Microbiology pharm – Protein synthesis (30/50s) inhibitors

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HY points about each drug followed by a quiz at the end

Buy ATT 30. CCELS at 50. (“Buy at 30. Sell at 50.”)

30s ribosomal subunit inhibitors: Aminoglycosides, Tetracyclines, Tigecycline

50s ribosomal subunit inhibitors: Chloramphenicol, Clindamycin, Macrolides (e.g., Erythromycin), Linezolid, Streptogramins

Aminoglycosides

Highest yield examples: gentamicin, tobramycin, amikacin.

MOA of aminoglycosides? –> answer = inhibit 30s ribosomal subunit.

  • More specifically: prevent formation of initiation complex and causes misreading of mRNA.

What are aminoglycosides effective against? –> answer = gram-negative rods.

  • Aminoglycosides require O2 for uptake, so occasionally you might here “aerobic gram-negative rods.” But truthfully, this detail about the oxygen requirement is superfluous. I only mention it because it’s highly perpetuated. You literally need to take home: aminoglycosides = gram-negative rods.

Two important uses of aminoglycosides for USMLE? –> answer = 1) empiric endocarditis Tx; 2) Pseudomonas.

  • Gentamicin, PLUS either vancomycin or ampicillin/sulbactam = empiric therapy for endocarditis.
  • Aminoglycosides are notably effective against pseudomonas.

Two important toxicities of aminoglycosides? –> answer = nephrotoxicity + ototoxicity.

  • The nephrotoxicity associated with aminoglycosides will always be acute tubular necrosis (ATN) on the USMLE.
    • E.g., 44M + commenced on gentamicin + vancomycin empirically for endocarditis + now has oliguria + BUN/Cr of 14; what’s the most likely explanation for this patient’s findings? –> answer = acute tubular necrosis.
  • Do not confuse aminoglycoside-induced ATN with interstitial nephropathy (tubulointerstitial nephritis) caused by beta-lactams, cephalosporins, and NSAIDs.
    • E.g., 44M + treated with 6 weeks of nafcillin for confirmed MSSA endocarditis +/- rash + urine shows WBCs (eosinophils); Dx? –> answer = interstitial nephropathy; wrong answer = acute tubular necrosis.
  • Ototoxicity caused by aminoglycosides need not be neurosensory hearing loss or tinnitus; it can also present as vertigo (patient is wobbly).

Tetracyclines

Highest yield examples: doxycycline, minocycline, tetracycline.

MOA of tetracyclines? –> answer = inhibit 30s ribosomal subunit.

  • More specifically: prevent aminoacyl-tRNA from binding to the A site.

What are tetracyclines effective against? –> answer = VACUUM THE BedRoom –> Vibrio spp., Acne, Chlamydia, Ureaplasma urealyticum, Mycoplasma, Tularemia, H. pylori, Ehrlichia, Borrelia spp., Rickettsia spp.

  • Vibrio cholerae on USMLE will always be “supportive care” or “rehydration therapy” as the answer. Tetracycline is almost always wrong. It will only be the answer if the question literally forces you into a position where you have to pick an antibiotic. However, Vibrio vulnificus is associated with sepsis and tetracyclines are notably associated with lower mortality.
  • Acne –> tetracyclines are 4th-line Tx for acne (HY for family medicine shelf); standard order for acne Tx for most patients:
    • 1) topical retinoids (i.e., topical tretinoin);
    • 2) benzoyl peroxide;
    • 3) topical clindamycin;
    • 4) Oral tetracycline;
    • 5) Oral isotretinoin (not to be confused with topical tretinoin).
  • Chlamydia –> doxycycline is second-line for chlamydial infections. Macrolides (i..e, azithromycin) are used first-line by most practitioners. For the treatment of chlamydial urethritis, azithromycin can be given as a one-off oral 1-gram stat dose, whereas doxycycline must be given BID (twice a day) for a week. Doxycycline can also be given for chalmydial atypical pneumonia (but same as urethritis, azithromycin is first-line by most practitioners).
  • Ureaplasma urealyticum –> low-yield and you will not get asked; can be a cause of UTIs; more just completes the mnemonic.
  • Mycoplasma  pneumoniae–> important cause of atypical pneumonia; azithromycin used first-line; doxycycline generally second-line. Should be noted that both Mycoplasma pneumoniae and Chlamydia pneumoniae cause atypical pneumonia and are treated second-line with doxy.
  • Tularemia –> Francisella tularensis –> rare cause of atypical pneumonia classically in those with pet rabbits; can also present as painless black skin lesions; can be treated with doxy.
  • H. pylori –> first-line Tx for H. pylori is CAP (Clarithromycin, Amoxicillin, Proton pump inhibitor); if CAP combination is not effective (i.e., urease breath test is still positive 4 weeks after Tx), assume resistance, so the clarithromycin and amoxicillin are replaced with the tetracycline, metronidazole, and bismuth. So second-line for H. pylori = tetracycline, metronidazole, bismuth, and proton pump inhibitor.
    • 1st-line for H. pylori = CAP = clarithromycin, amoxicillin, proton pump inhibitor (e.g., omeprazole).
    • 2nd-line for H. pylori = tetracycline, metronidazole, bismuth, and proton pump inhibitor.
  • Ehrlichia chaffeensis –> Ehrlichiosis –> presents similar to Lyme disease with a rash in a patient exposed to a tick, but the difference is Ehrlichia question stems will mention phagocytes with “berry cluster organisms” or “morulae.”
    • Essentially: Ehrlichia = Lyme disease-like presentation PLUS phagocytes with “berry cluster organisms” or “morulae.”
  • Borrelia spp. –> doxycycline is first-line for Lyme disease (Borrelia burgdorferi) and relapsing fever (Borrelia recurrentis).
    • USMLE wants you to know that for children age ≤8 and pregnant women do not receive doxy; give amoxicillin instead.
  • Rickettsia spp. –> doxy is first-line for Rickettsia rickettsii (Rocky Mountain spotted fever; spread by Dermacentor wood tick); Rickettsia prowazeki (epidemic typhus; spread by louse); Rickettsia typhi (endemic typhus; spread by fleas).

Important side-effects of tetracycines?

  • Photosensitivity
    • USMLE might say, e.g., 16M + recently treated for pneumonia + now has blistering of face and lips after soccer tournament; which antibiotic did he receive? –> answer = doxycycline (main side-effect is photosensitivity.
    • Topical retinoids in the treatment of acne also cause photosensitivity, but it tends to be more of the rash/desquamation type; in contrast, tetracycyclines are more associated with blistering photosensitivity.
  • Teeth discoloration (do not give to children age ≤8 or pregnant women [will affect the teeth of fetus]).
  • Minocycline is notably associated with drug-induced lupus (anti-histone antibodies).

Tigecycline

MOA of tigecycline?

  • Newer, third generation tetracycline derivative. However it’s technically considered to be in a newer class called the glycylcyclines.
  • Inhibits 30s same as tetracyclines.

Macrolides

Highest yield examples: azithromycin, erythromycin, clarithromycin (do not confuse these with the aminoglycosides, which sound similar).

MOA of macrolides? –> answer = inhibit the 50s ribosomal subunit.

  • More specifically: binds to the 23S rRNA of peptidyl transferase cavity but does not inhibit peptidyl transferase; blocks tunnel that channels nascent peptides away from peptidyl transferase center.

Important uses for macrolides? –> empiric Tx for community-acquired pneumonia (CAP); first-line for chlamydia; used as part of the first-line CAP regimen for H. pylori.

  • Azithromycin is standard first-line for patient with CAP who has not been on antibiotics in the past three months (otherwise we use a fluoroquinolone, such as levofloxacin). This is because it is effective against Strep pneumoniae (lobar pneumonia) as well as atypical pneumonia (bilateral interstitial pattern) caused by Mycoplasma, Legionella, and Chlamydia pneumoniae.
  • Azithromycin as an one-off, oral 1-gram stat dose is effective against most cases of Chlamydia trachomatis urethritis.
  • Clarithromycin is first-line as part of CAP (clarithromycin, amoxicillin, proton pump inhibitor) for Tx of H. pylori.

Highest yield side-effects of macrolides?

  • GI disturbance (diarrhea or constipation).
  • Prolongation of QT-interval on ECG (other HY drugs that do this: antipsychotics, metoclopramide).
  • P-450 inhibition (not azithromycin).

Chloramphenicol

MOA of chloramphenicol? –> answer = inhibits 50s ribosomal subunit.

  • More specifically: binds to the 23S rRNA of peptidyl transferase cavity + blocks peptidyl transferase; prevents tRNA from binding to A site.

Any notable use for chloramphenicol? –> answer = meningitis in the third-world.

  • Used for meningitis in some third-world countries; it’s a cheap drug that has good blood-brain barrier penetration; not used in the first-world because of its side-effects.

HY side-effects of chloramphenicol? –> answer = aplastic anemia; grey baby syndrome.

  • Aplastic anemia means RBCs, WBCs, and platelets are all down.
  • If given to pregnant women, can cause grey baby syndrome in neonate –> neonates have physiologic paucity of bilirubin-uptake enzyme at the liver (UDP glucuronosyl transferase) –> this enzyme is needed for elimination of chloramphenicol –> therefore drug builds up in blood stream and can deposit in skin, causing blue/grey discoloration.

Clindamycin

MOA of clindamycin? –> answer = inhibits 50s ribosomal subunit.

  • More specifically: binds to the 23S rRNA of peptidyl transferase cavity + blocks peptidyl transferase; prevents tRNA from binding to A and P sites.

Main use for clindamycin? –> answer = anaerobes above the diaphragm (i.e., pulmonary abscess).

  • 44M + alcoholic + fever + cough + CXR shows air-fluid level; which drug would have utility in treating this patient? –> answer = clindamycin.
  • Aspiration pneumonia and pulmonary abscess are classically treated with clindamycin as part of the regimen.
  • Clindamycin can also be used for MRSA skin infections (vancomycin has poor skin penetration).

Important side-effect of clindamycin? –> pseudomembranous colitis.

  • Will only cause pseudomembranous colitis if patient has ingested Clostridium difficile spores, but clindamycin, cephalosporins, and ampicillin are HY drugs known to increase the risk of pseudomembranous colitis.

Linezolid

MOA of linezolid? –> answer = inhibits 50s ribosomal subunit.

  • More specifically: binds to the 23S rRNA of peptidyl transferase cavity + blocks peptidyl transferase; prevents formation of initiation complex.

Use for linezolid? –> sometimes used for vancomycin-resistant Enterococcus (VRE); effective against MRSA, but vancomycin preferred in part to avert emergence of linezolid-resistant VRE.

  • Vancomycin has poor skin penetration, so patients with MRSA skin infections can be treated with linezolid, sulfonamides, TMP/SMX, or clindamycin.

Side-effects of linezolid? –> answer = HOT –> High risk of serotonin syndrome, Optic neuritis, Thrombocytopenia.

Streptogramins (quinupristin/dalfopristin)

MOA of the streptogramins? –> answer = inhibit 50s ribosomal subunit.

Use for streptogramins? –> answer = vancomycin-resistant Enterococcus (VRE).

1. MOA of aminoglycosides? (inhibit what):

 
 
 
 
 
 

2. MOA of linezolid? (inhibits what):

 
 
 
 
 
 

3. MOA of macrolides? (inhibit what):

 
 
 
 
 
 

4. MOA of tetracyclines? (inhibit what):

 
 
 
 
 
 

5. MOA of chloramphenicol? (inhibits what):

 
 
 
 
 
 

6. MOA of clindamycin? (inhibits what):

 
 
 
 
 
 

7. 44M + endocarditis + started on empiric treatment + now has tinnitus and the “room is spinning.” What’s the MOA of the drug causing the toxicity?

 
 
 
 
 
 

8. 42M + cellulitis caused by MRSA + started on antibiotic therapy + now tachycardia, flushing and diarrhea. His platelet count is 100,000 (NR 150,000-450,000). What’s the MOA of the drug causing the toxicity? (inhibits what):

 
 
 
 
 
 

9. 44M + alcoholic + cough + fever + CXR shows air-fluid level. What’s the MOA of the drug that notably is effective in treatment? (inhibits what):

 
 
 
 
 
 

10. Neonate + bluish skin tone + mom was treated for infection during pregnancy. What’s the MOA of the drug most likely responsible for the child’s presentation? (inhibits what):

 
 
 
 
 
 

11. 72M + cough + fever of 102F + CXR shows right lower lobe consolidation. Examination demonstrates dullness to percussion and decreased tactile fremitus over the right lower lobe. What’s the MOA of the empiric treatment for this patient? (inhibits what):

 
 
 
 
 
 

12. 30M + lives in Connecticut + 3-day Hx of rash of his wrists and ankles that has started to migrate in toward his trunk  + was hiking in a wooded area a few days ago; what’s the MOA of the most appropriate treatment for this patient?

 
 
 
 
 
 

13. Which drug classes (or single drugs) inhibit the 30s vs 50s ribosomal subunit? (6)

14. Gentamicin – 30s or 50s inhibitor?

 
 

15. Chloramphenicol – 30s or 50s inhibitor?

 
 

16. Clarithromycin – 30s or 50s inhibitor?

 
 

17. Minocycline – 30s or 50s inhibitor?

 
 

18. 40F + had surgery complicated by loss of blood and a drop of BP to 80/40 for 30 seconds + was adequately resuscitated + after surgery now has oliguria; the renal condition experienced by this patient can also be the result of a drug toxicity associated with which of the following agents?

 
 
 
 
 

19. What’s the empiric Tx for community-acquired pneumonia (CAP)?

20. 6F + went on a camping trip with family two days ago + today has a rash on her left leg with a central clearing; what’s the most appropriate treatment for this patient?

 
 
 
 
 

21. 16M + treated for pneumonia a few days ago + soccer tournament yesterday + now has blisters on lips and face; which antibiotic might he have received?

 
 
 
 
 

22. 56M + recently finished 6-week antibiotic regiment for confirmed MSSA endocarditis + now has rash + urinalysis shows 60 WBCs/hpf. Which agent is most likely responsible for this patient’s condition?

 
 
 
 
 

23. What kinds of organisms (broadly speaking) do aminoglycosides treat?

 
 
 
 

24. How do you treat Vibrio cholerae?

25. What role do tetracyline antibiotics have in the treatment of acne? (Think of the order of Tx)

26. How do you treat chlamydial pneumonia?

27. What’s the treatment for H. pylori?

28. How do you treat Ehrlichia chaffeensis and how do you differentiate the vignette from Lyme disease?

29. What are the three HY adverse-effects of macrolides for the USMLE.

30. What is tigecycline?

31. a) What’s the MOA of the streptogramins (quinupristin/dalfopristin)?

b) What are they used for?