Nucleic Acid Synthesis Inhibitors Part 3

What are rifamycins?

A group of macrocyclic antibiotics produced by Streptomyces mediterranei.

Name the major rifamycins.

Rifamycin, rifampin (rifampicin), and rifamide.

Are rifamycins bactericidal or bacteriostatic?

Bactericidal.

What enzyme is inhibited by rifamycins?

DNA-dependent RNA polymerase.

How do rifamycins inhibit bacterial growth?

They bind to DNA-dependent RNA polymerase, preventing RNA chain initiation and RNA synthesis.

Why are mammalian cells less affected by rifamycins?

Much higher drug concentrations are required to inhibit mammalian RNA polymerase.

Which combination is commonly used to treat Rhodococcus equi infection in foals?

Rifampin combined with a macrolide (erythromycin, azithromycin, or clarithromycin).

Which Gram-positive bacteria are susceptible to rifampin?

Staphylococcus spp., including methicillin-resistant strains, and Streptococcus spp.

Which intracellular pathogen is an important target of rifampin?

Rhodococcus equi.

Which other bacteria are susceptible to rifampin?

Corynebacterium pseudotuberculosis, Bacteroides spp., Clostridium spp., Neisseria spp., and Listeria spp.

Which bacteria are resistant to rifampin?

Pseudomonas aeruginosa, Escherichia coli, Enterobacter spp., Klebsiella pneumoniae, Proteus spp., and Salmonella spp.

For which mycobacterial diseases is rifampin commonly used in veterinary medicine?

Mycobacterium tuberculosis in elephants and Mycobacterium paratuberculosis in cattle and sheep.

Does rifampin eradicate Mycobacterium paratuberculosis?

No, it may induce remission but does not eradicate the organism.

With which antifungal does rifampin show synergism?

Amphotericin B.

How is rifampin absorbed?

Readily but incompletely from the gastrointestinal tract.

In what environment is rifampin absorption greatest?

An acidic environment.

How does feeding affect rifampin absorption?

It decreases oral absorption in foals and ruminants.

Why is rifampin effective against intracellular organisms?

It penetrates tissues and cells extensively.

Where is rifampin widely distributed?

Most body tissues and body fluids.

Which organs contain high concentrations of rifampin?

Lungs, pulmonary epithelial lining fluid, liver, bile, and urine.

How is rifampin eliminated?

Primarily through bile and to a lesser extent through urine.

What type of cycling occurs with rifampin?

Enterohepatic cycling.

What major adverse effect is associated with rifampin?

Hepatotoxicity.

What harmless body fluid discoloration can rifampin cause?

Red-orange discoloration of urine, sweat, and saliva.

Why should rifampin be avoided during pregnancy?

It is teratogenic.

What are nitrofurans?

Synthetic antimicrobial drugs derived from 5-nitrofuran.

Which nitro group is essential for nitrofuran activity?

The 5-nitro group.

Name the commonly used nitrofurans.

Nitrofurantoin and nitrofurazone.

Which nitrofuran has been banned in food-producing animals?

Furazolidone.

How are nitrofurans activated?

They are reduced by bacterial reductase enzymes to reactive intermediates.

How do nitrofurans inhibit bacteria?

They cause DNA fragmentation, inhibit nucleic acid synthesis, and interfere with microbial enzymes.

Are nitrofurans bactericidal or bacteriostatic?

Bacteriostatic.

Which nitrofuran is mainly used for lower urinary tract infections?

Nitrofurantoin.

Which nitrofuran is mainly used as a topical antimicrobial?

Nitrofurazone.

Why are nitrofurans ineffective for systemic infections?

They achieve very low blood and tissue concentrations.

In what environment are nitrofurans most active?

Acidic environments.

What enhances nitrofurantoin absorption?

Administration with food.

How is nitrofurantoin eliminated?

Rapidly by the kidneys, mainly through tubular secretion.

What CNS adverse effects can occur with nitrofurans?

Excitement, tremors, convulsions, and peripheral neuritis.

What gastrointestinal adverse effects are associated with nitrofurans?

Nausea, vomiting, and diarrhea.

What reproductive adverse effect can occur with nitrofurans?

Depression of spermatogenesis.

Why is furazolidone banned in food-producing animals?

Because of its mutagenic and carcinogenic potential.

How common is bacterial resistance to nitrofurans?

Rare and develops slowly.

Is there cross-resistance among nitrofurans?

Yes, complete cross-resistance exists within the class.

Is there cross-resistance between nitrofurans and other antibacterial classes?

No.

What are nitroimidazoles?

Heterocyclic drugs with antibacterial and antiprotozoal activity.

Which drug is the prototype nitroimidazole?

Metronidazole.

Name the major nitroimidazoles.

Metronidazole, ronidazole, ipronidazole, and dimetridazole.

How are nitroimidazoles activated?

Through nonenzymatic reduction under anaerobic conditions.

How do nitroimidazoles damage bacteria?

Their cytotoxic metabolites bind DNA, causing strand breakage and loss of DNA function.

Why are nitroimidazoles ineffective against aerobic bacteria?

Aerobic bacteria lack the reductive pathway required for drug activation.

Are nitroimidazoles bactericidal or bacteriostatic?

Bactericidal.

Which bacteria are highly susceptible to metronidazole?

Bacteroides spp., Fusobacterium spp., and Clostridium spp.

Against which protozoa is metronidazole effective?

Giardia lamblia, Tritrichomonas foetus, Entamoeba spp., and Histomonas meleagridis.

What are the principal clinical indications of metronidazole?

Anaerobic bacterial infections and protozoal infections.

Which additional therapeutic role does metronidazole have?

It acts as a radiosensitizer during radiotherapy.

How is metronidazole absorbed?

Well absorbed orally.

Does metronidazole cross the blood-brain barrier?

Yes.

Where else does metronidazole achieve therapeutic concentrations?

Abscesses and empyema fluid.

How is metronidazole eliminated?

By hepatic metabolism followed by renal and biliary excretion.

What neurologic adverse effects are associated with high-dose metronidazole?

Tremors, muscle spasms, ataxia, convulsions, and CNS excitement.

What hematologic adverse effect can metronidazole cause?

Reversible bone marrow depression.

What harmless discoloration may occur with metronidazole therapy?

Reddish-brown urine.

Why is metronidazole contraindicated in food-producing animals and pregnancy?

Because of its carcinogenic and teratogenic potential.

How common is resistance to metronidazole?

Rare.

What is the primary mechanism of nitroimidazole resistance?

Reduced intracellular drug activation.

Is cross-resistance complete among nitroimidazoles?

Yes.