Protein Synthesis Inhibitors (Antimicrobials) - 30S Inhibitors

Question 1

what drugs are protein synthesis inhibitors?

Answer 1

gentamicin
tobramycin
tetracycline
doxycycline
tigecycline
azithromycin
erythromycin
fidaxomicin
chloramphenicol 
clindamycin
linezolid 
mupirocin

Question 2

which agents bind to 30S ribosomal subunit

Answer 2

aminoglycosides (gentamicin, neomycin, amikacin, tobramycin, streptomycin –GNATS)

tetracyclines (doxycycline, tetracycline, minocycline)

glycylcycline (tigecycline)

Question 3

which agents bind to 50S ribosomal subunit

Answer 3

macrolides (azithromycin, erythromycin, clarithromycin)

Chloramphenicol
Clindamycin
Erythromycin
Linezolid (oxazolidinone)

Question 4

gentamicin route

Answer 4

topical, IV, IM

Question 5

tobramycin route

Answer 5

topical, IV, IM, nebulized

Question 6

general MOA of aminoglycosides

Answer 6

active transport across cell membrane into the cytoplasm by oxygen dependent process (so covers aerobes)

AND passive diffusion via porin channels across outer membrane (gram-)

(this is important)

Question 7

what do aminoglycosides do

Answer 7

bactericidal (bc irreversible binding to 30S and formation of aberrant proteins

Question 8

what does irreversible binding of 30S by aminoglycosides do

Answer 8

1. interferes with initiation complex of peptide formation - blocks
2. prevents proofreading of transcript (incorporation of incorrect AA) – miscoding
3. blocks movement of ribosomes after single initiation complex resulting in mRNA chain with just one ribosome – block translocation

Question 9

spectrum of aminoglycosides

Answer 9

aerobic gram - including pseudomonas

Question 10

what would happen if you gave an aminoglycoside with a cell wall agent for gram+

Answer 10

alone aminoglycoside wouldn’t work, but once cell wall agent destroys cell wall (give first) then aminoglycoside can penetrate
(aka synergy with cell wall agents on gram+ organisms)

Question 11

how is resistance conferred against aminoglycosides

Answer 11

1. production of transferase enzyme that inactivates aminoglycosides
2. imapired entry (decreased uptake and altered porins)
3. mutation of receptor on 30S ribosomal subunit (prevents aminoglycosides from binding)

Question 12

absorption of aminoglycosides

Answer 12

poorly absorbed, almost entire dose excreted in feces

Question 13

when does peak concentration occur in IM

Answer 13

within 30-90min

Question 14

peak concentration in IV

Answer 14

30-60min

Question 15

tissue concentration of drug?

Answer 15

low because poorly absorbed

Question 16

CNS concentration of drug

Answer 16

inadequate even with inflamed meninges

Question 17

where do aminoglycosides accumulate?

Answer 17

renal cortex, endolymph and perilymph of the inner ear

Question 18

side effects of aminoglycosides

Answer 18

nephrotoxicity and ototoxicity (ringing of ears)

Question 19

aminoglycosides and placenta

Answer 19

can cross placental barrier and accumulate in fetal plasma and amniotic fluid

Question 20

toxicity of aminoglycosides

Answer 20

1. since high concentrations in renal cortex, endolymph and perilymph of inner ear, then nephrotoxic and ototoxic
2. neuromuscular blockade
3. contact dermatitis

Question 21

what is oto and nephrotoxicity associated with

Answer 21

prolonged high trough levels (not peak levels)

Question 22

what is neuromuscular blockade associated with

Answer 22

direct intraperitoneal or intrapleural application of a large dose

(cannot get into the CNS but can directly administer)

Question 23

how are aminoglycosides cleared

Answer 23

renally – excretion is directly proportional to creatinine clearance

Question 24

why must aminoglycosides be monitored in kidney damage?

Answer 24

excretion is directly proportional to creatinine clearance so if kidney not working, less excretion

Question 25

describe aminoglycosides dosing

Answer 25

``` concentration dependent (looking for a high peak) with a post antibiotic effect (continues after drug wears off) ```

Question 26

when would once daily dosing be avoided?

Answer 26

1. renal impairment because accumlates 2. pregnancy (crosses placenta) 3. neonates (accumulates in fetal plasma and amniotic fluid) 4. bacterial endocarditis

Question 27

how to monitor aminoglycosides that are dosed once daily

Answer 27

check trough to makes sure the drug is washing out -- don't need to check peak

Question 28

what is the goal trough for aminoglycosides dosed once daily

Answer 28

less than 1mcg/mL between 18-24hours after dosing

Question 29

how to monitor aminoglycosides for traditional dosing

Answer 29

check peak and trough levels because want it in certain range

Question 30

goal peak for traditional dosed aminoglycosides

Answer 30

5-10mcg/mL

Question 31

goal trough for traditional dosed aminoglycosides

Answer 31

less than 2mcg/mL (less than 1 optimal)

Question 32

how many half lives to steady state

Answer 32

4-5

Question 33

what is a peak?

Answer 33

drug level 1 hour ish after administration

Question 34

what is a trough

Answer 34

drug level right before next dose is due

Question 35

why do we not have to be at steady state for aminoglycosides?

Answer 35

post antibiotic effect allows washout period with decreased side effects while still allowing action

Question 36

when would washing out not be beneficial?

Answer 36

when kidney damaged bc can't wash out anyway

Question 37

when to draw levels for aminoglycosides?

Answer 37

wait until reach stead state--4-5th dose

Question 38

what are the tetracyclines?

Answer 38

tetracycline, doxycycline, minocycline

Question 39

new tetracyclines

Answer 39

1. eravacycline 2. omadacycline 3. serecycline

Question 40

what do tetracyclines do

Answer 40

bacteriostatic

Question 41

why are aminoglycosides bactericidal

Answer 41

irreversible binding to 30S subunit and formation of aberrant proteins that interfere with initiation complex of peptide formation

Question 42

why are tetracyclines bacteriostatic

Answer 42

reversibly bind to 30S subunit

Question 43

MOA of tetracyclines

Answer 43

1. passive diffusion and energy dependent protein mechanism 2. reversibly bind to 30S subunit, blocking access of tRNA to mRNA at acceptor site

Question 44

spectrum of tetracyclines

Answer 44

``` broad spectrum 1. many gram+ including community acquired MRSA gram - 2. toxin secreters (cholera) 3. rickettsiae 4. spirochetes 5. mycoplasma (intracellulars) 6. chlamydia (intracellulars) ```

Question 45

what diseases do tetracycline work against

Answer 45

community acquired MRSA 1. COPD exacerbations 2. rocky mountain spotted fever 3. borrelia 4. mycoplasma 5. chlamydia 5. minocycline for acne 6. brucellosis 7. erlichiosis 8. granuloma inguinale 9. h pylori 10. vibrio

Question 46

how can resistance against tetracyclines occur

Answer 46

1. impaired influx or increased efflux by active transport 2. ribosome protection due to productions of proteins that interfere with tetracycline binding to the ribosome 3. enzymatic inactivation

Question 47

which drugs can work against tetracycline resistant strains?

Answer 47

doxycycline or minocycline because they are poor substrates for efflux pump that mediates resistance

Question 48

kinetics of tetracyclines

Answer 48

incompletely absorbed by mouth

Question 49

which abx are not to be taken with diary, Mg, aluminum antacids or iron

Answer 49

tetracyclines and fluroquinolones

Question 50

what can not be taken with tetracyclines and why

Answer 50

dairy, magnesium, aluminum antacids and iron because they form nonabsorbable chelates

Question 51

where are tetracyclines metabolized

Answer 51

liver

Question 52

why can't children or pregnant women get tetracyclines

Answer 52

concentrates in tissues with high calcium content so chelates with teeth and cause grey brittle teeth. also crosses the placenta and accumulates in fetal tissue.

Question 53

tetracyclines in pregnancy

Answer 53

crosses placenta, bad in pregnancy

Question 54

adverse effects of tetracycline

Answer 54

1. photosensitivity 2. chelation (calcium deposited in newly formed bones or teeth) 3. gastric discomfort (do not take with dairy and antacids, but take with food) 4. ototoxicity 5. pseudotumor cerebri 6. hepatotoxicity 7. nephrotoxicity

Question 55

tetracyclines in children

Answer 55

do not give in children under 8yo chelate to calcium deposited in newly formed bone or teeth

Question 56

what occurs if you take out of date tetracycline?

Answer 56

could cause nephrotoxicity and renal tubular acidosis

Question 57

which abx cause photosensitivity

Answer 57

tetracyclines, sulfonamides, fluroquinolones

Question 58

what ADE can demeclocycline cause

Answer 58

nephrogenic diabetes insipidus by blocking tubule cell response to ADH

Question 59

what can demeclocycline treat?

Answer 59

syndrome of inappropriate ADH (SIADH)

Question 60

MOA of tigecycline

Answer 60

reversibly binds to 30S ribosome interfering with tRNA binding

Question 61

what is tigecycline

Answer 61

bacteriostatic

Question 62

stectrum of tigecycline

Answer 62

broad spectrum MRSA acinetobacter gram negatives EXCEPT PSEUDOMONAS, PROTEUS, PROVIDENCIA

Question 63

what does tigecyclines NOT effective agaist

Answer 63

1. pseudomonas 2. proteus 3. providencia

Question 64

what conditions is tigecyclines used for

Answer 64

complicated skin/soft tissue, intraabdominal infections where MRSA is likely, community acquired pneumonia

Question 65

ADE of tigecycline

Answer 65

``` chelation (not with oral cations bc is IV only) n/v/d hepatotoxicity phototoxicity pseudotumor cerebri ```

Question 66

distribution of tigecycline

Answer 66

rapid distribution to tissues (so don't use for bacteremia)

Question 67

why can't tigecycline be used for bacteremia

Answer 67

rapid distribution goes to tissues fast, so don't stay in bloodstream. would be ineffective.

Question 68

why can't tigecycline be given in pregnancy or kids

Answer 68

risk of chelation with calcium high tissues (fetus)