Antimetabolites

Question 1

sulfamethoxazole

Answer 1

Antimetabolite- Sulfonamide

• false substrate that inhibits binding of PABA to DHPS enzyme
• blocks first step in bacterial synthesis of tetrahydrofolate
• tetrahydrofolate required for DNA, RNA, and protein synthesis
• bacterioSTATIC, and selective toxicity b/c DHPS does not function in humans
• bacteria synthesize folic acid whereas humans get through dietary intake
• Broad spectrum (gram+ and gram-, and some parasites)
• oral, can penetrate CNS, liver metab., excreted via kidney (need to reduce dose in renal failure)
• resistance wide-spread with cross resistance to all sulfas d/t overproduction of PABA, DHPS enzyme with dec. affinity to sulfa, and up-regulation of efflux
• Toxicity: bone marrow and liver, GI, Stevens-Johnson syndrome, kernicterus in infants
• usually used in combo with trimethoprim

Question 2

trimethoprim

Answer 2

Antimetabolite- DHFR inhibitor

• blocks later step in folic acid synthesis and has much higher affinity for bacterial DHFR then human DHFR
• bacterioSTATIC when used alone

Question 3

trimethoprim-sulfamethoxazole (cotrimoxazole, Bactrim)

Answer 3

Antimetabolite- DHFR inhibitor

• combination produces BACTERICIDAL synergism b/c inhibiting mult. steps in folic acid synthesis
• Broad spectrum (gram+, gram-)
• oral, wide distribution, excretion in urine
• Resistance d/t over-expression of DHFR, and mutant DHFR resistant to trimethoprim (resistance increasing)
• more common bone marrow suppression, anti-folate effect
• Used for: UTIs, pneumonia in HIV, MRSA

Question 4

ciprofloxacin

Answer 4

Antimetabolite- Fluoroquinolones

• fluorine substitution gives greater potency and expanded spectrum
• MOA: concentration-dependent BACTERICIDAL, rapid inhibitors of bacterial DNA synthesis, inhibits bacterial DNA gyrase, induces irreversible DNA damage
• Gram- activity cipro > levo > moxi
• gram+ activity moxi > levo> cipro
• great against nosocomial infections
• resistance d/t dec. drug permeability, inc. efflux pump, and mutation of enzymes
• one point mutation requires elevation of MIC, mutations in both genes cause high level of resistance (nearly all MRSA is resistant)
• usually well tolerated, GI issues common, achilles tendon rupture, liver toxicity, MRSA/D-diff colonization (cipro most common cause of CDAC)
• Uses: UTIs, pneumonia, STD (use only when necessary)

Question 5

levofloxacin

Answer 5

Antimetabolite- Fluoroquinolones

• fluorine substitution gives greater potency and expanded spectrum
• MOA: concentration-dependent BACTERICIDAL, rapid inhibitors of bacterial DNA synthesis, inhibits bacterial DNA gyrase, induces irreversible DNA damage
• Gram- activity cipro > levo > moxi
• gram+ activity moxi > levo> cipro
• great against nosocomial infections
• resistance d/t dec. drug permeability, inc. efflux pump, and mutation of enzymes
• one point mutation requires elevation of MIC, mutations in both genes cause high level of resistance (nearly all MRSA is resistant)
• usually well tolerated, GI issues common, achilles tendon rupture, liver toxicity, MRSA/D-diff colonization (cipro most common cause of CDAC)
• Uses: UTIs, pneumonia, STD (use only when necessary)

Question 6

moxifloxicin

Answer 6

Antimetabolite- Fluoroquinolones

• fluorine substitution gives greater potency and expanded spectrum
• MOA: concentration-dependent BACTERICIDAL, rapid inhibitors of bacterial DNA synthesis, inhibits bacterial DNA gyrase, induces irreversible DNA damage
• Gram- activity cipro > levo > moxi
• gram+ activity moxi > levo> cipro
• great against nosocomial infections
• resistance d/t dec. drug permeability, inc. efflux pump, and mutation of enzymes
• one point mutation requires elevation of MIC, mutations in both genes cause high level of resistance (nearly all MRSA is resistant)
• usually well tolerated, GI issues common, achilles tendon rupture, liver toxicity, MRSA/D-diff colonization (cipro most common cause of CDAC)
• Uses: UTIs, pneumonia, STD (use only when necessary)

Question 7

metronidazole (Flagyl)

Answer 7

Antimetabolite- DNA Damaging Agent

• initially important antiprotozoal agent but also antibacterial activity against obligate anaerobes
• MOA: nitro group reduction in cells generates DNA-damaging species
• BACTERICIDAL
• effective against obligate anaerobes, both gram+ and gram-, but does not perturb commensal aerobic flora
• Resistance is limited but growing and is enhanced by promiscuous use for classic chronic periodontitis
• Toxicity: disulfiram-like response to alcohol, serotonin syndrome
• interacts with alcohol, disulfiram, and warfarin