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

Empiric treatment for endocarditis^1,2

• Vancomycin or ampicillin/sulbactam, PLUS an aminoglycoside (e.g., gentamicin)
• Add rifampin in patients with prosthetic valves

This patient has acute tubular necrosis (ATN) due to gentamicin.

Aminoglycosides such as gentamicin are well-established causative agents of acute tubular necrosis (ATN) and ototoxicity.^{3, 4}

They bind to the 30S ribosomal subunit, thereby inhibiting formation of the initiation complex and causing misreading of the mRNA.⁵

With respect to the 50S ribosomal subunit inhibitors, all bind to the 23S ribosomal RNA (rRNA) at the peptidyl transferase cavity. Chloramphenicol and clindamycin block peptidyl transferase; macrolides do not.⁶ 

Chloramphenicol: “50S ribosomal subunit; 23S rRNA of peptidyl transferase cavity; blocks peptidyl transferase; prevents tRNA from binding to A site.”⁶ 

Clindamycin: “50S ribosomal subunit; 23S rRNA of peptidyl transferase cavity; blocks peptidyl transferase; prevents tRNA from binding to A and P sites.”⁶ 

Macrolides (e.g., erythromycin): “50S ribosomal subunit; 23S rRNA of peptidyl transferase cavity; does not block peptidyl transferase; blocks tunnel that channels nascent peptides away from peptidyl transferase center.”⁶ 

Linezolid: “50S ribosomal subunit; 23S rRNA nucleotides; prevents formation of initiation complex.”^{7, 8}

Tetracycline: “Inhibits 30S ribosomal subunit – prevents aminoacyl-tRNA from binding to the A site.”⁹

Mnemonic: “Buy AT 30. CCEL at 50.” (“Buy at 30. Sell at 50.”) – Aminoglycosides, Tetracyclines are 30S; Chloramphenicol, Clindamycin, Erythromycin (macrolides), Linezolid are 50S.

Bottom line: Aminoglycosides cause nephrotoxicity (acute tubular necrosis) and ototoxicity. The 30S ribosomal subunit inhibitors are aminoglycosides and tetracyclines. The high-yield 50S inhibitors are clindamycin, chloramphenicol, and macrolides. Knowing which ones are 30S vs 50S is exceedingly HY for the USMLE Step 1. The more specific mechanisms of action are occasionally asked and are worth memorizing if you have any desire for a 250+.

1) https://www.aafp.org/afp/2012/0515/p981.html

2) https://www.ncbi.nlm.nih.gov/pubmed/19713420

3) https://www.ncbi.nlm.nih.gov/pmc/articles/PMC89104/

4) https://www.ncbi.nlm.nih.gov/pubmed/17266591

5) https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5187519/

6) https://www.ncbi.nlm.nih.gov/pubmed/11677599 (https://www.weizmann.ac.il/Structural_Biology/faculty_pages/Yonath/Nat10.01.pdf)

7) https://watermark.silverchair.com/dkg249.pdf?token=AQECAHi208BE49Ooan9kkhW

8) https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3264260/#__sec3title

9) https://www.ncbi.nlm.nih.gov/pmc/articles/PMC99026/

Chloramphenicol: “50S ribosomal subunit; 23S rRNA of peptidyl transferase cavity; blocks peptidyl transferase; prevents tRNA from binding to A site.”

Clindamycin: “50S ribosomal subunit; 23S rRNA of peptidyl transferase cavity; blocks peptidyl transferase; prevents tRNA from binding to A and P sites.”

Macrolides (e.g., erythromycin): “50S ribosomal subunit; 23S rRNA of peptidyl transferase cavity; does not block peptidyl transferase; blocks tunnel that channels nascent peptides away from peptidyl transferase center.”

Linezolid: “50S ribosomal subunit; 23S rRNA nucleotides; prevents formation of initiation complex.”

Tetracycline: “Inhibits 30S ribosomal subunit – prevents aminoacyl-tRNA from binding to the A site.”

Aminoglycosides: “30S ribosomal subunit – inhibits formation of initiation complex and causes misreading of mRNA”

Chloramphenicol: “50S ribosomal subunit; 23S rRNA of peptidyl transferase cavity; blocks peptidyl transferase; prevents tRNA from binding to A site.”

Clindamycin: “50S ribosomal subunit; 23S rRNA of peptidyl transferase cavity; blocks peptidyl transferase; prevents tRNA from binding to A and P sites.”

Macrolides (e.g., erythromycin): “50S ribosomal subunit; 23S rRNA of peptidyl transferase cavity; does not block peptidyl transferase; blocks tunnel that channels nascent peptides away from peptidyl transferase center.”

Linezolid: “50S ribosomal subunit; 23S rRNA nucleotides; prevents formation of initiation complex.”

Tetracycline: “Inhibits 30S ribosomal subunit – prevents aminoacyl-tRNA from binding to the A site.”

Aminoglycosides: “30S ribosomal subunit – inhibits formation of initiation complex and causes misreading of mRNA”

Chloramphenicol: “50S ribosomal subunit; 23S rRNA of peptidyl transferase cavity; blocks peptidyl transferase; prevents tRNA from binding to A site.”

Clindamycin: “50S ribosomal subunit; 23S rRNA of peptidyl transferase cavity; blocks peptidyl transferase; prevents tRNA from binding to A and P sites.”

Macrolides (e.g., erythromycin): “50S ribosomal subunit; 23S rRNA of peptidyl transferase cavity; does not block peptidyl transferase; blocks tunnel that channels nascent peptides away from peptidyl transferase center.”

Linezolid: “50S ribosomal subunit; 23S rRNA nucleotides; prevents formation of initiation complex.”

Tetracycline: “Inhibits 30S ribosomal subunit – prevents aminoacyl-tRNA from binding to the A site.”

Aminoglycosides: “30S ribosomal subunit – inhibits formation of initiation complex and causes misreading of mRNA”

Chloramphenicol: “50S ribosomal subunit; 23S rRNA of peptidyl transferase cavity; blocks peptidyl transferase; prevents tRNA from binding to A site.”

Clindamycin: “50S ribosomal subunit; 23S rRNA of peptidyl transferase cavity; blocks peptidyl transferase; prevents tRNA from binding to A and P sites.”

Macrolides (e.g., erythromycin): “50S ribosomal subunit; 23S rRNA of peptidyl transferase cavity; does not block peptidyl transferase; blocks tunnel that channels nascent peptides away from peptidyl transferase center.”

Linezolid: “50S ribosomal subunit; 23S rRNA nucleotides; prevents formation of initiation complex.”

Tetracycline: “Inhibits 30S ribosomal subunit – prevents aminoacyl-tRNA from binding to the A site.”

Aminoglycosides: “30S ribosomal subunit – inhibits formation of initiation complex and causes misreading of mRNA”

Chloramphenicol: “50S ribosomal subunit; 23S rRNA of peptidyl transferase cavity; blocks peptidyl transferase; prevents tRNA from binding to A site.”

Clindamycin: “50S ribosomal subunit; 23S rRNA of peptidyl transferase cavity; blocks peptidyl transferase; prevents tRNA from binding to A and P sites.”

Macrolides (e.g., erythromycin): “50S ribosomal subunit; 23S rRNA of peptidyl transferase cavity; does not block peptidyl transferase; blocks tunnel that channels nascent peptides away from peptidyl transferase center.”

Linezolid: “50S ribosomal subunit; 23S rRNA nucleotides; prevents formation of initiation complex.”

Tetracycline: “Inhibits 30S ribosomal subunit – prevents aminoacyl-tRNA from binding to the A site.”

Aminoglycosides: “30S ribosomal subunit – inhibits formation of initiation complex and causes misreading of mRNA”

Gentamicin (an aminoglycoside) causes both nephro- and ototoxicity.

Chloramphenicol: “50S ribosomal subunit; 23S rRNA of peptidyl transferase cavity; blocks peptidyl transferase; prevents tRNA from binding to A site.”

Clindamycin: “50S ribosomal subunit; 23S rRNA of peptidyl transferase cavity; blocks peptidyl transferase; prevents tRNA from binding to A and P sites.”

Macrolides (e.g., erythromycin): “50S ribosomal subunit; 23S rRNA of peptidyl transferase cavity; does not block peptidyl transferase; blocks tunnel that channels nascent peptides away from peptidyl transferase center.”

Linezolid: “50S ribosomal subunit; 23S rRNA nucleotides; prevents formation of initiation complex.”

Tetracycline: “Inhibits 30S ribosomal subunit – prevents aminoacyl-tRNA from binding to the A site.”

Aminoglycosides: “30S ribosomal subunit – inhibits formation of initiation complex and causes misreading of mRNA”

Answer = linezolid.

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.

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Chloramphenicol: “50S ribosomal subunit; 23S rRNA of peptidyl transferase cavity; blocks peptidyl transferase; prevents tRNA from binding to A site.”

Clindamycin: “50S ribosomal subunit; 23S rRNA of peptidyl transferase cavity; blocks peptidyl transferase; prevents tRNA from binding to A and P sites.”

Macrolides (e.g., erythromycin): “50S ribosomal subunit; 23S rRNA of peptidyl transferase cavity; does not block peptidyl transferase; blocks tunnel that channels nascent peptides away from peptidyl transferase center.”

Linezolid: “50S ribosomal subunit; 23S rRNA nucleotides; prevents formation of initiation complex.”

Tetracycline: “Inhibits 30S ribosomal subunit – prevents aminoacyl-tRNA from binding to the A site.”

Aminoglycosides: “30S ribosomal subunit – inhibits formation of initiation complex and causes misreading of mRNA”

Answer = clindamycin.

Classically used for 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.

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Chloramphenicol: “50S ribosomal subunit; 23S rRNA of peptidyl transferase cavity; blocks peptidyl transferase; prevents tRNA from binding to A site.”

Clindamycin: “50S ribosomal subunit; 23S rRNA of peptidyl transferase cavity; blocks peptidyl transferase; prevents tRNA from binding to A and P sites.”

Macrolides (e.g., erythromycin): “50S ribosomal subunit; 23S rRNA of peptidyl transferase cavity; does not block peptidyl transferase; blocks tunnel that channels nascent peptides away from peptidyl transferase center.”

Linezolid: “50S ribosomal subunit; 23S rRNA nucleotides; prevents formation of initiation complex.”

Tetracycline: “Inhibits 30S ribosomal subunit – prevents aminoacyl-tRNA from binding to the A site.”

Aminoglycosides: “30S ribosomal subunit – inhibits formation of initiation complex and causes misreading of mRNA”

Answer = chloramphenicol.

HY side-effects of chloramphenicol? –> 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.

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Chloramphenicol: “50S ribosomal subunit; 23S rRNA of peptidyl transferase cavity; blocks peptidyl transferase; prevents tRNA from binding to A site.”

Clindamycin: “50S ribosomal subunit; 23S rRNA of peptidyl transferase cavity; blocks peptidyl transferase; prevents tRNA from binding to A and P sites.”

Macrolides (e.g., erythromycin): “50S ribosomal subunit; 23S rRNA of peptidyl transferase cavity; does not block peptidyl transferase; blocks tunnel that channels nascent peptides away from peptidyl transferase center.”

Linezolid: “50S ribosomal subunit; 23S rRNA nucleotides; prevents formation of initiation complex.”

Tetracycline: “Inhibits 30S ribosomal subunit – prevents aminoacyl-tRNA from binding to the A site.”

Aminoglycosides: “30S ribosomal subunit – inhibits formation of initiation complex and causes misreading of mRNA”

Answer = azithromycin (a macrolide).

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.

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Chloramphenicol: “50S ribosomal subunit; 23S rRNA of peptidyl transferase cavity; blocks peptidyl transferase; prevents tRNA from binding to A site.”

Clindamycin: “50S ribosomal subunit; 23S rRNA of peptidyl transferase cavity; blocks peptidyl transferase; prevents tRNA from binding to A and P sites.”

Macrolides (e.g., erythromycin): “50S ribosomal subunit; 23S rRNA of peptidyl transferase cavity; does not block peptidyl transferase; blocks tunnel that channels nascent peptides away from peptidyl transferase center.”

Linezolid: “50S ribosomal subunit; 23S rRNA nucleotides; prevents formation of initiation complex.”

Tetracycline: “Inhibits 30S ribosomal subunit – prevents aminoacyl-tRNA from binding to the A site.”

Aminoglycosides: “30S ribosomal subunit – inhibits formation of initiation complex and causes misreading of mRNA”

Answer = doxycycline (a tetracycline antibiotic). Patient has Rocky Mountain spotted fever (Rickettsia rickettsii). Rash can show up as wrists/ankles (need not be palms/soles); the key is that it is centripetal (moves toward the trunk). Patients are usually in the Eastern US, despite the name of the condition.

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Chloramphenicol: “50S ribosomal subunit; 23S rRNA of peptidyl transferase cavity; blocks peptidyl transferase; prevents tRNA from binding to A site.”

Clindamycin: “50S ribosomal subunit; 23S rRNA of peptidyl transferase cavity; blocks peptidyl transferase; prevents tRNA from binding to A and P sites.”

Macrolides (e.g., erythromycin): “50S ribosomal subunit; 23S rRNA of peptidyl transferase cavity; does not block peptidyl transferase; blocks tunnel that channels nascent peptides away from peptidyl transferase center.”

Linezolid: “50S ribosomal subunit; 23S rRNA nucleotides; prevents formation of initiation complex.”

Tetracycline: “Inhibits 30S ribosomal subunit – prevents aminoacyl-tRNA from binding to the A site.”

Aminoglycosides: “30S ribosomal subunit – inhibits formation of initiation complex and causes misreading of mRNA”

Buy AT 30. CCEL at 50. (“Buy at 30. Sell at 50.”)

30s ribosomal subunit inhibitors: Aminoglycosides, Tetracyclines.

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

Gentamicin is an aminoglycoside.

Buy AT 30. CCEL at 50. (“Buy at 30. Sell at 50.”)

30s ribosomal subunit inhibitors: Aminoglycosides, Tetracyclines.

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

Buy AT 30. CCEL at 50. (“Buy at 30. Sell at 50.”)

30s ribosomal subunit inhibitors: Aminoglycosides, Tetracyclines.

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

Clarithromycin is a macrolide.

Buy AT 30. CCEL at 50. (“Buy at 30. Sell at 50.”)

30s ribosomal subunit inhibitors: Aminoglycosides, Tetracyclines.

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

Minocycline is a tetracycline antibiotic.

Buy AT 30. CCEL at 50. (“Buy at 30. Sell at 50.”)

30s ribosomal subunit inhibitors: Aminoglycosides, Tetracyclines.

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

Amikacin is an aminoglycoside, which can cause acute tubular necrosis (ATN).

ATN can be caused by acute ischemia, drugs (i.e., notably aminoglycosides), myoglobinuria secondary to rhabdomyolysis (myoglobin is nephrotoxic), and IV contrast agents.

Azithromycin (if patient has received antibiotics for another cause in the past three months, give a fluoroquinolone instead, such as levofloxacin).

Kid has Lyme disease. Rash is erythema chronicum migrans (target rash). Don’t give tetracycilne antibiotics (i.e., doxycycline) to kids age ≤8 or to pregnant women. Give amoxicillin to these patients instead. (HY “trick” Q on USMLE)

Tetracycline antibiotics are a HY cause of photosensitivity.

Empiric Tx for community-acquired pneumonia is azithromycin, however some practitioners are old-school and will occasionally pick a tetracycline antibiotic (which is second-line). USMLE likes this question.

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).

In broad terms:

Aminoglycosides target gram-negative rods.

In contrast, vancomycin targets gram-positives.

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.

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).

Chlamydial pneumonia (C. pneumoniae, not trachomatis) is an atypical pneumonia, so is treated the same as Myoplasma and Legionella pneumonias.

Azithromycin first-line. Doxycycline is second-line. If azithro isn’t listed but doxy is, just go with doxy.

If the Q is about urethritis and it says no organisms grew, the answer is chlamydia. You must co-treat for gonorrhea by adding IM ceftriaxone unless the Q explicitly states that gonococcal testing was negative.

So for urethritis: always co-treat with ceftriaxone PLUS either azithro or doxy.

If Q says gonococcal testing was negative: just give azithro or doxy.

For chlamydial pneumonia (C. pneumonia), just give azithro (first-line) or doxy.

Should be noted that if a neonate has C. trachomatis pneumonia from vertical transmission through the birth canal (conjunctivitis that progresses to pneumonia), the answer is oral erythromycin. A lot to talk about there but let’s keep things concise enough here.

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.

Essentially: Ehrlichia = Lyme disease-like presentation PLUS phagocytes with “berry cluster organisms” or “morulae.”

GI disturbance (diarrhea or constipation).

Prolongation of QT-interval on ECG (other HY drugs that do this: antipsychotics, metoclopramide).

P-450 inhibition (not azithromycin).

Tigecycline is a newer, third generation tetracycline derivative. However it’s technically considered to be in a newer class called the glycylcyclines.

a) Inhibit 50s ribosomal subunit