• organisms that are sufonamide sensitive organisms require PABA for folate biosynthesis
• folates are needed for nucleic acid synthesis
• sulfonamides mimic PABA and inhibit dihdryopteroate synthase

Synergistic when combined with dihydrofolate reductase inhibitors (trimethroprim or pyrimethamine).

• sulfisoxazole
• sulfamethoxazole
• cotrimazole
• dapsone

• structurally similar to PABA (the substrate for dihydropteroate synthase in folate syn.)
  • allow for inhibition of dihydropteroate synthase
• insoluble in water and soluble in sodium salts
  • can precipitate, so it requires hydration

• either agent alone is bacteriostatic, but together is bacteriocidal
  • lower sulfonamide dosage
• administer in 1:5 ratio (TMP:SMZ) to obtain a 20:1 plasma ratio

• oral/absorbable
  • sulfisoxazole (UTI) (short half life)
  • sulfamethoxazole (UTI w/TMP)
  • sulfadiazine (long acting)
  • sulfadoxine (only long acting sulfa in US)
• oral/nonabsorbable
  • sulfasalazine (GI problems)
• topical
  • sodium sulfacetamide (ophthalmic soln-bact. conjunctivitis)
  • silver sulfadiazine (prevent infection of burns)
• other's: Dapsone (leprosy)

• absorption- oral tablet readily absorbed from small intestines
• distribution- large volume of distribution including CNS and CSF
  • protein binding wide range (20-90%)- important in toxicity
  • maximum blood levels 2-6 hrs after administration
• metabolism- hepatic via CYP2C8/9
  • conjugated via acetylation and glucoronidation
• excretion- urine
  • clincial application- renal failure requires dose reduction

• some mammalian cells just dont make folates from PABA
• mutate dihydropteroate synthase as a result of selective pressures
  • plasmid encoded
• impaired uptake
• mutation leads to increased PABA

• hypersensitivity
• hematopoeitic toxicity
• crystallization in urine
• kernicterus in newborns
  • CI: newborns, pregnant women, women breastfeeding
• displace other drugs from plasma proteins

• mech.- metabolism leads to protein reactive metabolite aka Ag
• more commmon with antibiotic sulfonamides than nonantibiotic (ex: diuretics)
• Stevens-Johnson syndrome

• hemolytic/aplastic anemia
• granulocytopenia
• thrombocytopenia
• hemolytic reactions in individuals with G6P deficiency

• cystalluria, hematuria, obstruction
• treatment for crystalluria- give sodium bicarbonate and give with fluids
  • tends to precipitate in acidic urine
• other conditions
  • allergic nephritis
  • nephrosis

• sulfonamides will bind to albumin and displace billirubin
• newborns are unable to glucoronidate billirubin, so it cannot be excreted
• billiruben will enter brain, accumulate, and cause fatal kernicterus

• structure- synthetic fluorinated analongs of nalidixic acid
• clinical app.- nalidixic acid in low plasma levels cause limited antimicrobial activity

• advantage- newer drugs active against gram positive and negative bacteria
  • better tissue penetration, so longer half life

• inhibit topoisomerase II aka DNA gyrase at subunit A (breakage and unit section)
  • now, bacteria cant relax supercoiling
  • useful in gram negative organisms
• inhibit topoisomerase IV
  • now, DNA can't seuparate during cell division
  • useful in gram positive bacteria

• concentration dependent killing is exhibited
• must have specific inhibitor of DNA gyrase
• so low conc. of ciprofloxacin, norfloxacin can inhibit bacterial enzyme
• in high conc., mammalian and bacterial would be inhibited

• oral administration
• large volume of distribution
  • [urine, kidney, lung, prostate tissue, stool, bile, macrophages, neutrophils] > [serum]
  • [CSF, bone, prostate] < [serum]
• absorption impaired by divalent cation compounds aka antacids)
• excretion- readily in the urine
  • clinical app.- dose reduction in renal failure
  • except perfloxacin and moxifloxacin are hepatic excretion

• organisms exhibit mainly Pseudomonas and staphylococci
• mechanims
  • mutation of topoisomerase II or IV
  • enhanced drug efflux
  • decreased drug influx

fluoroquinolones: toxicity

• GI toxicity
• cartilage damage
• interact with P450 to impact metabolism of other drugs
  • warfarin
  • phenytoin
  • caffeine
• Tourrette like syndrome
  • acute psychosis
  • confusion
  • agitation
  • depression
  • hallucinations
  • paranoia

• caution when used with antiarrhythmia
  • can prolong QT interval
• CI
  • those using NSAIDS
    • fluoroquinolones interact with GABA-A receptor and its augmented with NSAID's
  • pregnant women (due to cartilage damage)
  • nursing mothers (due to cartilage damage)
  • kids (due to cartilage damage) 
    • (except those with CF where u must way risk and benefit)

• esp. with those taking theophyline or NSAID
• fluoroquinolones may inhibit metabolism of theophyline

• tendinitis
• Achilles rupture
• arthralgias
• joint swelling

• concentrate in urine
• low systemic distribution
• poorly absorbed

• bladder and kidney infections caused by:
  • gram positive bacteria
  • some gram negative bacteria

nitrofurantoin

methenamine

1. activated by reduction by bacteria in gut
2. leads to potential free radical damage

• pulmonary toxicity leading to fibrosis with extended use (immunological cause)
• neuropathy esp. with impaireed renal function (high systemic levels)
• urine turns brown

• Proteus, Pseudomonas (have urease to make ammonia, leading to increase urine pH)
• pregnancy
• newborns
• renal impairment

1. activated by low pH in urine to yield formaldehyde
   • acidification increase activity
   • no action in other tissue
2. formaldehyde react with proteins and crosslink
3. leads to lower UT sterilization

• bladder irritation
• release ammonia, so could be toxic in hepatic disease
• precipitate with sulfonamides, so crystalize

• taking suflonamides
• hepatic disease
• Proteus

• resistance rare
• indications- gram negative organisms