Antimicrobial Pharmacology II

What is the sequence of daptomycin's mechanism of action?

Binds membrane → forms calcium-dependent complexes → potassium loss and membrane depolarization

Is daptomycin bactericidal or bacteriostatic?

Bactericidal

What are the major muscle-related adverse effects of daptomycin?

Myopathy, rhabdomyolysis, and increased creatine phosphokinase (CPK)

Why should daptomycin NOT be used for pneumonia?

Pulmonary surfactant inactivates it

What enzyme does fosfomycin inhibit?

MurA (UDP-N-acetylglucosamine enolpyruvyl transferase)

What stage of bacterial cell wall synthesis does fosfomycin block?

An early, first step in peptidoglycan precursor synthesis (UDP-N-acetylmuramic acid formation)

What are the two fosfomycin resistance mechanisms?

- Reduced MurA affinity

- Reduced bacterial uptake through glycerophosphate/glucose-6-phosphate transporters

How does bacitracin inhibit bacterial cell wall synthesis?

Prevents dephosphorylation/recycling of the bactoprenol lipid carrier

Why is bacitracin generally used only topically?

It is highly nephrotoxic when administered systemically

Which two antibiotic classes bind the 30S ribosomal subunit?

Aminoglycosides and Tetracyclines

Which four antibiotic groups bind the 50S ribosomal subunit?

- Macrolides

- Chloramphenicol

- Lincosamides (clindamycin)

- Oxazolidinones (linezolid)

What kind of bacteria are aminoglycosides mainly used against?

Aerobic gram-negative bacteria

What are the three principal actions of aminoglycosides at the ribosome?

Block initiation, cause mRNA misreading, and block translocation

Are aminoglycosides bactericidal or bacteriostatic?

Bactericidal

What is the most common clinically encountered aminoglycoside resistance mechanism?

Enzymatic inactivation by transferases

What cell entry changes can cause aminoglycoside resistance?

Loss/mutation of porins or failure of oxygen-dependent transport

Why are aminoglycosides usually given IV or IM instead of orally for systemic infection?

They are very poorly absorbed from the GI tract

Are aminoglycosides concentration-dependent or time-dependent killers?

Concentration-dependent

What are the two major dose-limiting toxicities of aminoglycosides?

Ototoxicity and Nephrotoxicity

Which patient factors increase aminoglycoside toxicity risk?

- Older age

- Renal insufficiency

- Prolonged therapy (especially >5 days)

Which diuretic should generally be avoided with aminoglycosides because of toxicity risk?

Loop diuretics

Which seven tetracycline-family drugs are listed in Part II?

- Tetracycline

- Demeclocycline

- Doxycycline

- Minocycline

- Tigecycline

- Eravacycline

- Omadacycline.

What tetracycline derivative is a glycylcycline?

Tigecycline

Which tetracycline derivative is classified as a fluorocycline?

Eravacycline

Which tetracycline derivative is an aminomethylcycline?

Omadacycline

How do tetracyclines inhibit bacterial protein synthesis?

Bind 30S and prevent incoming charged tRNA from binding

Are tetracyclines bactericidal or bacteriostatic?

Bacteriostatic

What are the three tetracycline resistance mechanisms?

- Reduced influx/increased efflux

- Ribosomal protection

- Enzymatic inactivation

What types of ions chelate tetracyclines and reduce absorption?

Divalent cations (Ca2+, Mg2+, Fe2+) and trivalent cations (Al3+)

How should patients take tetracyclines to reduce esophageal irritation?

With a full glass of water

What dermatologic adverse effect is associated with tetracyclines?

Photosensitivity

Why are tetracyclines generally avoided during pregnancy or in young children?

They deposit in developing bones/teeth, causing growth and tooth discoloration problems

How do macrolides inhibit bacterial protein synthesis?

Bind the 50S ribosomal subunit and block transpeptidation

What are four macrolide resistance mechanisms?

- Active efflux

- Ribosomal methylation

- Hydrolysis by esterases

- 50S ribosomal mutations

Which macrolides inhibit CYP3A4?

Erythromycin and Clarithromycin

Which listed macrolide does NOT inhibit CYP3A4?

Azithromycin

What are the main class toxicities of macrolides listed in the lecture?

GI upset and QTc prolongation

Which macrolide has a long half-life and once-daily dosing?

Azithromycin

Which macrolide stimulates motilin receptors to promote GI motility?

Erythromycin

What distinctive adverse effect is associated with clarithromycin?

Dysgeusia (altered taste)

How does chloramphenicol inhibit protein synthesis?

Binds 50S and blocks transpeptidation

What are the major toxicities of chloramphenicol?

- Dose-related anemia

- Aplastic anemia

- Gray baby syndrome

What causes gray baby syndrome from chloramphenicol?

Neonates have insufficient glucuronidation, leading to accumulation of toxic chloramphenicol metabolites.

How does clindamycin inhibit protein synthesis?

Blocks transpeptidation and ribosomal translocation

Why are aerobic gram-negative bacteria intrinsically resistant to clindamycin?

Poor permeability of their outer membrane

What are two major adverse effects of clindamycin?

C. difficile colitis and esophageal irritation

How can patients minimize esophageal irritation from oral clindamycin?

Take with a full glass of water and remain upright for at least 30 minutes

What infections is clindamycin used for according?

Skin/soft tissue infections and anaerobic infections

How does linezolid inhibit bacterial protein synthesis?

Prevents formation of the protein-synthesis initiation ribosomal complex

Against which bacteria is linezolid bacteriostatic?

Staphylococci and Enterococci

Against which bacteria is linezolid bactericidal?

Streptococci

What two resistant organisms are key indications for linezolid?

MRSA and VRE

What blood-related toxicities can occur with linezolid?

Duration-dependent bone marrow suppression and thrombocytopenia

What neurologic toxicities are associated with linezolid?

Peripheral neuropathy and optic neuritis

Why can linezolid cause serotonin syndrome?

It has MAOI-related effects that can interact with serotonergic medicines

What key MAO-related distinction is made for tedizolid?

Tedizolid does not possess MAO inhibition

What are the six fluoroquinolones?

- Ciprofloxacin

- Levofloxacin

- Moxifloxacin

- Delafloxacin

- Gatifloxacin

- Ofloxacin

Which two bacterial enzymes are inhibited by fluoroquinolones?

DNA gyrase (topoisomerase II) and topoisomerase IV

Which fluoroquinolone target predominates in gram-negative organisms?

DNA gyrase (topoisomerase II)

Which fluoroquinolone target predominates in gram-positive organisms?

Topoisomerase IV

Are fluoroquinolones bactericidal or bacteriostatic?

Bactericidal

What are the three fluoroquinolone resistance mechanisms?

- Altered topoisomerase targets

- Increased efflux

- Decreased porin expression

Why are ciprofloxacin oral doses typically higher than its IV doses in the slides?

Its oral bioavailability is lower (~70%)

Which fluoroquinolone has primarily nonrenal excretion?

Moxifloxacin

Why should moxifloxacin not be used for a UTI?

It does not achieve adequate urinary concentrations

Which two newer fluoroquinolones are specifically identified with QTc prolongation?

Levofloxacin and Moxifloxacin

Which methylxanthines can have increased levels and seizure risk with fluoroquinolones?

Theophylline and Caffeine

What ions can decrease oral fluoroquinolone absorption?

Calcium, Magnesium, Iron, and Aluminum cations

Hhow should oral fluoroquinolones be separated from cation-containing products?

2 hours before or 4 hours after products containing these cations

What tendon injury is associated with fluoroquinolones?

Tendinopathy and tendon rupture

What peripheral nerve adverse effect is associated with fluoroquinolones?

Peripheral neuropathy

What blood sugar disturbances are associated with fluoroquinolones?

Hypoglycemia and hyperglycemia

What serious neuromuscular condition can be worsened by fluoroquinolones?

Myasthenia gravis