11. Chloramphenicol. Polymyxins. Antifolate drugs Flashcards
What is the MOA of Chloramphenicol?
Binds 50s ribosomal unit.
What spectrum does Chloramphenicol cover?
Gram+ and Gram- anaerobes and aerobes:
- Rickettsiae, Spirochetes
- Staph, Strep, Salmonella, Shigella, E. coli, B. fragilis
What are the side effects of Chloramphenicol?
- GI symptoms: Nausea, Vomitting and Diarrhea.
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Bone marrow suppression: 2 types
- Dose-related, reversible - in 100% pts with dose > 20 g. 1st RBCS, then WBCs + platelets
- Irreversible, dose-independent: aplastic anemia in 1:20,000 pts, tx with marrow transplantation.
What are the indications of Chloramphenicol?
Few due to high toxicity
- Severe Rickettsia in children under 8 - above 8 y/o tetracyclines are used (since tetracyclines can cause problems in growing bone)
- Meningitis by pneumococci, meningococci or H. flu - if there is cephalosporin allergy
- Brain abscess - with resistance to metronidazole
- (Eye infections - topically as a cream; but many other good options, so only when they are ineffective)
What interactions can occur with Chloramphenicol?
- Inhibits CYP enzymes → altered drug effects.
What is the mechanism of resistance to Chloramphenicol?
Resistance is due to decreased permeability or by deacetylation via chloramphenicol acetyltransferases.
How is Chloramphenicol metabolized?
Degraded by glucuronide conjugation in the liver. Immature enzymes in newborns → accumulation in skin → grey baby syndrome (flaccid muscles, hypothermia, vomiting, shock + collapse).
Where in the world is Chloramphenicol used?
- It is rarely used in developed countries.
- SE are more commonly seen in developing countries due to the fact that it’s cheap.
How are the absorption and distribution properties of Chloramphenicol?
Good oral absorption + distribution (enters CNS, abscesses, IC space, eye, pleural + peritoneal cavity)
What is the MOA of Polymixins?
Colistin also known as polymyxin E. Polymixin E is a cationic detergent → membrane disruption.
What are the indications of Polymixins?
- Severe multi-resistant infections (multi-resistant Acinetobacter “MACI”, etc.). UTI, cystitis (as local wash).
What are the side effects of Polymixins?
- Highly toxic → nephro- and peripheral neurotoxic (no CNS entry).
List the Antifolate drugs.
- Trimethoprim + Sulfamethoxazole (combo = cotrimoxazole)
What is the MOA of antifolate drugs?
- SMX is PABA analog → inhibits dihydropteroate synthase.
- TMP inhibits DHFR.
- Together have a bactericidal effect.
What spectrum does antifolate drugs cover?
Gram + cocci and Gram - rods:
- Staph, Strep (but S. pyogenes + Enterococci are resistant)
- E. coli, Klebsiella, H. flu, Proteus, Salmonella, Shigella
- More rare infections: Nocardia, Brucella, Aeromonas, P. jiroveci, Yersinia
What is the route of administration of antifolate drugs?
Given orally every 8-12 hrs.
What are the side effects of antifolate drugs?
Mostly from SMO:
- Skin reactions: including SJS + photosensitivity
- Allergy: Fever, urticaria, rash
- Hematologic Rxns: pancytopenia or megaloblastic anemia; contraindicated in G6PD deficiency → hemolytic anemia.
- Renal effects: type IV RTA, crystalluria and interstitial nephritis.
- Long term → ↓ folic acid → give leucovorin (folic acid)
- (Teratogen if used in 1st trimester → neural tube defects; kernicterus if used in last trimester)
- (Displaces warfarin from albumin → increased bleeding risk)
- (Inhibits CYP450)
What are the indications for antifolate drugs?
- Respiratory infections: sinusitis, otitis, acute exacerbation of chronic bronchitis (not tonsillopharyngitis b/c ↓ S. pyo effect)
- UTI: 1st line treatment for simple UTI, not pyelonephritis.
- Prostatitis
- Recurrent Cystitis: 4-6 wks treatment
- Traveller’s Diarrhea: Salmonella etc.
- P. jiroveci: 1st line (2nd clindamycin or atovaquone) + other rare infections above.
What spectrum does Polymyxin E/Colistin cover?
Covers a narrow spectrum, only Gram - aerobe (GI rods), but Proteus, Serratia are resistant. Pseudomonas + Acinetobacter are highly susceptible.
How are anti-folate drugs metabolized and excreted?
- Metabolized in liver
- Excreted in urine (↓ dose in kidney impairment)
What are the side effects of Polymyxin E/Colistin?
- Highly toxic → nephro- and peripheral neurotoxic (no CNS entry)