antimetabolites, quinolones, and metronidazole

Question 1

sulfonamides and trimethoprim

Answer 1

• act in sequential steps to block bacterial folic acid synthesis –> inhibi DNa, RNA, PRO synthesis and reduce thymidine, purine, methionine production
• *high selective toxicity: DHPS enzyme does not function in humans
• *synergistic combos: -sulfonamides + trimethoprim
• *bactericidal

Question 2

sulfonamides MOA

Answer 2

• bacteria synthesize own folate; sulfonamides block 1st step and trimethoprim blocks last step (tetrahydrofolate)
• *false substrates, competitively inhibit binding of PABA to DHPS enzyme
• high PABA levels (pus) inhibit activity
• *bacteriostatic

Question 3

sulfonamides PK

Answer 3

• oral admin, can be IV
• well distributed, CNS + including CSF
• excretion: liver metabolism, kidney excretion
• dose reduction in renal failure

Question 4

sulfonamides spectrum

Answer 4

**BROAD
-many gram - and +
some parasite: plasmodium (malaria) and toxoplasma gondii

Question 5

sulfonamides resistance

Answer 5

• *widespread, common in staph, strep, enterobacteriaceae, neisseria
• cross resistance to all sulfas is typical
• overprod of PABA
• encode mutant DHPS enzyme with decreased affinity for sulfas (plasmid)
• upreg efflux pumps

Question 6

sulfonamides toxicity and adverse

Answer 6

• GI distress, rash
• BM and liver tox (uncommon)
• hemolytic anemia with G6PD deficiency
• kernicterus: in infants, sulfa competes for bilirubin binding sites on albumin and increases levels of unconjugated bili = CNS toxicity
• *stevens-johnson syndrome

Question 7

sulfonamides uses

Answer 7

**not typically used alone for common bacterial infections - resistance
-malaria
CNS toxoplasmosis

Question 8

sulfonamides

Answer 8

sulfamethoxazole (in combo with trimethoprim = cotrimoxazole)
-oral po med

Question 9

trimethoprim MOA

Answer 9

blocks later step in folic acid synthesis p/way than sulfonamides

• *affinity for bacterial DHFR 100000x higher than for human DHFR
• *alone = bacteriostatic

Question 10

trimethroprim-sulfamethoxazole

Answer 10

• *trimethoprim acts synergistically with sulfamethoxazole

* *tmp-sulfa combos are bactericidal (synergistic)

Question 11

trimethoprim-sulfamethoxazole spectrum

Answer 11

• broad spectrum, many gram + and gram - organisms
• not pseudomonas
• not anaerobes
• not atypical bacteria

Question 12

trimethoprim-sulfamethoxazole resistance

Answer 12

2 ways:
-overexpression of DHFR
-mutant DHFR that is resistant to trimethoprim (plasmid-mediated)
-resistance increasing, location dependent
> 20% E coli are resistance in some regions

Question 13

trimethoprim-sulfamethoxazole SE

Answer 13

• same toxicities as sulfas
• more commonly see BM suppression w neutropenia
• can cause anti-folate effect: used in caution in patients with sub-optimal folate nutrition

Question 14

trimethoprim-sulfamethoxazole uses

Answer 14

• UTIs decreased efficacy with increasing E coli resistance
• pneumocystis PNA in AIDS/transplant pt
• sinusitis, otitis media
• community acquired MRSA

Question 15

quinolones

Answer 15

• ciprofloxacin, levofloxacin, moxifloxacin
• greater potency and expanded spectrum (better gram + coverage)
• big guns

Question 16

quinolones MOA

Answer 16

• *bactericidal
• rapid inhibitors of DNA synthesis
• *inhibit DNA gyrase (topoisomerase II and IV) blocks DNA unwinding
• induces irreversible DNA damage

Question 17

fluoroquinolones spectrum

Answer 17

gram - including pseudomonas (cipro > levo > moxi)
gram + including steptococci (moxi > levo > cipro)
-poor anaerobic activity
-excellent against nosocomial infections and atypical bacteria (legionella, mycoplasma, chlamydia)
**do not achieve synergy when used with other antimicrobials

Question 18

fluoroquinolones resistance

Answer 18

• decreased permeability d/t change in pores
• efflux pump
• mutation of enzymes (point mutation in gyrA or par C [gram - gets gryA first then par C, opposite for gram +)
• one point mutation causes modest elevation in MIC, both = high level resistance
• increasing resistance **nearly all MRSA resistant [cipro = risk factor for MRSA]

Question 19

fluoroquinolones SE

Answer 19

• well tolerated, GI issues common
• arthopathy in rats (not approved for kids)
• achilles tendon rupture
• hepatotoxicity
• MRSA and C. diff colonization
• *cipro most common cause of CDAC
• severe effects and fatalities led to removal of several class members from market

Question 20

fluorquinolones clinical uses

Answer 20

• complicated UTI/prostatitis
• PNA
• STD
• prophylaxis for anthrax
• limit use

Question 21

metronidazole

Answer 21

• imp antiprotozoal agen (thrichomonas)

* *excellent antibacterial activity against obligate anaerobes in common orofacial infections

Question 22

metronidazole MOA

Answer 22

nitro group reduction in cells generates DNA damaging species
**bactericidal

Question 23

metronidazole spectrum

Answer 23

• obligate anaerobes
• gram neg and pos
• *does not perturb commensal aerobic flora

Question 24

metronidazole resistance

Answer 24

• limited but growing drug resistance (exception -resistant parasites and up to 50% resistance in H pylori)
• chromosomally and plasmid mediated genes that control nitroreductase activity
• *enhanced by promiscuous use for chronic periodontitis

Question 25

metronidazole SE

Answer 25

• disulfiram like response to ETOH
• serotonin syndrome
• dark urine

drug interactions: ETOH, warfarin, disulfiram