C.11 Flashcards
Chloroamphenicol. Polymyxins. Antifolate drugs
- Chloroamphenicol,
- miscellaneous antibiotics: Colistin,
- Antifolate drugs: Sequential blockade - sulfonamide + antimetabolite: Sulfamethoxazole +Trimethoprim,
- Antimetabolite antibiotics: Polymyxins: Proguanil
Chlorampenicol
pectrum: Broad spectrum, but risk of severe toxicity - limited use, some strains of H.influenza, N. meningiditis, and bacteroides;
MOA: 50S subunit, blockade of peptidyl transferase; bacteriostatic, but can be bactericidal (high susceptibility);
Pharmacokinetics: Very good→ good absorption, wide distribution (CNS, Absceses, placenta), conjugated (glucurnoid conjugation) in the liver and excreted by urine;
SEs: BM suppression, dose-related reversible or idiosyncratic irreversible (aplastic anaemia), Gray baby syndrome, GI symptoms (dysbacteriosis, candidiasis);
IND: rarely used (brain abscesses, severe rickettsiosis (used in pregnancy in Europe), severe meningitis, severe salmonellosis → ONLY if we DON’T have alternatives);
Drug-Interaction: Inhibition of hepatic microsomal enzymes (phenytoin, oral anticoagulants, methotrexat)
Colistin/Polymixin E (Polymixins)
MOA: Binds and inactivates endotoxin - interact with LPS of Gram - bacteria (acts as cationic detergent) → disrupting cell membrane, causes pore formation in cell membrane → bactericid;
Spectrum: Gram - (P. aeruginosa, Acinetobacter, Klebsiella (PAK);
IND: Superficial skin infections, Pneumonia, Urinary bladder disinfection.
-Topical (→ superficial skin infections, P. aeruginosa, Klebsiella),
-Systemic (→ Last resort for multidrug-resistant Gram (-) → i.e. Pneumonia (P. aeruginosa, Klebsiella pneumonia, Acinetobacter (MACI)));
Penetration: Cannot cross BBB;
Extra: Last resort;
SEs: Neuro (dizziness, ataxia, parasethesia) + nephrotoxicity (acute tubular necrosis);
ROA: Topical/parentral - systemic use is limited due to severe SE
sulfonamides
MOA: Analogues of PABA → competitive inhibition of dihydrofolic acid syntheses → bacteriostatic. Mammalian cells do not synthesize folic acid, depend on exogenous source of folate → not susceptible to sulfonamides;
Mechanism of resistance: overproduction of PABA, production of folic acid-synthesizing enzyme with lower affinity for sulfonamides, decreased permeability;
Pharmacokinetics: Oral absorption, good absorption from GI tract, wide distribution (CSF, placenta, fetus), high protein binding, metabolism in liver (acetylation, glucuronidation), excretion with urine (in part unchanged), glomerular filtration, tubular reabsorption - 3 pharmacokinetic groups:
1.short acting,
2. medium acting (sulfamethoxazole, sulfadiazine - important in combination),
3. long acting (e.g. sulfadoxine - malaria treatment);
SEs:
-Allergy (skin rash, fever, exfoliative dermatitis, SJS, Lyell syndrome), can be cross-allergenic,
-photosensitivity,
-GI symptoms(→nausea, vomiting, loss of appetite, GI pain, diarrhea),
-Nephrotoxicity (→precipitation in the urine - crystalluria, hematuria → Hydration is important, rarely- nephrosis, allergic nephritis),
-Hematotoxic (→hemolytic anemia, aplastic anemia, granulocytopenia, thrombocytopenia),
-In newborns- competition with bilirubin → risk of Kernicterus
Trimethoprim
MOA: Selective inhibitor for the bacterial dihydrofolate reductase;
IND: Antibacterial, antiprotozoa;
Monotherapy: In case of uncomplicated (community aquired) acute UTIs only (in case of sulfonamide-allergy → rapid development of resistance);
Pharmacokinetics: Similar to sulfamethoxazole, better penetration into brain, very high concentration in prostatic and vaginal fluid (high antibacterial activity here);
SEs: Predictble adverse effects of an antifolate drug- megaloblastic anemia, leuokpenia, granulocytopenia → prevented by simultaneous adm. of folinic acid!
Proguanil
MOA: Antimetabolite → disrupts folate synthesis;
Spectrum: malaria prophylaxis with Atovaquone;
ROA: oral, prodrug;
SEs: Generally well-tolerated, GI distress, fever, rash
Sulfamethoxazole +trimethoprim
Often bactericidal;
IND: UTI (→cytstitis, acute pyelonephritis, acute prostatitis (reduced dose for prophylaxis, in some cases → recurrent UTI in women)), Systemic salmonella infections (→ by ampicillin or chlorampenicol-resistant strains), in acute Typhus abdominalis alterative possibility (Quinolones are the first choice), Serratia, stenothropomonas, Therapy or prophylaxis of Pneumocystis carinii infections → therapy high dose!, Nocardia infections → high dose!
Antimetabolite
A substance inhibiting cell growth by competing with, or substituting for, a natural substrate in an enzymatic process
Sequential blockade
the combined effect of 2 different drugs that inhibit sequential steps in a pw. of bacterial metabolism; enables synergestic enhancement
Gray baby syndrome
Decreased RBCs, Cyanosis, cardiovascular collapse in infants → involves decreased activity of glucuronic acid conjugation mechanism for the degradation and detoxification of chlorampenicol
Lyell’s syndrome
same as toxic epidermal necrolysis. Rare, potentially life-threatening mucocutaneous disease, usually provoked by administration of a drug and characterized by acute necrolysis of the ski
