26. Antimicrobial Drugs - INH Bacterial Protein Synthesis

Are most protein synthesis inhibitors bacteriostatic or bactericidal?

Most are bacteriostatic, but some (e.g., aminoglycosides, streptogramins) are bactericidal against specific organisms.

What are common mechanisms of resistance to tetracyclines and macrolides?

• Impaired influx or increased efflux

• Interference with ribosomal binding

• Enzymatic inactivation

Why are protein synthesis inhibitors selective for bacteria?

They target bacterial ribosomes, which differ structurally from mammalian ribosomes, allowing selective toxicity.

How are most protein synthesis inhibitors administered?

Orally

What are the two subunits of the bacterial ribosome and their functions?

• 30S subunit: Binds to mRNA

• 50S subunit: Catalyzes peptide bond formation between amino acids

Where are bacterial ribosomal subunits located when not synthesizing proteins?

In the cytoplasm, existing separately until they assemble on mRNA during translation.

How do antibiotics inhibit bacterial protein synthesis?

They bind to either the 30S or 50S ribosomal subunit, disrupting translation by blocking initiation, elongation, or peptide bond formation.

How can bacteria develop resistance to protein synthesis inhibitors?

By altering drug binding sites, even a single amino acid change can reduce drug affinity and prevent effective binding.

What is the mechanism of action of aminoglycosides?

They irreversibly bind to the 30S ribosomal subunit, blocking initiation of translation and causing misreading of mRNA, leading to production of nonfunctional proteins.

What type of bacteria are aminoglycosides primarily used to treat?

Aerobic Gram-negative bacilli infections.

What are the major side effects of aminoglycosides with extended use?

• Nephrotoxicity

• Ototoxicity

• Neuromuscular toxicity

Why are aminoglycosides usually administered parenterally?

They are highly polar and poorly absorbed from the GI tract, so oral administration is ineffective.

How do penicillins enhance aminoglycoside activity?

Penicillins cause cell wall abnormalities, allowing aminoglycosides to gain entry into bacteria.

What is unique about aminoglycoside dosing and killing?

• Concentration-dependent killing → efficacy increases with higher peak concentrations

• Often given as a single daily dose

• Post-antibiotic effect → antibacterial activity persists even after drug levels fall below MIC.

What is Gentamicin (Gentak)?

An aminoglycoside that irreversibly binds to 30S subunits.

What is Tobramycin (Tobrex)?

An aminoglycoside that irreversibly binds to 30S subunits.

What is Neomycin (Neo-Fradin)

An aminoglycoside that irreversibly binds to 30S subunits.

What is Streptomycin (Ambistryn-S)?

An aminoglycoside that irreversibly binds to 30S subunits.

What is the mechanism of action of tetracyclines?

They reversibly bind to the 30S ribosomal subunit, blocking tRNA attachment to the ribosome and preventing continuation of protein synthesis.

What is the spectrum of activity and route of administration for tetracyclines?

Broad-spectrum antibiotics, effective against Gram (+) and Gram (–) organisms. Most are absorbed orally.

Why should tetracyclines not be taken with dairy products or antacids?

They form chelates with polyvalent metal ions (Ca²⁺, Mg²⁺, Fe²⁺, Al³⁺), creating insoluble tetracycline-metal complexes that reduce absorption by 50–90%.

What is the consequence of tetracycline chelation in the body?

Chelation with Ca²⁺ in bones and teeth can cause damage and discoloration, especially in fetuses and children.

How do tetracyclines distribute in the body?

They cross the placenta, are excreted in breast milk, and can bind to growing bones and teeth.

What are common clinical indications for tetracyclines?

Treatment of bacterial infections involving skin, intestines, respiratory tract, urinary tract, genitals, lymph nodes, and others.

What GI-related adverse effects can tetracyclines cause?

• Superinfections due to destruction of normal gut flora

• Nausea, vomiting, diarrhea (can be reduced by taking with food or lowering dose)

Why should tetracyclines be avoided during pregnancy and in children <8 years?

They bind calcium, causing brown tooth discoloration and bone growth defects.

What is a notable dermatologic side effect of tetracyclines?

Photosensitivity, increased sensitivity to sunlight or UV light, especially in fair-skinned individuals.

What is Coxycycline (Vibramycin)?

A tetracycline that reversibly binds to 30S subunit of ribosome. 

What is Minocycline (Minocin)?

A tetracycline that reversibly binds to 30S subunit of ribosome.

What is Tetracycline (Sumycin)?

A tetracycline that reversibly binds to 30S subunit of ribosome. 

What is the mechanism of action of macrolides?

They reversibly bind to the 50S ribosomal subunit, preventing continuation of protein synthesis (blocks elongation).

What is the spectrum of activity of macrolides?

Effective against a variety of Gram-positive organisms and limited Gram-negative coverage.

What are common clinical uses of macrolides?

Treatment of community-acquired respiratory tract infections, especially pneumonia.

How are macrolides typically administered?

Well absorbed orally, making them convenient for outpatient therapy.

What are the most common GI adverse effects of macrolides?

Anorexia, nausea, vomiting, and diarrhea due to GI irritation.

What hepatotoxic effect can occur with chronic macrolide use?

Liver damage and jaundice (cholestatic hepatitis).

What is a notable neurologic/otologic adverse effect of macrolides?

Ototoxicity, which can cause hearing impairment.

What is Azithromycin (Zithromax)?

A macrolide that reversibly binds to 50S subunit.

What is Clarithromycin (Biaxin)?

A macrolide that reversibly binds to 50S subunit.

What is Erythromycin (Erythrocin)?

A macrolide that reversibly binds to 50S subunit.

What is the mechanism of action of chloramphenicol?

It reversibly binds to the 50S ribosomal subunit, preventing peptide bond formation during protein synthesis.

Is chloramphenicol bacteriostatic or bactericidal?

It can be bacteriostatic or bactericidal, depending on the bacterial species.

What is the spectrum of activity and why is chloramphenicol rarely used?

Broad spectrum (Gram-positive cocci and Gram-negative organisms), but reserved for life-threatening infections (e.g., typhoid fever, meningitis) due to severe toxicity. 

What is the rare but lethal adverse effect of chloramphenicol?

Aplastic anemia, bone marrow failure (Increased bleeding & infections) 

What common GI side effects occur with chloramphenicol?

Nausea and diarrhea.

What is Gray Baby Syndrome and why does it occur?

Gray skin color in infants, d/t their decreased ability to conjugate chloramphenicol, leading to high conc blood levels.

What is the mechanism of action of clindamycin?

It binds to the 50S ribosomal subunit, specifically the peptidyl transferase center, inhibiting peptide bond formation and preventing continuation of protein synthesis.

Is clindamycin bacteriostatic or bactericidal?

Bacteriostatic, but can be bactericidal at high concentrations.

What is the spectrum of activity of clindamycin?

Narrow spectrum: effective against a wide range of Gram-positive cocci and anaerobes; almost no activity against Gram-negative bacteria due to poor outer membrane permeability.

What is the most serious adverse effect of clindamycin?

Antibiotic-associated diarrhea, including pseudomembranous colitis caused by Clostridium difficile (which is resistant to clindamycin).

What are common side effects of clindamycin?

• Nausea

• Vomiting

• Rash

What is the mechanism of action of oxazolidinones?

They bind to the 50S ribosomal subunit, preventing formation of the initiation complex and interfering with protein synthesis initiation.

What is the spectrum of activity for oxazolidinones?

Active against Gram-positive cocci and rods, including MRSA, VRE, and Mycobacterium tuberculosis.

Are oxazolidinones bacteriostatic or bactericidal?

Bacteriostatic overall, but bactericidal against Streptococcus species.

What are the main clinical uses of oxazolidinones?

Treatment of MRSA infections and vancomycin-resistant Enterococcus (VRE) infections.

What is Linezolid?

An oxazolidinone that binds to 50s subunit to interfere with initiation.

Why is resistance to oxazolidinones relatively slow to develop?

Because the drug is synthetic and not found in nature, reducing pre-existing resistance mechanisms. (Recent reports: target site mutations & efflux transporters.)

What are the major adverse effects of oxazolidinones?

• Hematologic: Thrombocytopenia, anemia, and neutropenia.

• Optic neuropathy and peripheral neuropathy

• Diarrhea

What is the mechanism of action of streptogramins?

They bind two different sites on the 50S ribosomal subunit, inhibiting protein synthesis.

Which drugs make up the streptogramin combination therapy, and why are they given together?

Quinupristin + Dalfopristin (Synercid). They are always given together for their synergistic action.

What is the main clinical use of streptogramins?

Treat skin infections caused by methicillin-susceptible S. aureus or Streptococcus pyogenes.

What is the spectrum and killing effect of streptogramins?

Mostly active against Gram-positive bacteria; bactericidal against MRSA, VRSA, and VRE.

What are the adverse effects of streptogramins?

• Jaundice

• Local pain, local inflammation (at infusion site), localized edema

• Joint and/or muscle pain

• Diarrhea, nausea, vomiting 

What is the mechanism of action of pleuromutilins?

They interfere with the function of the 50S ribosomal subunit, inhibiting bacterial protein synthesis.

Which drugs belong to the pleuromutilin class and what are their main uses?

• Retapamulin (Altabax): Topical treatment of impetigo caused by S. aureus or Streptococcus pyogenes.

• Lefamulin (Xenleta): Oral/IV treatment of community-acquired respiratory tract infections (RTIs).

What is the origin of pleuromutilins?

Derived from a fungal fermentation product

How does pleuromutilin resistance compare to other antibiotic classes?

Unaffected by resistance to major antibiotic classes; develops slowly with low spontaneous mutation frequency and stepwise resistance.

What are the common adverse effects of Lefamulin (Xenleta)?

Diarrhea, nausea, injection site pain, and liver inflammation.

What is the most common adverse effect of Retapamulin (Altabax)?

Local irritation at the application site.

What is the mechanism of action of mupirocin?

It inhibits isoleucyl-tRNA synthetase, blocking RNA and protein synthesis.

What is the origin and spectrum of mupirocin?

Topical antibiotic isolated from Pseudomonas; highly active against staphylococci, streptococci, and some Gram-negative bacteria.

What are the main clinical uses of mupirocin?

Treatment of superficial skin infections.

What are common adverse effects of mupirocin?

Burning, stinging, pain, itching, rash, redness, dryness, tenderness, or swelling at the application site.