Antibacterials - Protein Synthesis Inhibitors

Question 1

List the types of protein synthesis inhibitors?

Answer 1

1. Tetracyclines
2. Glycylcyclines
3. Aminoglycosides
4. Macrolides
5. Chloramphenicol
6. Clindamycin
7. Streptogramins
8. Linezolid
9. Mupirocin

Question 2

What is the MOA of protein synthesis inhibitors?

Answer 2

MOA: bind to and interfere with ribosome since bacterial ribosomes (70S: 30S+50S) differ from mammalian ribosomes (80S); mostly bacteriostatic

Question 3

What are the 3 Tetracyclines, their MOA, and 3 mechanisms of widspread resistance (plasma meadiated)?

Answer 3

Doxyxycline, Minocycline, Tetracycline

MOA: passive diffusion & energy-dependent transport to bind reversibly to 30S subunit of ribosome

1. Impaired influx or increased efflux
2. Production of proteins that interfere with bindind to ribosomes
3. Enzymatic inactivation

Question 4

What are the clinical applicatrions of tetracyclines?

Answer 4

• severe acne/rosacea,
• Empiric therapy of community-acquired PNA,
• Infections of (respiratory tract, sinuses, middle ear, urinary tract, intestines), atypical PNAs (Mycoplasma, Chlamydia, Legionella)

Question 5

What are the pharmacokinetics of tetracylcines?

Answer 5

• Variable oral absoprtion because of divalent & trivalent cations
• Doxycycline is lipid soluble (STDs and prostatitis)
• Excreted by urine except doxycycline in bile
• Teratogenic - cross placenta and excreted in breast milk

Question 6

What are the adverse effect of Tetracyclines?

Answer 6

• Discoloration & hyperplasia of teeth, stunting of growth
• Photosensitization

Question 7

What is the Glycylcycline drug and what differentiate it from the other protein inhibitors and what is its clinical applications?

Answer 7

Tigecycline

• Broad-spectrum against multidrug-resistant gram postive/negative & anaerobic organisms
• Little resistance
• CA: treatment of complicated skin, soft tissue, and intra-abdominal infections (black box warning of increased mortaility)

Question 8

What are the PK/AE of glycylcyclines?

Answer 8

• IV only with primarily bile/fecal elimination
• Well tolerated with AE similar to tetracyclines

Question 9

What are the Aminoglycosides and what differentiates them?

Answer 9

Amikacin, Gentamicin, Tobramycin, Streptomycin, Neomycin

• Bactericidal
• Serious toxicites
• Largely replaced by safer antibiotics

Question 10

What is the MOA and specturm of aminoglycosides?

Answer 10

MOA: covalently bind to 30S ribosomal subunit; passively diffuse across membranes of gram negative or active O₂ dependent transport

• Mostly aerobic Gram-negative bactera

Question 11

What are the 3 principal mechamisns of aminoglycosides resistance?

Answer 11

1. Plasmid-associated synthesis of enzymes that modify/inactivate drug by acetylation, phosphorylation, and adenylation
2. Decreased accumulation of drug
3. Receptor protein on 30S ribosomal subinit maybe deleted or altered due to mutation

Question 12

What are the clinical application of aminoglycosides?

Answer 12

• Used mostly in combination
• Emperic therapy of serious infection (septicemia, nocosomial RTIs, complicated UTIs, endocarditis with vancomycin)
• Neomycin for bowel surgery, hepatic enchephalophathy, and topically

Question 13

What are the pharmacokinetic factors of aminoglycosides?

Answer 13

• Paraenteral administration only
• Once daily administration
• High levels in renal cortex and inner ear

Question 14

What are the adverse effects of amioglycosides?

Answer 14

• Both time and concentration dependent
• Ototoxicity
• Nephrotoxicity

Question 15

What is oral Neomycin comonly used for?

Answer 15

Adjunct or alternative treatment for hepatic encephalopathy

Question 16

What is the MOA and AE of Lactulose?

Answer 16

MOA: degreded by intestinal bacteria > lactic acid + other organic acids > acidfication of gut lumen > formation of NH₄⁺ > reduced plamsa ammonia concentration

AE: osmotic diarrhea, flatulence, abdominal cramping

Question 17

What are the Macrolides, their MOA, and specturm?

Answer 17

Erythromycin, Clarithromycin, Azithromycin, Telithromycin

MOA: reversibly bind to 23S rRNA of the 50S subunit

Spectrum: mostly gram positive

Question 18

What are the clinical application of macrolides?

Answer 18

• Empiric therapy of community-acquired PNA
• Treating atypical PNAs (mycopalsma, chlamydia, legionella)
• Treating URIs and soft tissue infections
• Common substitue for pts with penicillin allergy

Question 19

What are the PK and contraindication of macrolides?

Answer 19

• CYP P450 inhibition (excepot azithromycin)
• Dont use statins because of CYP P450 inhibition
• Telithromycin has more severe symptoms so only for major illnesses

Question 20

What is the MOA, specturm, and AE of chloramphenicol?

Answer 20

MOA: binds reversibly to 50S ribosome subunit and can inhibit protein synthesis in mitochondrial ribosomes leading to bone marrow toxicity

Spectrum: very broad spectrum, never given systemically for minor infections because of AE

AE: bone marrow depression, Gray baby syndrome (cyanosis)

Question 21

What are the clinical applications and PK of chloramphenicol?

Answer 21

• Serious infeciont resistant to less toxic drugs
• Superior penetrability
• VRE
• Topical eye infections

PK: inhibits hepatic oxidases (3A4 & 2C9)

Question 22

What is the MOA and AE of Clindamycin?

Answer 22

MOA: binds to 50S subunit of ribosomes

AE: potentially fatal pseudomembranous colitis (superinfection of C. difficile)

Question 23

What are the clinical applications of Clindamycin?

Answer 23

• Anaerobic infections
• Skin and soft tissue infections
• Alternative for prophylaxis in penicillin-allergic pts