Antibiotic Agents Interfering with DNA/Proteins - Pilch 4/26/16

Question 1

classification of antibiotics by targets

Answer 1

• vast majority target either cell wall or proteins
• DNA biosynthesis and replication is next on list
• cell membrane agents are last (typically not specific enough, especially for systemic use)

1. DNA replication inhibitors

• targets: DNA gyrase, DNA topo IV
  ex. fluroquinolones

2. DNA biosynthesis inhibitors

• targets: folate metabolism
  ex. trimethoprim, sulfonamides

3. protein synthesis inhibitors

• target: 50S subunit
  ex. macrolides, clindamycin, streptagramins, linezolid
• target: 30S subunit
  ex. aminoglycosides, tetracyclines

4. cell wall synthesis

ex. penicillins, cephalosporins, carbapenems, monobactams, vancomycin

5. cell membrane synthesis

ex. polymyxins, daptomycin

Question 2

protein synthesis inhibitors

Answer 2

exploit diffs between bacterial 70S/human 80S ribosome

• selectivity is compromised by similarities between mitochondrial and bacterial ribosomes

1. inhibitors of 30S ribosomal subunit

• aminoglycosides : streptomycin, gentamicin, tobramycin, neomycin, kanamycin, amikacin
• tetracyclines : tetracycline, demeclocycline, minoclycine, doxycycline, oxytetracycline, tigecycline

2. inhibitors of 50S ribosomal subunit

• macrolides : erythromycin, clarithromycin, azithromycin, telithromycin
• lincosamide : clindamycin
• streptogramins : quinupristin/dalfopristin
• oxazolidinone : linezolid

Question 3

aminoglycosides:

pharmacodynamics

Answer 3

bind to 30S subunit, irreversibly interfere with protein synth in 3 ways:

1. blocks initiation
2. blocks translocation and elongation; triggers premature termination

3. favors incorp of incorrect a.a. [unique]

• administration: all cationic and polar; have to be given IV bc won’t be absorbed orally
• mess with proofreading ability: rapidly bacteriocidal against aerobic Gram-
• significant postantibiotic effect: effect persisting beyond time that measurable drug is present (due to damage done to proofreading mechs) → allows for once-daily dosing that avoids toxicity

Question 4

aminoglycosides:

clinical uses

Answer 4

streptomycin

• mainly 2nd line agent for TB (should be used in combo with IHN or rifampin to avoid creating resistance)

tobramycin, gentamicin

• most commonly used systemic aminoglycosides → severe infections that are resistant to other drugs (sepsis, pneumonia)
• often used in combo with beta-lactam to take adv of synergistic effects, prevent resistance
• gentamicin often preferred over tobramycin bc cheaper

amikacin

• semisythetic derivative of kanamycin (less toxic)
• not as good as genta/tobra, but resistant to many enzymes that inactivate getamicin, kanamycin

all others…too toxic for systemic use!

neomycin, kanamycin

• mostly topical (skin, eyes, injected into jts, or cavity/space/abscess where infection present) as neomycin/polymyxin/bacitracin combo like Neosporin

Question 5

aminoglycosides:

primary adverse effects

Answer 5

nephrotoxicity

• all nephrotoxic, esp if : > 5 days, at high dose, elderly, renal insufficiency
  
  • avoid concurrent use with other nephrotox agents!
• most nephrotoxic: neo-, tobra-, gentamicin
• effects reversible with discontinuation

ototoxicity (ear)

• all ototoxic, esp if : > 5 days, high dose, elderly
• can manifest as auditory damage or vestibular damage (vertigo, ataxia)
  
  • auditory: neomycin, kanamycin, amikacin
  • vestibular: streptomycin, gentamicin
• effects tend to be irreversible, even on discont, bc they damage nerve cells (irreplaceable/dont regen)

Question 6

tetracyclines:

pharmacodynamics

Answer 6

bind to 30S subunit and prevent aminoacyl-tRNA from binding to A site → prevents elongation!

bacteriostatic for several aerobic/anaerobic Gram+/- bacteria (incl rickettsiae, mycoplasma, chlamydia), also active against some protozoa

diffs in clinical efficacy are due mostly to pharmacokinetics

Question 7

tetracyclines:

pharmacokinetics

Answer 7

almost all orally taken, vary on duration of action

• short (6-8h): tetracycline, oxytetracycline
• intermed (12h): demeclocycline
• long (16-18h): doxyclycline (can also take IV), minocycline
• v long (36h): tigecycline (IV only)

absorption of oral admin is impaired by food and alk pH

• chelate multivalent cations (Ca, Mg, Fe, Al) → absorption is impaired by foods containing them (antacids, dairy products)

Question 8

tetracyclines:

clinical uses

Answer 8

Rickettsial infections : Rocky Mtn spotted fever, typhus, Q fever

STIs : chlamydia, urethritis, cervicitis, epididymititis

resp tract infections : comm acq pneumonia

skin/soft-tissue infections : comm acq Staph, mod/severe acne

doxycycline indicated for Lyme disease (need to catch before crosses blood/brain barrier, bc doxycycline can’t cross)

tigecycline indicated for MDR infections

Question 9

tetracyclines:

primary adverse reactions

Answer 9

GI disturbances : nausea, vomiting, diarrhea

affects forming bony structures/teeth : binds Ca, esp in kids (bc bones/teeth forming) → fluorescence, enamel dysplasia, discoloration (teeth); deformity or growth inhibition (bone)

• contraindicated for long periods in kids under 8

photosensitization

liver disturbances (contraindicated during pregnancy)