Provisional guidance on the role of specific antibiotics in the management of Mycobacterium ulcerans disease (Buruli ulcer)
Annex 1 - Information on rifampicin, streptomycin and amikacin4
Group: antimycobacterial agent
Capsule or tablet: 150 mg, 300mg
Rifampicin, a semisynthetic derivative of rifamycin obtained from Streptomyces mediterranei, is a complex macrocyclic antibiotic that inhibits ribonucleic acid synthesis in a broad range of microbial pathogens. Rifampicin is lipid soluble. Following oral administration, it is rapidly absorbed and distributed throughout the cellular tissues and body fluids. A single dose of 600 mg produces a peak serum concentration of about 10 µg/ml in 2–4 hours, which subsequently decays with a half-life of 2–3 hours. It is extensively recycled in the enterohepatic circulation, and metabolites formed by deacetylation in the liver are eventually excreted in the faeces. Since resistance readily develops, rifampicin must always be administered in combination with other effective antimycobacterial agents.
Uses: Rifampicin is a component of all TB and leprosy chemotherapeutic regimens currently recommended by WHO.
Administration and dosage: Rifampicin should preferably be given at least 30 minutes before meals, since absorption is reduced when it is taken with food. This may not, however, be clinically significant, and food can reduce intolerance to drugs. Adults and children: 10 mg/kg (8–12 mg/kg) daily, maximum 600 mg daily.
Contraindications: Known hypersensitivity to rifamycins. Hepatic dysfunction.
Precautions: Serious immunological reactions resulting in renal impairment, haemolysis or thrombocytopenia are on record in patients who resume taking rifampicin after a prolonged lapse of treatment. In this rare situation, it should be immediately and definitively withdrawn. Careful monitoring of liver function is required in the elderly and in patients who are alcohol dependent or have hepatic disease. Patients should be warned that treatment may produce reddish coloration of urine, tears, saliva and sputum, and that contact lenses may be irreversibly stained.
Side-effects: Rifampicin is well tolerated by most patients at currently recommended doses, although gastrointestinal intolerance can be unacceptably severe. Other adverse effects (fever, influenzalike syndrome and thrombocytopenia) are more likely to occur with intermittent administration, and skin rashes are just as likely. Moderate rises in serum concentrations of bilirubin and transaminases, which are common at the outset of treatment, are often transient and without clinical significance. However, dose-related hepatitis can occur, which is potentially fatal. It is consequently important not to exceed the maximum total daily dose of 600 mg.
Drug interactions: Rifampicin induces hepatic enzymes, and may increase the dosage requirements of drugs metabolized in the liver. These include corticosteroids, steroid contraceptives, oral hypoglycaemic agents, oral anticoagulants, phenytoin, cimetidine, cyclosporin and digitalis glycosides. Since rifampicin reduces the effectiveness of oral contraceptives, women should be advised to choose between one of the following two options for contraception. Firstly, following consultation with a clinician, the patient may use an oral contraceptive pill containing a higher dose of estrogen (50 µg). Alternatively, a non-hormonal method of contraception may be used throughout rifampicin treatment and for at least one month subsequently. Biliary excretion of radiocontrast media and sulfobromophthalein sodium may be reduced and microbiological assays for folic acid and vitamin B12 disturbed.
Overdosage: Gastric lavage may be of value if undertaken within a few hours of ingestion. Very large doses of rifampicin may depress central nervous function. There is no specific antidote and treatment is supportive.
Storage: Capsules and tablets should be kept in tightly closed containers, protected from light.
Group: antimycobacterial agent
Injection (powder for solution for injection): 1 g (as sulfate) in vial
Streptomycin, an aminoglycoside antibiotic derived from Streptomyces griseus, is used in the treatment of TB and susceptible Gram-negative infections. After intramuscular administration, streptomycin diffuses readily into the extracellular component of most body tissues. In adults, a single injection of 1 g (15 mg/kg) produces a peak serum concentration of about 30–40 µg/ml in 1–2 hours. The plasma half-life, which is normally 2–3 hours, is considerably extended in the newborn, the elderly, and patients with severe renal impairment. Streptomycin is excreted unchanged in the urine.
Uses: Streptomycin is a component of several TB chemotherapeutic regimens currently recommended by WHO.
Administration and dosage: Streptomycin must be administered by deep intramuscular injection. The dose for adults and children is 15 mg/kg body weight daily. Syringes and needles should be adequately sterilized to exclude any risk of transmitting viral pathogens.
Drug interactions: Other ototoxic or nephrotoxic drugs should not be administered to patients receiving streptomycin. These include other aminoglycoside antibiotics, amphotericin B, cefalosporins, etacrynic acid, cyclosporin, cisplatin, furosemide, and vancomycin. Streptomycin may potentiate the effect of neuromuscular blocking agents administered during anaesthesia.
Side-effects: Severe nausea, vomiting, dizziness, rash and fever. Loss of hearing has been reported following long-term use. Streptomycin should not be used in patients with kidney impairment because it increases the risk of severe toxic reactions. Symptoms subside and recovery is usually complete after treatment is stopped. Roaring noises or ringing in the ears are signs that treatment with streptomycin should be stopped. Ototoxicity, deafness, vertigo or reversible nephrotoxicity may occur.
Overdosage: Haemodialysis can be beneficial. There is no specific antidote and treatment is supportive.
Storage: Solutions retain their potency for 48 hours after reconstitution at room temperature and for up to 14 days when refrigerated. Powder for injection should be stored in tightly closed containers, protected from light.
Amikacin is an aminoglycoside bactericidal agent, obtained from Streptomyces. Its bactericidal effect and adverse reactions are very similar to those of other aminoglycosides.
Presentation and dosage: Amikacin is presented as a sterile white powder for intramuscular injection in sealed vials containing the equivalent of 250 mg, 500 mg or 1 g of drug. The drug should be dissolved in 2 ml of 0.9% sodium chloride or water for injection. The optimal dose is 15 mg/kg body weight, usually 750 mg to 1 g in total, given daily by deep intramuscular injection or intravenously. Rotation of injection sites avoids local discomfort.
Side-effects: Side-effects are similar to those associated with streptomycin. Ototoxicity, deafness, vertigo or reversible nephrotoxicity may occur.
Precautions: In patients with impaired renal function, the daily dosage should be reduced and/or the intervals between doses increased, to avoid accumulation of the drug. In these patients, renal function should be monitored regularly during antibiotic treatment. This drug should not be used in pregnant women except as a last resort.
4 Adapted from (25)