antimetabolites, quinolones, and metronidazole Flashcards
sulfonamides and trimethoprim
- 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
sulfonamides MOA
- 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
sulfonamides PK
- oral admin, can be IV
- well distributed, CNS + including CSF
- excretion: liver metabolism, kidney excretion
- dose reduction in renal failure
sulfonamides spectrum
**BROAD
-many gram - and +
some parasite: plasmodium (malaria) and toxoplasma gondii
sulfonamides resistance
- *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
sulfonamides toxicity and adverse
- 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
sulfonamides uses
**not typically used alone for common bacterial infections - resistance
-malaria
CNS toxoplasmosis
sulfonamides
sulfamethoxazole (in combo with trimethoprim = cotrimoxazole)
-oral po med
trimethoprim MOA
blocks later step in folic acid synthesis p/way than sulfonamides
- *affinity for bacterial DHFR 100000x higher than for human DHFR
- *alone = bacteriostatic
trimethroprim-sulfamethoxazole
- *trimethoprim acts synergistically with sulfamethoxazole
* *tmp-sulfa combos are bactericidal (synergistic)
trimethoprim-sulfamethoxazole spectrum
- broad spectrum, many gram + and gram - organisms
- not pseudomonas
- not anaerobes
- not atypical bacteria
trimethoprim-sulfamethoxazole resistance
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
trimethoprim-sulfamethoxazole SE
- 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
trimethoprim-sulfamethoxazole uses
- UTIs decreased efficacy with increasing E coli resistance
- pneumocystis PNA in AIDS/transplant pt
- sinusitis, otitis media
- community acquired MRSA
quinolones
- ciprofloxacin, levofloxacin, moxifloxacin
- greater potency and expanded spectrum (better gram + coverage)
- big guns
quinolones MOA
- *bactericidal
- rapid inhibitors of DNA synthesis
- *inhibit DNA gyrase (topoisomerase II and IV) blocks DNA unwinding
- induces irreversible DNA damage
fluoroquinolones spectrum
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
fluoroquinolones resistance
- 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]
fluoroquinolones SE
- 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
fluorquinolones clinical uses
- complicated UTI/prostatitis
- PNA
- STD
- prophylaxis for anthrax
- limit use
metronidazole
- imp antiprotozoal agen (thrichomonas)
* *excellent antibacterial activity against obligate anaerobes in common orofacial infections
metronidazole MOA
nitro group reduction in cells generates DNA damaging species
**bactericidal
metronidazole spectrum
- obligate anaerobes
- gram neg and pos
- *does not perturb commensal aerobic flora
metronidazole resistance
- 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
metronidazole SE
- disulfiram like response to ETOH
- serotonin syndrome
- dark urine
drug interactions: ETOH, warfarin, disulfiram
