Protein synthesis and DNA synthesis inhibitors

Question 1

Gentamicin and Amikacin are common members of what class of protein synth inhibitors?

Answer 1

Aminoglycosides

**note Tobramycin and Streptomycin are there but just not as common?**

Question 2

What is the MOA of aminoglycosides?

Answer 2

Binds 30S ribosomal subunit; Misreads or terminates genetic code; Inhibits bacterial protein synthesis

Question 3

T/F: Most aminoglycosides are cidal and not static because they eliminate bacterial protein synthesis

What would you do to overcome the fact that these drugs don’t penetrate the gram positive cell wall?

Answer 3

Falsehood. Generally inhibits protein synthesis, not eliminating all protein synthesis so these drugs are static, but can be cidal if we give a high enough dose of the drug

Conc to become cidal depends on amount of drug required to get protein synthesis to a low enough level such that the bacterial cell can’t survive anymore

Synergy with beta-lactams >> holes get punched into bacterial cell wall >> allows the aminoglycosides to get into the bacterial cell

Question 4

Aminoglycosides work against (gram pos/neg) bugs and have no anaerobic or atypical coverage

Answer 4

Aminoglycosides work against gram neg bugs (+Pseudomonas) and have no anaerobic or atypical coverage

For gram pos, need to use w/ beta lactams otherwise useless when used alone

(S. aureus, Enterococci (for very difficult to treat infections/biofilms/in privileged sites/infections where you need to give a prolonged course)

Question 5

Because aminoglycosides concentrate highly in the urinary tract system, the only time they would be used alone is in the case of a ___

These drugs are also used for double coverage, which is what?

Answer 5

Because aminoglycosides concentrate highly in the urinary tract system, the only time they would be used alone is in the case of a UTI

These drugs are also used for double coverage, which is giving 2 agents that have activity against the unknown bug in question. Reason for doing double coverage: used when you don’t know what the causative agent is and you suspect resistance/just in the case the bug might be resistant

**when using 2 agents for an unknown infection, the usual 2nd agent is an aminoglycoside**

Question 6

Clinical indications for aminoglycosides include: endovascular gram +ve infections and ___

Answer 6

Clinical indications for aminoglycosides include: endovascular gram +ve infections and systemic infections (used IV only)

**others: tularemia, plague, brucellosis, restistant MTB infection

Question 7

Aminoglycosides are contraindicated in Pneumonia (why?), used for complex UTIs and concentrate highly in which parts of the body?

Answer 7

Aminoglycosides are contraindicated in Pneumonia due to low concentration in lungs/inhibited by pH, used for complex UTIs and concentrate highly in the ears and kidney

Question 8

Adverse events involving aminoglycosides include ototoxicity and ___

Answer 8

• Ototoxicity: Irreversible; Cochlear damage >> hearing loss; Vestibular damage >> vertigo
• Nephrotoxicity/Tubular Necrosis

Variable damage (leading to hemodialysis), irreversible, risk w/ radiocontrast, cyclosporin, Amphotericin B, Vancomycin

Question 9

What are the 3 main modes used to prevent aminoglycoside adverse events?

Answer 9

3 ways to prevent adverse events: monitor levels, take advantage of PK/PB to improve dosing, avoid other nephrotoxic agents

Question 10

Since aminoglycoside activity is concentration dependent, how can you exploit this to avoid adverse events?

Answer 10

Give ideal conc for organism to be affected, once a day, wait 24 hours (ear and kidney can start metabolizing drug so it doesn’t accumulate in those sites before the next dose given 24 hours later)

Question 11

What is a unique (potentially fatal) adverse effect of aminoglycosides? (hint: same etiology for MG and that’s why you wouldn’t use it in patients with MG)

Answer 11

Contraindicated in folks with Myasthenia Gravis and similar conditions because they’ll experience respiratory depression

Question 12

Another class of drugs that inhibit the 30S bacterial ribosomal subunit are the tetracyclines. Name 3 drugs in that group

Answer 12

Doxycycline, Tetracycline, Minocycline

I was just cyclin down the street and I ran into Mino carrying his tetrad looking backpack and walking his dog Doxy

Question 13

What is the MOA of tetracyclines? Are they static or cidal?

Answer 13

Binds 30S ribosomal subunit (reversible) and blocks access of tRNA to mRNA (so these are bacteriostatic)

Inhibits bacterial protein synthesis

Lipophilic, allows entry into GN/GP

Question 14

Resistance in tetracyclines is __ mediated and mechanisms of resistance include active efflux from bacterial cell and ___

Answer 14

Resistance in tetracyclines is plasmid mediated and mechanisms of resistance include active efflux from bacterial cell and #RPPs (ribosomal protection proteins)

Question 15

Describe how ribosomal protection proteins work to mediate tetracycline resistance

Answer 15

Ribosomal protection proteins bind to a diff part of the composite ribosome such that the tetracycline is displaced and the bacteria can continue making proteins

Question 16

Tetracyclines cover (gram pos/neg) bugs and (do/don’t include) Pseudmonas

What are the atypicals covered by tetracycline?

Answer 16

Tetracyclines cover both GN and GP bugs and don’t include Pseudmonas

Atypicals: Chlamydia, Mycoplasma

**note also ltd anaerobic activity and Doxy works against CA-MRSA

Question 17

Clinical indications for tetracyclines include community acquired upper respiratory infections, STIs, esp ___. Other uses include doxy for __ prophylaxis, minocycline for __ (you have it when you eat chocolate) and Rickettsiae

Answer 17

Clinical indications for tetracyclines include community acquired upper respiratory infections, STIs, esp Chlamydia. Other uses include doxy for malaria prophylaxis, minocycline for acne (you have it when you eat chocolate) and Rickettsiae

Question 18

Why wouldn’t you take tetracyclines with milk, antacids, or iron containing preps?

Why are tetracyclines contra-indicated in pregnant women and young kids?

Answer 18

All of those have divalent cations which decrease gut absorption of the drugs

Binds to tissues undergoing calcification >> concentrates in teeth and bones >> contraindicated in young kids and pregaz women

**deposition in bone and teeth causes staining of teeth, hypoplasia of teeth, and stunted growth**

Question 19

Another unique side effect of tetracyclines is ___ (aka increased sunburns)

Answer 19

Photosensitivity

Question 20

Macrolides are another class of drug that inhibit protein synthesis. Name 3 drugs in this group and their MOA

Answer 20

allthemycins #A_C_E

Azithromycin

Clarithromycin

Erythromycin

Bind to 50S ribosomal subunit, blocks translocation and inhibits bacterial protein synthesis

Question 21

Mechanisms of resistance for macrolides include decreased microbial entry, permeability, ___, target site alterations (erm gene) and enzymatic drug inactivation

Answer 21

Decreased microbial entry, permeability

Efflux pumps

Target Site Alterations (erm gene)

Enzymatic Drug Inactivation

Question 22

The spectrum of activity of macrolides include (GP/GN), anaerobes and ___

Answer 22

+Gram-negative (not Pseudomonas)

+Gram-positive: Staphylococci, Streptococci (including susceptible pneumococcus but resistance increasing)

+Anaerobes: Some GN anaerobes

+Atypical: Mycoplasma, Legionella, Chlamydia

Question 23

Clinical indications of macrolides include:

Atypical community acquired pneumonias, STIs caused by ___, traveler’s diarrhea and ___ prophylaxis in HIV

Answer 23

Clinical indications of macrolides include:

Atypical community acquired pneumonias, STIs caused by Chlamydia, traveler’s diarrhea and MAC (Mycobacterium avium complex) prophylaxis in HIV

Question 24

Macrolides are bacteriostatic/cidal. Azithromycin has a long/short half life and erythromycin is metabolized by which enzyme system?

Answer 24

Macrolides are bacteriostatic. Azithromycin has a long half life and erythromycin is metabolized by CP450s

Question 25

Adverse effects of macrolide use include ___ (MACRO)

Answer 25

GI Motility issues (epigastric distress)

Arrhythmia (QTc prolongation)

**others you nned to know for step**

Question 26

Which macrolide is a prokinetic agent used to improve GI motility issues?

Which macrolide is used to treat Mycobacterium avium complex disease and H. pylori infection?

Answer 26

Erythromycin

Gut motility, prokinetic (increases gut motility so it’ll be mainly used for this and not so much infection)

Clarithromycin

Mycobacterium avium complex disease (similar to TB)

H. pylori (causes duodenal ulcers)

Question 27

There’s one drug in the class of lincosamides which bind the bacterial 50S ribosomal subunit. Name it

Answer 27

That hoe Clinda(mycin)

**recall that this is one of the C-diffogenic ones**

Question 28

Describe inducible clindamycin resistance. Which gene is induced to lead to resistance?

Answer 28

Erythromycin is a potent inducer of the erm gene

Double disk diffusion: agar plate with a bug growing, two antibiotic disk so one has erythromycin and the other has clindamycin

One has resistance to erythromycin, and the other is susceptible to clindamycin

Circled in red: induced clindamycin resistance (induced by erythromycin); resistance also develops with prolonged clindamycin use

Question 29

Lincosamides cover (gram pos/neg) bugs and are commonly used for anaerobic infections (including Bacteriodes fragilis)

Answer 29

Lincosamides cover gram pos bugs only (Staphylococci (+ some CA-MRSA, Streptococci) and are commonly used for anaerobic infections (including Bacteriodes fragilis)

Question 30

Clinical indications for lincosamides include community aspiration pneumonia (aspirating anaerobes), __ infection, human bite wounds and __

Answer 30

Clinical indications for lincosamides include Community aspiration pneumonia (aspirating anaerobes), oral/ENT infection, human bite wounds and abscesses

**also used for skin/soft tissue infection due to CA-MRSA**

Question 31

T/F: Clindamycin is mainly bacteriostatic but can be bacteriocidal at high enough doses

Adverse effects of lincosamides include ___ (recall this thing can hapen with ANY antibiotic)

Answer 31

Truth. It can indeed

Adverse effects of lincosamides include ___ (recall this thing can hapen with ANY antibiotic)

Question 32

Oxazolidinones are a class of drugs that also bind the 50S ribosomal subunit. Name the drug(s) in the class and describe the MOA

Answer 32

Linezolid (pretty zolid line) and Tedizolid (think about teddy from Mr. Bean)

Binds to 50S ribosomal subunit and prevents formation of 70S complex

Inhibits translocation process

Inhibits bacterial protein synthesis

Question 33

How does tedizolid have increased potency against bugs?

Answer 33

Tedizolid has additional target site interactions with the peptidyl transferase binding region of rRNA – Increased Potency

Question 34

What are the mechanisms of resistance in oxazolidinones?

(Which drug in this class overcomes this resistance?)

Answer 34

Generally uncommon but spontaneous point mutations at drug target site and acquisition of plasmid-mediated resistance gene, cfr

Question 35

The spectrum of activity for oxazolidinones include __, some atypicals and mycobacteria and nocardia

Answer 35

Gram-positive ONLY

Staphylococci (including MRSA)

Streptococci

Enterococci (including VRE)

No Gram-negative, No Anaerobic

Some atypicals

Other: Mycobacteria, Nocardia

Question 36

Clinical indications for oxazolidinones includes VRE, ___ and ___

Answer 36

See below

(VRE, Hosp acquired pneumonia due to MRSA and complicated skin/soft tissue infections)

Question 37

Oxazolidinones (aka Linezolid) are generally bacteriostatic and have __ bioavailability upon one condition. They can also be given orally or IV

Answer 37

Oxazolidinones are generally bacteriostatic and have 100% bioavailability upon one condition: as long as patient has functioning gut. They can also be given orally or IV

Question 38

Unique advsere effects of oxazolidinones include ___, peripheral neuropathy, ___ due to MOA inhibition, and ___

Answer 38

Unique advsere effects of oxazolidinones include bone marrow suppression (+thrombocytopenia), peripheral neuropathy, serotonin syndrome due to MOA inhibition, and lactic acidosis

**note Serotonin syndrome can be fatal when given with SSRIs, mainly seen with linezolid**

Question 39

What is the MOA of muporicin? (hint: it’s the only one that has something to do with tRNA binding)

Answer 39

Muporicin: binds bacterial tRNA synthetase (reversible) and inhibits protein and RNA synthesis

Question 40

What is the spectrum of activity of muporicin?

Answer 40

(imagine that there’s a kid named Mupo wearing a purple shirt and holding clusters of purple grapes and a chain of purple grape candy)

Gram-negatives: No appreciable activity

Gram-positives: Highly active against S. aureus, other Staphylococcus spp, Streptococci

No activity against Enterococci

NO anaerobic coverage

**note: Muporicin is a topical agent that is highly active against skin flora that normally cause disease (Staph and Strept) whereas it has weaker activity against those that don’t cause disease

Question 41

Clinical indications for Mupirocin include skin infections caused by S. aureus and Streptococcus pyogenes, ___ and prophylaxis against ___

Answer 41

Clinical indications for Mupirocin include **skin infections caused by S. aureus and Streptococcus pyogenes, •MRSA decolonization of nares and prophylaxis against catheter-related infection

**Generally localized skin infections w/o any systemic symptoms/effects

Question 42

How is Mupirocin administered and what are the adverse effects?

Answer 42

Topical only

Adverse events: Propylene glycol base may irritate mucous membranes or broken down skin

Contact dermatitis