Antifolates, fluoroquinolones, and others

  1. sulfamethoxazole
    • false substrate competitively inhibits binding of PABA to DHPS enzyme
    • bacteriostatic
    • typically oral, can be given IV
    • well distributed, CNS and CSF
    • excretion: liver metabolism, excreted by kidneys (dose reduction in renal failure)
    • broad spectrum - many G+ and G-, also targets parasites, NOT Ricksettsia
    • resistance: widespread, cross resistance to all sulfas is typical
    • Resistance mechanism: overproduction of PABA, encode mutant DHPS enzyme with decreased affinity for sulfas, upregulation of efflux pumps
    • adverse effects: gi distress, common rash, bone marrow and liver toxicity not uncommon, hemolytic anemia with G6PDD, kernicterus (in infacts, sulfa competes for bilirubin binding sites on albumin and increases levels of unconjugated bilirubin = CNS toxicity), Stevens-Johnson syndrome (hypersensitivity with mucosal sloughing, skin eruptions
    • use: not typically used alone for common bacterial infections - bacteriostatic / resistance, malaria, CNS toxoplasmosis
    • synergistically used with trimethoprim
  2. trimethoprim
    • blocks later step in folic acid synthesis pathway
    • inhibits bacterial DHFR
    • alone - bacteriostatic, with sulfonamides - cidal
    • Broad spectrum - G+ and G-, not pseudomonas, not anaerobes, not atypical bacteria*
    • oral admin, wide distribution, good absorption, excretion in urine
    • resistance increasing - location dependent
    • Can cause anti-folate effect
    • use: UTI's, Pneumocystis pneumonia, community acquired MRSA, contraindicated in infants
  3. ciprofloxacin, levofloxacin, and moxifloxacin
    • fluoroquinolones (fluorine substitution) - most modern quinolones, greater potency, expanded spectrum (better G+ coverage)
    • bactericidal - concentration dependent killing
    • rapid inhibitors of bacterial DNA synthesis (inhibits DNA gyrase, topoisomerase, blocks DNA unwinding, induces irreversible DNA damage)
    • oral or IV
    • distribution - wide and high bioavailability, CSF low, forms chelates with cations, reduces absorption
    • elimination: hepatic or renal, depending on drug
    • spectrum: G- including pseudomonas where cipro > levo > moxi
    • G+ including Streptococci where moxi > levo > cipro
    • poor anaerobic activity
    • excellent against nosocomial infections, atypical bacteria
    • resistance: increasing resistance, nearly all MRSA, N gonorrhea, Salmonella, Campylobacter
    • adverse effects: generally well tolerated, GI issues common, Achilles tendon rupture (rare), MRSA and C diff colonization, arthropathy in juvenile rats
    • use: complicated UTI, serious acute bacterial prostatitis, pneumonia, STDs, majority of use is considered inappropriate, contraindicated in pregnancy
  4. polymyxin B
    • cationic detergent
    • use: superficial skin lesion and eye infections, G- infections only
    • adverse effects: highly toxic
    • topical
  5. daptomycin
    • membrane depolarization
    • IV
    • use - similar to vancomycin (G+ microbes) but treats VREF and MRSA
    • adverse effects: myopathy
  6. rifaximin
    • binds bacterial RNA polymerase, inhibits RNA synthesis
    • oral
    • use: travellers diarrhea, also IBS-D
    • adverse effects: well tolerated
  7. nitrofurantoin
    • complex mechanism: converted to highly reactive species by bacterial reductases, disrupts DNA/RNA/protein synthesis
    • oral
    • contraindicated with renal insufficiency
    • important alternative oral agent for uncomplicated UTI
  8. metronidazole
    • selective reduction and accumulation of toxic products in anaerobes = dirupts bacerial DNA
    • use: prophylaxis and therapy - anaerobes (bacteroides and C sp), C diff
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Antifolates, fluoroquinolones, and others
MOHD 4 lecture 15