Harrold Misc Antibiotics

Advantage of sodium succinate ester prodrug of chloramphenicol

Increases water solubility, allowing for formulation of concentrated IV solutions

Advantage of palmitate ester prodrug of chloramphenicol

Increases palatability

Mechanism of chloramphenicol

Binds to the 50S ribosome and inhibits the enzyme peptidyl transferase by preventing attachment of tRNA to the A site

• Same mechanism as tetracyclines at a different site

Chloramphenicol is primarily metabolized by _____

Glucuronyl transferase

• Glucuronide conjuagtion reaction that produces a compound that is inactive and harmless

Notable toxic effects of chloramphenicol

Toxic Bone-Marrow Depression

• Reversible and dose-related

Gray Baby Syndrome

• Ashen gray color

• Caused by decreased concentration of glucuronyl transferase

• Occurs in infants <1 month old and especially in premature babies

Chloramphenicol causes Toxic Bone-Marrow Depression due to the fact that _____

Human mitochondrial ribosomes resemble bacterial ribosomes more than mammalian ribosomes and that erythropoietic cells are particularly sensitive to this inhibition

• Not seen with other inhibitors of bacterial protein synthesis because they cannot penetrate into the mitochondria

Mechanism of bacterial resistance to chloramphenicol

Some bacteria have acetyltransferase enzymes → acetylate the primary hydroxyl group → prevents the drug from binding to its target

_____ is the most active naturally occurring lincosamide

Lincomycin

What differs in the structure of clindamycin compared to lincomycin?

Substitution of Cl for OH

• Improves antibacterial activity

• Provides better oral absorption

• More lipid character → better water/lipid balance

Notable toxicity of lincosamides

Pseudomembranous colitis (antibiotic associated colitis)

• Caused by clindamycin-resistant strains of C. diff

• Can be fatal

• Treated by discontinuation of the drug and PO vancomycin, fidaxomicin, or metronidazole

Orally available clindamycin products have a black box warning for C. diff-associated diarrhea (CDAD)

Mechanism of lincosamides

Binds to the 50S ribosome and inhibits the enzyme peptidyl transferase by preventing attachment of tRNA to the A site

• Same mechanism as tetracyclines at a different site

Quinupristin/Dalfopristin are classified as _____

Streptogramins

Mechanism of quinupristin/dalfopristin

Bind to distinct sites on the 50S ribosome and forms a ternary complex

Binding of both drugs constricts the exit channel on the 50S ribosome where newly synthesized polypeptides/proteins leave

Inhibits tRNA synthesis → decreases peptide synthesis

Quinupristin/dalfopristin can cause drug interactions due to the fact that is is a _____

Weak CYP3A4 inhibitor

Linezolid and tedizolid are classified as _____

Oxazolidinones

Mechanism of oxazolidinones

Bind to the 23S subunit of the 50S ribosome

• Specifically bind to ribosomal proteins L3 and L4

• Inhibits the formation of a functional 70S complex

Mechanism of bacterial resistance to oxazolidinones

Mutations in chromosomal genes encoding 23S rRNA or ribosomal proteins L3 and L4 → alters binding site

Drug interactions with linezolid

Weak, nonselective, reversible inhibitor of MAO → decreases metabolism of norepinephrine → potential hypertensive crisis

• Also seen to a lesser extent with tedizolid

Severe hypertension if taken concominantly with foods rich in tyramine (precursor to NE)

• Cheddar and aged cheese, beer, bananas, soy sauce

Mechanism of methenamine

Prodrug of formaldehyde

Methenamine + 4 H⁺ + 6 H₂O → 6 CH₂O + 4NH₄⁺

Formaldehyde denatures proteins → bacteriocidal effect

Since formaldehyde is formed from methenamine only in an acidic environment, it is essential that _____

The pH of the urine is kept at ≤ 5.5

When taking methenamine, the acidic pH of the urine is maintained by using _____

Water soluble salts of methenamine that are not metabolized, but rather filtered into the urine

• The acids used and mandelic acid and hippuric acid

• Serves a double function because low pH alone is bacteriocidal

Any drug that _____ will decrease the effectiveness of methenamine

Increases urine pH

• Thiazides via inhibition of carbonic anhydrase

Mechanism of nitrofurantoin

Reduced by bacterial flavoproteins to reactive intermediates that inactivate or alter bacterial ribosomal proteins leading to inhibition of protein synthesis, aerobic energy metabolism, DNA, RNA, and cell wall synthesis

Nitrofurantoin is _____ in urine at therapeutic doses

Bacteriocidal

The lack of acquired bacterial resistance to nitrofurantoin is likely because _____

The necessary multiple and simultaneous mutations of the target macromolecules would likely be lethal to the bacteria

Why is nitrofurantoin selectively toxic to microbial cells?

High serum concentrations are not reached in humans

Also, bacterial cells reduce the drug much faster than human cells

There are two forms of nitrofurantoin available:

Crystalline form

Macrocrystalline form

The macrocrystalline form of nitrofurantoin is associated with _____

Increased GI tolerance

The most serious adverse reactions associated with nitrofurantoin are _____

Pulmonary reactions

Mechanism of mupirocin

Inhibits bacterial protein synthesis by reversibly and specifically binding to bacterial isoleucyl tRNA synthetase. As a result, isoleucine cannot be incorporated into bacterial proteins → proteins not able to function properly

Mechanism of retapamulin/lefamulin

Inhibit bacterial protein synthesis through interactions with the A and P sites of the peptidyl transferase center (PTC) in a specific domain of the 23S rRNA of the 50S subunit

Binding to ribosomal protein L3 is also involved

The binding pocket of the bacterial ribosome closes around the mutilin core for an induced fit that prevents correct positioning of tRNA

Drug interactions with lefamulin

Strong or moderate inducers or inhibitors of CYP3A4

Potential to prolong the QT interval → interaction with other drugs that affect cardiac conduction

Chemical classification of rifaximin

Rifamycin

Mechanism of rifaximin

Inhibits DNA-dependent RNA polymerase (uses DNA as a template to make RNA) → inhibits the binding of the enzyme to DNA and blocking RNA transcription → bacteria can’t make proteins

Why is rifaximin selective for bacteria?

Does not bind to RNA polymerase in human cells

PK properties of rifaximin

<0.4% absorbed from the GI tract → selective effect in the GI tract

97% excreted unchanged in the feces

Why is it not generally relevant that rifaximin can induce CYP3A4 (like all rifamycins)?

It is not absorbed, so it does not get to the liver

Mechanism of metronidazole

Readily taken up by passive diffusion and activated by susceptible anaerobic organisms

Reduction generates free radicals, superoxide, and other ROS such as hydrogen perioxide and hydroxide radicals

Free radicals can damage DNA’s helical structure → inhibits bacterial nucleic acid synthesis → bacterial cell death

Equally effective against dividing and nondividing cells

Why is metronidazole selective for anaerobic bacteria?

The electron transport proteins necessary to reduce metronidazole are only found in anaerobic bacteria

Most serious adverse reactions associated with metronidazole

Convulsive seizures and peripheral neuropathy

Notable drug interactions with metronidazole

May increase serum concentrations of warfarin

Concurrent use with ethanol may cause a disulfiram-like reaction

• Metronidazole inhibits aldehyde dehydrogenase → increases concentration of acetaldehyde

• Symptoms of flushing, palpitations, tachycardia, and N/V

• Avoid alcohol consumption during therapy and up to 3 days after