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Lecture 3
DNA Disrupting Antibacterials
| Question | Answer |
|---|---|
| Folate Antagonists: folic acid | coenzyme; necessary for synthesis of RNA, DNA, some amino acids; mammals use dietary folic acid to make tetrahydrofolic acid |
| Folate Antagonists: folic acid | bacteria cannot use exogenous folate --> make their own |
| Folate Antagonists: folic acid | medications that target bacterial folic acid synthesis: sulfonamides, trimethoprim, interfere with the bacterial DNA synthesis |
| Sulfonamides Mechanism of Action | bacteria use dihydropyeroate synthetase to create dihydrofolic acid from PABA |
| Sulfonamides Mechanism of Action | structurally similar to p-aminobenzoic acid (PABA) |
| Sulfonamides Mechanism of Action | compete with PABA to inhibit dihydropteroate synthetase and the beginning of bacterial dihydrofolic acid |
| Sulfonamides Metabolism ** | acetylated and conjugated in liver --> acetylated metabolite has no antimicrobial activity but retains toxic potential to precipitate at neutral or acidic pH (**causes crystalluria and potential kidney damage**) |
| Sulfonamides Clinical uses | rarely used as single agent; fixed combination of trimethoprim-sulfamethoxazole |
| Sulfonamides Clinical uses: topical agents | sodium sulfacetamide ophthalmic solution or ointment; silver sulfadiazine |
| Sulfonamides Adverse Effects: **crystalluria, hypersensitivity | adequate hydration and alkalization of urine can prevent** |
| Sulfonamides Adverse Effects: hematopoietic disturbances | hemolytic anemia in patients with glucose-6 phosphate dehydrogenase deficiency (G6PD); granulocytopenia and thrombocytopenia |
| Sulfonamides Adverse Effects: kernicterus | bilirubin-associated brain damage; occurs in newborns; sulfa drugs displace bilirubin from binding sites, freeing bilirubin to pass into CNS |
| Sulfonamides contraindications | newborns and infants <2 months of age; pregnant women at term; concurrent use with methenamine |
| Trimethoprim | inhibitor of bacterial dihydrofolate reductase |
| Trimethoprim | much less efficient inhibitor of mammalian dihydrofolic acid metabolism |
| Trimethoprim | bacteriostatic when used alone |
| Trimethoprim | used in combo with sulfamethoxazole (bactericidal in combination) |
| Trimethoprim Adverse Effects | effects of folic acid deficiency: megaloblastic anemia, leukopenia, granulocytopenia, reversed by administering colonic acid (leucovorin) |
| Trimethoprim Adverse Effects | potassium-sparing effect may cause hyperkalemia |
| Combination Trimethoprim -sulfamethoxazole: brand names | Septra, bactrim, sulfatrim |
| Combination Trimethoprim -sulfamethoxazole: 5 parts sulfamethoxazole/1 part Trimethoprim | SMZ 400/TMP 800 and SMZ 800/TMP 160; typically dosed BID |
| Combination Trimethoprim -sulfamethoxazole: greater antimicrobial activity then either drug alone -->____ | synergism |
| Combination Trimethoprim -sulfamethoxazole: MOA = inhibits two sequential steps in ____ | tetrahydrofolate synthesis. SMZ inhibits incorporation of PABA --> inhibits dihydropteroate synthase. TMP inhibit dihydrofolate reductase --> prevents reduction of dihydrofolate to tetrahydrofolate |
| Clinical Use: Oral Trimethoprim -sulfamethoxazole (TMP-SMZ) | UTI, prostatitis, active against most S aureus strains, commonly used for treatment of uncomplicated skin and soft tissue infections, susceptible strains of Shigella, Salmonella, nontuberculous mycobacteria |
| Clinical Use: IV Trimethoprim -sulfamethoxazole | moderately to severe pneumocystis pneumonia; alternative for serious Listeria infections in those intolerant to ampicillin |
| Trimethoprim -sulfamethoxazole pharmacokinetics | generally administered orally; IV available for severe pneumonia caused by pneumocystis jirovecii; crosses BBB; parent drugs and metabolites excreted in urine |
| Trimethoprim -sulfamethoxazole adverse effects ** | skin rash, nausea/vomiting, hematologic toxicity, hyperkalemia, crystalluria, photosensitivity (WATER, PROTECTION FROM SUN) |
| Patient Counseling for SMZ/TMP | ensure not allergic to any component; maintain adequate hydration; photosensitivity |
| Fluoroquinolones bacterial overview | enzymes involved with DNA replication: DNA gyrase=relaxes positively supercoiled DNA required for normal transcription and translation; topoisomerase IV=separates daughter chromosomes once replication completed |
| Fluoroquinolones brands/generics | ciprofloxacin (cipro), levofloxacin (levaquin), ofloxacin (floxin) |
| Fluoroquinolones Mechanism of Action (part 1) | Fluoroquinolones enter cell wall through porins; bind to DNA gyros and topoisomerase IV and interfere with DNA ligation |
| Fluoroquinolones Mechanism of Action (part 2) | increases number of permanent chromosomal breaks, causing cell lysis; different targets for gram positive (topoisomerase IV) causing rapid cell death |
| Fluoroquinolones Absorption ** | well absorbed after oral administration; **reduced by ingesting sucralfate, aluminum or magnesium containing antacids, dietary supplements with iron or zinc** |
| Fluoroquinolones Distribution | all tissues and body fluids; concentrations high in bone, urine, kidney, prostatic tissue, and lungs; CSF penetration good |
| Fluoroquinolones Adverse Reactions (part 1)** | generally well tolerates; common effects are nausea, vomiting, headache, dizziness |
| Fluoroquinolones Adverse Reactions (part 2) ** | boxed warnings for tendinitis, peripheral neuropathy, CNS effects (seizures) = avoid in chilled and pregnancy |
| Fluoroquinolones Adverse Reactions (part 3)** | phototoxcity; blood glucose disturbances; QT prolongation |
| Fluoroquinolones Drug Interactions | ciprofloxacin inhibits P450 1A2 and 3A4 mediated metabolism; increases serum concentrations of theophylline, tizanidine, warfarin, ropinirole, duloxetine, caffeine, sildenafil, zolpidem |
| Fluoroquinolones Clinical Uses: ciprofloxacin | activity against gram negative bacilli; traveler's diarrhea, typhoid fever, anthrax; option for infections of intra-abdominal, lung, skin, urine sources; 250mg, 500mg, 750mg PO tablets |
| Fluoroquinolones Clinical Uses: levofloxacin | similar activity to ciprofloxacin; enhanced activity against S pneumonia; treatment of CAP; 250mg, 500mg, 750mg PO tablets |
| Fluoroquinolones Common Dosing | Cipro 500mg one tablet PO BID; Levaquin 500 or 750mg one tablet daily |
Created by:
bluedolphin7
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