Intracellular, rod-shaped, acid fact organism, 1-7 um long, 0.25 um wide. GENERATION TIME IS 12-13 DAYS!! LONGEST KNOWN FOR BACTERIA.
· Chronic inflammatory disease
probably related to host's ability to develop specific cell mediated immunity.
High resistance-- develop high cell mediated immunity and keep disease localized, typically to skin and nerve tissue.
Low resistance -- generalized
An early form, between tuberculoid and lepromatous. 75% heal spontaneously
· Structure / Origin
·· Synthetic
·· Analog of p-aminobenzoid acid (like sulfonamides!)
·· Bacteriostatic primarily, but may have some cidal action
·· MIC for M. tuberculosum is 10 ug/ml; for M. leprae, estimated at 1-10 ng/ml.
·· Drug of choice for all patients with dapsone sensitive M. leprae.
·· Decreases infectivity in a mouse model 90% within 28 days and completely by 90 days.\dP<B1>
·· Presumably same as the sulfonamides\dP<B1>
·· Oral administration
·· Bioavailability 100%
·· Half-life extremely variable, 10-50 h (mean - 28 h)
·· Biotransformed -- 70-80% excreted as conjugate (N-glucuronide or N-sulfamate). Urine elimination of these is probenecid sensitive
·· Acetylation (some) -- rate is genetically determined like isoniazid. If pattern is same as with isoniazid, Fast acetylators would be Eskimos and Japanese; Slow acetylators would predominate among Scandinavians, Jews, and North African caucasians. (Variable rates of acetylation not mentioned by AMADE90,1:29! perhaps because non of these groups is signficantly affected by the disease of leprosy.)
·· Enterohepatic circulation of acetylated form is significant and can lead to "appreciable" tissue levels for 3 weeks.
·· DRUG INTERACTION: Rifampin LOWERS dapsone concentration to 10 - 13% of normal by increasing biotransformation.
·· Usually mild and infrequent
(worse if Glucose-6-phosphate dehydrogenase deficiency, G6PD)
Incidence ~ 100% above 200-300 mg/day; 0% below 100 mg/day. Normal dose 100 mg/day (1-2 mg/kg).
may occur, especially if there is an NADH dependent methemoglobin reductase deficiency.
Rare hypersensitivity reaction that begins 1 to 4 weeks after administration. Signs include fever, malaise, exfoliative dermatitis, jaundice with hepatic necrosis, lympadenopathy, methemoglobinemia, and anemia. At least partially reversible if stop drug and give corticosteroids. May be worse in poorly nourished patients. Process thought to be similar to that of Jarisch-Herxheimer reaction. [J-H reaction: an inflammatory reaction in syphilitic tissues (skin, mucous membrane, nervous system, or viscera) induced by specific treatment with Salvarsan, mercury, or antibiotics, believed to be due to rapid release of treponemal antigen with associated allergic rection in patient ...Stedman]
But no teratogenic effects reported from use in humans, yet. In FDA Pregnancy Category C. [AMADE90, 1:29]
High amounts excreted in breast milk --high enough to cause one reported case of hemolytic anemia in an infant.
Many and signficant, e.g., because of blood dyscrasias, should do complete blood counts and liver function tests at recommended intervals.
· a Phenazine dye (red!)
· Uncertain -- binds preferentially to Mycobacterial DNA and interferes with growth.
· Slowly bactericidal -- requires 50 days of therapy before biopsy of tissue yields no growth.
· Active against M. avium isolates -- and, therefore, is used in combination with up to 5 other antimycobacterial agents in treatment of atypical mycobacterial infections (associated with Mycobacterium avium-intracellulare) in patients with AIDS. Despite high in vitro activity, has often been clinically ineffective. [USPDI94]
· Resistance is rare
· No cross resistance with dapsone or rifampin
Highly lipophilic, deposited in fatty tissue and RE cells. Also in macrophages throughout body, breast milk, mesenteric lymph nodes, adrenal glands, etc. Apparently not cross blood-brain barier. [USPDI94]
Half-life -- varies. One dose = 10 days!!!; After long term Rx = 2-3 months!!!!
Mean serum concentration after 4 years of therapy
Fecal/biliary -- up to 50% unchanged
Renal -- 1-2%
Excreted in breast milk -- not recommended in nursing mothers
Dosing varies -- may be 50 to 100 mg daily; WHO has recommended 300 mg monthly and 50 mg daily for some forms. Leprosy reactions may require 100 mg q8h!
50% of patients
Nausea, vomiting, and diarrhea uncommon at doses <100 mg/day
Larger doses may produce abdominal pain and signs of bowel obstruction (caused by deposition of drug in wall of small bowel causing it to become edematous). This may be the "eosinophilic enteritis" mentioned in GG8th90,p1161. ·· History of gastrointestinal problems should cause careful consideration of risk/benefit
May discolor skin and conjunctivae (75-100% of patients) skin may ultimately become mahogany brown;
May discolor urine, sputum(may alter taste), and sweat
If feces black or tarry, should besure not due to blood
May alter many lab tests (See USPDI94)