Nucleic Acid Synthesis

Question 1

Refampin (rifamycin)

Answer 1

Mechanism:
Bactericidal- Binds bacterial RNA polymerase at the active center, blocking the elongation of the mRNA

Spectrum: Gram + and -, Mycobacteria tuberculosis

Resistance:
Intrinsic resistance- in some bacterial strains the drug is unable to bind to the β subunit of RNA polymerase
Acquired resistance- the strain acquires mutations in rpoB gene preventing drug binding
Treat Mycobacteria tuberculosis with 4 antibiotics due to the high rate of resistance.

Adverse effects:
GI side effects, Hypersensitivity- Fever

Hepatotoxic-
Use caution when administering to patients with chronic liver disease

Induction of cytochrome P450 enzymes can induce the metabolism of other medicines leading to organ rejection and loss of seizure control

Turns body fluids orange-red and can stain contact lens

Question 2

Fidaxomicin

Answer 2

Mechanism: Bactericidal- Inhibits RNA polymerase by binding to sigma subunit of RNA polymerase

Spectrum: narrow spectrum sparing many of the gut flora, Gram positive anaerobes, C. difficile better at preventing recurrent infections

Resistance: Point mutation in RNA polymerase has been observed in vitro

Side effects:
Low absorption
Nausea, vomiting

Question 3

Fluoroquinolones.

Answer 3

Generic: Ciprofloxacin, levofloxacin, moxifloxacin

Question 4

Folate antagonists

Answer 4

Sulfonamides, Trimethoprim

Question 5

Sulfonamides

Answer 5

Generic name: Sulfamethoxazole (only one we’re responsible for)

Mechanism:
Bacteriostatic- drug is a para-aminobenzoic acid analog and acts as a competitive inhibitor of Dihydropteroate synthetase

Resistance: change in dehydropteroate synthetase, increased efflux
increased production of PABA

Adverse effects:
Hypersensitivity- Rash, Stevens-Johnson syndrome
Cross reaction to other drugs containing sulfonamide moieties
Crystalluria leading to acute renal failure
Hemolysis if Glucose-6-phosphate dehydrogenase deficient
Kernicterus (Sulfonamides can compete for binding to albumin leading to kernicterus in infants and complications with drugs like warfarin )

Question 6

Trimethoprim

Answer 6

Mechanism: Bacteriostatic- Inhibits bacterial dihydrofolate reductase.

Resistance:
Altered dihydrofolate reductase
Increased amounts of dihydrofolate reductase.
Alternative metabolic pathways.

Adverse effects:
Bone marrow suppression
Hyperkalemia

Question 7

Trimethoprim and sulfamethoxazole (TMP-SMX)

Answer 7

Sequential blockade is bactericidal.

Mechanism: Sequential blockage of the folate synthesis pathway

Spectrum: broad treatment of UTIs, Shigella, Salmonella, Pneumocystis

Question 8

Metronidazole

Answer 8

Mechanism: Bactericidal- metronidazole reduced (electron sink). The activated form generates free radicals leading to DNA strand breaks and cell death.

Spectrum: Protozoa (Giardia), Anaerobic bacteria including Clostridium difficle

Resistance: Rare

Adverse effects:
Nausea, diarrhea, headache, and metallic taste. Avoid during pregnancy
Disulfiram-like reaction with alcohol

*Only metabolized to active form in anaerobes

Question 9

What treatment is preferred for UTI?

Answer 9

Nitrofurantoin.

Question 10

Nitrofurantoin.

Answer 10

Mechanism: Bactericidal- Nitrofurantoin is reduced by bacterial flavoproteins to reactive intermediates, which inactivate or alter bacterial ribosomal proteins and other macromolecules. Leading to an inhibition of the synthesis of DNA, RNA, cell wall, and protein

Spectrum: Broad Spectrum, Rapidly excreted in the urine in an active form
Only reach high concentrations in the urine

Resistance: Lack of bacterial resistance since the drug interferes with a variety of processes.

Adverse effects: Vomiting and Pulmonary Toxicity

Important facts: Ineffective for infections outside of lower urinary tract