Antimicrobial Pharmacology III

Why are bacteria susceptible to antifolate antibiotics?

- They synthesize their own folate

- Mammalian cells obtain folate from the diet

What enzyme do sulfonamides inhibit?

Dihydropteroate Synthase

Which endogenous molecule do sulfonamides resemble and compete with?

PABA (para-aminobenzoic acid)

What enzyme does trimethoprim inhibit?

Bacterial dihydrofolate reductase (DHFR)

Which folate conversion does trimethoprim block?

Dihydrofolic acid (DHF) to tetrahydrofolic acid (THF)

Why are sulfamethoxazole and trimethoprim synergistic?

They sequentially block two enzymes in the bacterial folate synthesis pathway

Are SMX and TMP bacteriostatic or bactericidal alone vs. together?

- Each is bacteriostatic alone

- SMX-TMP combination is bactericidal

Which component determines weight-based dosing of SMX-TMP?

The trimethoprim (TMP) component

What are important mechanisms of sulfonamide resistance?

- Increased PABA

- Reduced permeability

- Altered/overproduced dihydropteroate synthase

What are important mechanisms of trimethoprim resistance?

- Altered/overproduced DHFR or reduced permeability

- Resistant DHFR can be plasmid-encoded

Why can sulfonamides increase bleeding risk with warfarin?

CYP2C9 inhibition and displacement of warfarin from protein-binding sites

Why is trimethoprim problematic with methotrexate?

Both inhibit DHFR, increasing risk of bone marrow suppression.

What serious hypersensitivity reaction is associated with sulfonamides?

Stevens-Johnson syndrome (also rash, fever, photosensitivity)

Which patients risk hemolysis with sulfonamides?

Patients with G6PD deficiency

What renal adverse effects can sulfonamides cause?

Crystalluria and hematuria, especially due to low solubility in acidic urine

What hematologic adverse effects can trimethoprim cause?

Megaloblastic anemia, leukopenia, and granulocytopenia

What are the key uses of SMX-TMP?

- MRSA infections

- Urinary tract infections,

- Pneumocystis jirovecii pneumonia.

How does metronidazole kill susceptible organisms?

Reduction in anaerobic organisms produces free radicals that damage DNA

Is metronidazole bacteriostatic or bactericidal?

Bactericidal

Which organisms or infections are targeted by metronidazole in this lecture?

Anaerobes, especially gut and genitourinary anaerobes; susceptible protozoa.

What key adverse effects/interactions are associated with metronidazole?

- Peripheral neuropathy

- Disulfiram-like reaction with alcohol

How does metronidazole interact with warfarin?

It increases the INR (and bleeding risk)

What activates nitrofurantoin inside bacteria?

Bacterial nitroreductase enzymes

What cellular targets are damaged by activated nitrofurantoin?

Bacterial ribosomal proteins, RNA, and DNA

What is the main therapeutic use of nitrofurantoin?

Urinary tract infections

What characteristic adverse effects are associated with nitrofurantoin?

- Brown urine discoloration

- Pulmonary toxicity with prolonged use

What are the main stages of the viral life cycle in order?

Attachment, entry, uncoating, replication/transcription, translation, assembly, release.

Where do most DNA viruses vs. most RNA viruses replicate?

- DNA viruses: nucleus

- RNA viruses: cytoplasm (influenza is an exception)

What are the three main anti-influenza drug groups?

- Adamantanes

- Baloxavir

- Neuraminidase inhibitors

Which two drugs are adamantanes?

Amantadine and Rimantadine

What do adamantanes inhibit, and which viral step is blocked?

- M2 proton channe

- Prevents influenza viral uncoating

Which influenza type is targeted by adamantanes, and are they recommended?

- Influenza A only

- Not recommended

What enzyme does baloxavir inhibit?

- Polymerase acidic (PA) endonuclease

- Blocks viral gene transcription.

What is the brand name and dosing pattern of baloxavir marboxil?

- Xofluza

- One-time oral dose

Which influenza types does baloxavir cover?

Influenza A and B

What should not be coadministered with baloxavir?

Antacids, calcium, or iron (multivalent cations)

Which three drugs are neuraminidase inhibitors?

- Oseltamivir

- Zanamivir

- Peramivir

What viral step is inhibited by neuraminidase inhibitors?

Release of new influenza virions from infected cells

Match Oseltamivir, Zanamivir, and Peramivir with their routes:

- Oseltamivir: PO

- Zanamivir: inhaled

- Peramivir: IV

Which neuraminidase inhibitor is contraindicated in asthma or COPD?

Inhaled zanamivir

Which neuraminidase inhibitor is often used when PO/inhaled routes cannot be used?

IV peramivir

Which anti-herpes drugs inhibit viral DNA polymerase?

- Acyclovir

- Valacyclovir

- Famciclovir

- Penciclovir

- Foscarnet

What enzyme performs the first activation step of acyclovir?

- Virus-specified thymidine kinase

- Host kinases complete phosphorylation

How does acyclovir triphosphate stop viral DNA synthesis?

Inhibits viral DNA polymerase and causes DNA chain termination

Why is acyclovir selectively activated in infected cells?

The initial phosphorylation requires a viral thymidine kinase

What is the major renal adverse effect of acyclovir?

- Nephrotoxicity

- Adequate hydration reduces risk

What is valacyclovir a prodrug of?

- Acyclovir

- Oral valacyclovir improves systemic exposure

What is famciclovir converted into?

Penciclovir (after deacetylation and oxidation)

Which antiviral from the famciclovir pair is also available as a topical 1% cream?

Penciclovir

What type of analog is foscarnet, and does it require phosphorylation?

- Inorganic pyrophosphate analog

- No phosphorylation needed

What enzymes does foscarnet directly inhibit?

- Viral DNA polymerase

- RNA polymerase

- HIV reverse transcriptase

Which four anti-CMV agents are listed as DNA polymerase inhibitors?

- Ganciclovir

- Valganciclovir

- Foscarnet

- Cidofovir

Which anti-CMV drug is the oral prodrug of ganciclovir?

Valganciclovir

Why is valganciclovir given orally instead of oral ganciclovir?

- Better oral bioavailability

- Ganciclovir has poor oral bioavailability

What major toxicity is shared by ganciclovir and valganciclovir?

Myelosuppression

Which two anti-CMV drugs are especially associated with nephrotoxicity?

Foscarnet and Cidofovir

Why does cidofovir not require a viral kinase for initial activation?

- It already has a monophosphate group

- Host kinase forms the active diphosphate

Which CMV enzyme does maribavir inhibit?

CMV pUL97 kinase

Why should maribavir not be combined with ganciclovir or valganciclovir?

pUL97 inhibition prevents their required viral-kinase activation

What viral complex does letermovir inhibit?

The CMV DNA terminase complex

What step of CMV replication is blocked by letermovir?

Viral DNA cleavage, processing, and packaging.

Which anti-CMV agents are oral vs. IV?

- PO: Valganciclovir, Maribavir

- IV: Ganciclovir, Foscarnet, Cidofovir

- Both: Letermovir