phase

______ phase of aminoglycoside elimination is elimination from drug through kidney

beta phase

_______ phase of aminoglycoside elimination is slow release from tissue binding site where conc. is not detectable

gamma

aminoglycosides are based on ____/MIC ratio

Cmax

Cmax/MIC for aminoglycosides should be...

8-10

aminoglycosides have ______ effect, which is persistant suppression of bacteria after short exposure, justifying _______

- post-antibiotic effect

- once daily dosing

conventional aminoglycoside dosing is...

3x a day

the only time aminoglycosides are used alone for gram+ is for treatment of...

UTI

to treat gram+ with aminoglycoside, you must couple them with _____ except for treatment of _____

- cell wall active agents

- UTI

which of the following gram + do aminoglycosides + cell wall active agents 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.

NOT pneuonmia (poor lung)

c. viridans strep

d. MSSA/MSSE

e. MRSA/MRSE

f. E. faecalis

g. E. faecium

aminoglycosides are active against all gram- except...

neisseria

______ aminoglycoside is active against mycobacteria

amikacin

amikacin is active against ______

mycobacteria

most common mechanism of resistance of aminoglycosides is enzyme modification which is _____ mediated

plasmid

3 mechanisms of resistance of aminoglycosides...

--> ______ modification

--> decreased ______

--> altered ______

- enzymatic

- uptake

- ribosome

do enzymatic modifications of aminoglycosides confer to all AGs?

no

decreased uptake of AG by altered transport or efflux is _____ mediated, meaning it IS/IS NOT cross resistant to all AGs

- chromosomally

- is

______ requires 1 ribosome mutation to be resistant

other AGs require ____ mutations

- streptomycin

- multiple

3 main adverse effects of aminoglycosides

- ototoxicity (auditory and vestibular)

- nephrotoxicity

- neuromuscular blockade

ototoxicity is greatest with which AG?

streptomycin

aminoglycoside nephrotoxicity results in _____ renal failure, meaning they CAN/CANNOT produce urine and CAN/CANNOT remove toxins

- non-oliguric

- can

- cannot

AG nephrotoxicity results in slow rise in ____ and retention of small portion of administered dose in epithelial cells in ________ after filtration, which are then translocated into ______ causing tubular cell injury

- SCr

- proximal tubule

- lysosomes

AG ototoxicity is caused by degeneration of _____ and _____ in cochlea correlating with hearing loss

- hair cells

- neurons

is there correlation with peak/trough and ototoxicity?

no

aminoglycoside ototoxicity is likely due to accumulation of AG in _____ and _____ fluid that diffuses into blood slowly, so there is no safe _____ to minimize this

- perilymph

- endolymph

- dose

auditory ototoxicity can start with _____ tinnitus that is hard to notice at first, then can persist for _____

high pitched

weeks

vestibular ototoxicity can start in first 1-2 days with ______, then after 1-2 weeks, acute phase of ______ occurs and 2 months can have chronic _______

--> recovery can take up to ____ months

- moderate headache

- N/V, vertigo

- chronic labyrinthitis

- 18 months

only monotherapy use of aminoglycoside is for

UTI

AG are used in synergy in patients with ______ infections

deep seated gram + (endocarditis)

new aminoglycoside semisynthetically developed

plazomicin

plazomicin brand name

zemdri

plazomicin has potent activity against ______

enterobacterales

which resistance can plazomicin overcome... (3)

- ESBL

- AG resistance

- carbapenem resistant enterobacterales

carbapenem resistant enterobacterales is carried on ______ and often accompanyed by ______ modifying enzymes

- plasmid

- AG

plazomicin PK

--> POOR/GOOD BA

--> IV/PO

--> elimination?

- poor

- IV

- renal

which of the following gram + does plazomicin w/synergy 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

plazomicin has activity against all gram - except...

neisseria

plazomicin is STRONGER/WEAKER than other AG against pseudomonas and acitinobacter

weaker, more resistance

plazomicin is active against gram negative bacilli with ______-resistance, especially ______ producers EXCEPT if ______

- gentamicin

- carbapenamase

- pseudomonas

is plazomicin active against gentamicin resistant pseudomonas?

no

dosing of AG is _____ based

--> _____mg/kg/day

weight

15

is there renal dosing adjusted for AG?

yes

TDM wants Cmin to be _____ in patients with UTI on AG

nephrotoxicity from AG occurred more in patients with impaired ______ and may be _____ related

- renal function

- concentration

TOBRAMYCIN/GENTAMYCIN

--> conventional dosing: ____mg/kg __x daily

--> once daily dosing: _____ mg/kg

- 1-2mg/kg TID

- 3-7mg/kg

AMIKACIN

--> conventional dosing: ____mg/kg ___x daily

--> once daily dosing: _____ mg/kg

- 5-7.5mg/kg BID

- 15-20 mg/kg

is conventional or ODA dosing preferred?

ODA, except for few patient populations

conventional dosing is preferred if...

--> severe renal disease with CrCl ____

--> on ______

--> _____

--> ______ disease

--> extensive ______

--> ______ and ______ population

--> synergy for ______

-

for synergy with gram+, is ODA or conventional dosing preferred?

conventional

greater post antibiotic effect occurs with HIGHER/LOWER peaks

higher

does ototoxicity occur with ODA or conventional dosing?

both

uptake of aminoglycosides into proximal tubule is ______, so it may be safer to give ODA or CONVENTIONAL

- saturable

- ODA

10 steps of stepwise dose individualization

1. collect patient specific data to determine if you should use ______ or ______

2. determine dosing ______

3. estimate ______

4. estimate ______

5. estimate ______

6. estimate ______

7. choose goal ______ and ______ value

8. calculate ______

9. calculate ______

10. estimate ______ and ______

1. ODA or conventional

2. weight

3. CrCl

4. Ke

5. t1/2

6. Vd

7. peak and trough

8. dosing interval (tau)

9. dose

10. peak and trough

step 1: patient specific info...

--> _______ data

--> _______ data

--> _______ data

--> significant ______

- demographic (age, weight)

- lab data (SCr)

- infection data --> goal peak/trough

- PMH or current medical issues

CG equation for CrCL

(140-age)(IBW)/72(SCr) * (0.85 for women)

use adj body weight if >____% of IBW

if _____, use TBW

- >25%

- TBW

MDRD is reasonable for eGFR of ____

CKD-EPI is reasonable for eGFR of _____

-

______ is reasonable for eGFR of

MDRD

CKD-EPI

typical half life for AG is ___hrs

2-3

Vd formula...

X (dose)/ Cp (plasma conc.)

drug variables impacting Vd...

--> ______ vs ______ drugs

--> _______

- lipophilic vs. hydrophilic

- plasma protein binding

trauma and burns --> INCREASE/DECREASE Vd

obesity --> INCREASE/DECREASE Vd

fluid collection (ascites) --> INCREASE/DECREASE Vd

cystic fibrosis --> INCREASE/DECREASE Vd

pregnancy --> INCREASE/DECREASE Vd

dehydration --> INCREASE/DECREASE Vd

overhydration --> INCREASE/DECREASE Vd

- increase

- increase

- increase

- increase

- increase

- decrease

- increase

calculate emperic Vd based on _______ by multiplying L/kg with body weight

- population estimate

for ODA dosing, if CrCL is

for ODA dosing, if CrCL is

3mg/kg

7.5mg/kg

steps to perform serum drug conc using patient data

1. plot _____ on _____

2. determine true patient... (5)

3. adjust ____ and/or _____ to achieve desired serum drug con

1. measured conc --> graph

2. Ke, t1/2, Cmax, Cmin, Vd

3. dose or interval

preferred strategy for pulling serum concentrations is to give _____, the check first concentration at ______ then check second concentration at _______

- dose

- end of infusion

- before next dose is due

non-preferred, but easier way to pull serum conc is to check ______, then give patient a dose then check ______

- trough

- peak at end of infusion

Ke calculations come from...

drug levels

ideal drug levels for Ke calculations are _____ half lives between levels

2-4

conventional dosing serum conc is obtained after ______ doses where patient is at _______

- 3 to 4

- steady state

ODA dosing serum conc is ______ and ______

- 4hr post dose

- 12hr pose dose

extrapolated peak that accounts for distribution phase

Cmax

obtained after distribution phase (0.5h post infusion)

clinical peak

obtained prior to next dose

measured trough

level right before next dose

Cmin

we use ______ and ______ to calculate Cmax, Cmin, and Ke parameters

- clinical peak

- clinical trough

clinical peak is usually ____ mins after infusion due to ______

- 30 min

- distribution phase

distribution phase LENGTHENS/SHORTENS with larger doses ODA to ___h

- lengthens

- 1-2h

for Vd calculations, do you use Cmax and Cmin or clinical peak and clinical trough?

Cmax and Cmin

for subtherapubtic dosing, we should increase ______

dose

for supratherapeutic trough, we should _____

lengthen dosing interval

for supratherapeutic peak and non-toxic trough, we should ______

lower dose

_____ levels are important to monitor for efficacy of AG

peak levels

peak levels are monitoring for ______

efficacy

_____ levels should be monitored to minimize risk of nephrotoxicity

trough

lower troughs should be targeted to minimize...

nephrotoxicity

repeat levels q_____ depending on...

--> changes in _____

--> changes in ____

--> changes in ____ (often lags behind)

q3-7 days

- renal function

- urine output

- SCr

_____ should be measured using baseline audiometric testing

ototoxicity