PEDIATRIC PHARMACOTHERAPY A Monthly Newsletter for Health Care Professionals from the University of Virginia Children’s Hospital • celebrating 10 years of publication • Volume 10 Number 11 November 2004 **Important Notice to Readers Outside of the UVA Health System on Last Page** Use of Rifampin in Pediatric Infections Marcia L. Buck, Pharm.D., FCCP ifampin, first isolated in 1957, is a wide - disease. Therapy is typically continued for 1 R spectrum antibiotic that has been used in a year, using the same dosing range as for variety of infections in children. 1 Unfortunately, tuberculosis. 6 the emergence of bacterial resistance limits its utility. Rifampin is now typically thought of as The American Academy of Pediatrics Committee part of combination antimicrobial regimens in on Infectious Diseases also recommends rifampin resistant infections or for chemopr ophylaxis after as part of com bination regimens for the treatment exposure to invasive bacterial disease. This issue of several other types of infection. Because of the of Pediatric Pharmacotherapy will review the high likelihood for the development of pharmacology of rifampin and its uses and resistance, rifampin monotherapy is not administration in children. recommended. 7-13 Rifampin may be added to other antibiotics for the treatment of Mechanism of Action/Antimicrobial Spectrum strep tococcal or staphylococcal infections Rifampin inhibits DNA -depe ndent RNA (usually in combination with vancomycin) or polymerase activity in susceptible bacterial Heamophilus influenzae type b infection. 7-9,14 strains, resulting in a disruption of protein synthesis. It has demonstrated both in vivo and The combination of doxycycline and rifampin is in vitro bactericidal activity against recommended for the treatment of brucellosis, Mycobacterium tuberculosis and Neisseria using doses of 15 to 20 mg/kg/d ay up to a meningitides . Rifampin ha s also been shown to maximum of 900 mg/day in one or two divided have in vitro activity against several other doses. 10 Rifampin may be added to therapy with organisms, including M. leprae , Haemophilus azithromycin in patients with Legionella influenzae , coagulase -positive and negative infections who are immunocompromised or who staphylococcal species, Streptococcus fail to respond to azithromycin alone. 11 It has pneumoniae , and Peptosteptococcus species, as also been shown to be effective in the treatment well as Chlamydia trachomatis and C. psittaci . of cat -scratch disease ( Bartonella henselae The development of resistance to rifampin is infection) 12 and in combination with other common, occurring as single step mutations of antimicrobials for refractory cases of meningitis the DNA -dependent RNA polymerase. 1-3 caused by Naegleria fowleri and Acanthamoeba .13,15 Clinical Use in Children There are two indications for rifampin approved In selected cases, rifampin has bee n used as by the Food and Drug Ad ministration: the monotherapy. Krause and colleagues, in a report treatment of tuberculosis and the eradication of published in Pediatrics last year, used rifampin at Neisseria meningitides in asymptomatic a dose of 10 mg/kg given twice daily as single - carriers. 2,3 For tuberculosis, rifampin, in agent therapy in two children with human combination with ethambutol and isoniazid, is granulocytic ehrlichiosis. 16 The authors chose to administered at doses of doses of 10 to 20 use ri fampin rather than doxycycline, the drug of mg/kg/day for 2 to 6 months, depending on the choice, because of the risk of dental staining in location and severity of infection. 4 Rifampin is their patients, aged 4 and 6 years. also recommended for combination treatment of nontuberculous mycobacterial infections in Rifampin is often used for postexposure children. 5 In the treatment of Mycobacterium prophylaxis in patients who have been in contact leprae infections, rifampin is given in with a patient having invasive Hae mophilus combination with dapsone for paucibacillary influenzae type b or meningococcal disease. 9,17 For Haemophilus infections, prophylaxis is elevated liver function tests, and muscular indicated in all household contacts in households weakness. Rare, but severe, adverse effects where there is at least one patient < 4 years of include transient leukopenia, anemia, age who is unimmunized or only partially thrombocytopenia, hepatitis, hypersensitivity immunized, hous eholds with a child < 1 year of reactions, porphyria, interstitial n ephritis, and age who has not had the primary series, and acute tubular necrosis. Rifampin is also known households with an immunocompromised child. to reduce concentrations of adrenal and thyroid It is also recommended for child care centers hormones, as well as alter vitamin D metabolism. when there have been two or more cases within a High dose intermittent therapy (> 25 mg/kg per 60 day period. The index case should rec eive week) has been shown to produce a flu -like prophylaxis if less than 2 years of age or if synd rome consisting of fever, chills, headache, residing in a household with a susceptible dizziness, and bone pain in up to 50% of contact, unless treatment consisted of cefotaxime patients. 2,3 or ceftriaxone. 9 Prophylaxis is recommended for all household contacts of a patient with In addition to being counseled about reporting meningococcal disease, as well as individuals the presence of any symptoms suggesting adverse having close social or child care setting contact effects, patients and their families should be with the index case within 7 days before the aware that rifa mpin will cause tears, sputum, onset of illness. 17 sweat, and urine to become red -orange in color. Rifampin may permanently stain contact Rifampin is also recommended for eradication of lenses. 2,3 Oral suspensions of rifampin may stain N. meningitides or group A beta -hemolytic clothing or plastic items on contact. streptococcus in pharyng eal carriers. It has been used to clear pharyngeal carriage of Group B Drug Interactions streptococcus in infants who have had repeated Rifampin is known to induce cytochrome P450 invasive disease, but there have recently been 3A4 (CYP3A4) enzymes. Concomitant reports of treatment failures with rifampin as a administration of rifampin may decrease the single agent therapy. 2,3,7,18 serum concentration of many drugs through this mechanism and others. The following agents are Pharm acokinetics likely to be affected: After oral administration, rifampin is well absorbed. Peak serum concentrations are amiodarone typically reached within 1 to 4 hours. In adults, angiotensin converting enzyme ( ACE) inhibitors peak concentrations range from 4 to 32 mcg/ml. azole antifungals Children have been found to achieve lower peak barbiturates concentration s with oral dosing, ranging from 3.5 benzodiazepines to 15 mcg/ml. Food reduces the bioavailability beta blockers of rifampin by approximately 30%. Rifampin is buspirone widely distributed throughout the body, with a chloramphenicol volume of distribution at steady state of corticosteroids approximately 0.64 L/kg in adults. It is 80% cyclosporine protein bound. Rifampin undergoes deactylation dapsone in the liver to form an active metabolite. The delavirdine elimination half -life of rifampin in adults is 2 to 5 digoxin hours after initial dosing, decreasing to 2 to 3 disopyramide hours with repeated administration. In a stud y of doxycycline 12 children between 3 months and 12 years of estrogens age), half -life ranged from 1.04 to 3.81 hours. fluoroquinolones Both parent compound and metabolite are haloperidol excreted in the urine and bile. Dosage losartan adjustment is recommended in patients with macrolide antibiotics hepatic dysfunction. No adjustmen t is required mexiletine for renal dysfunction. 2,3 nifedipine ondansetron Adverse Effects opioids The most commonly reported adverse effects oral contraceptives after rifampin use include headache, drowsiness, phenytoin fatigue, dizziness, flushing and itching of the skin progestins (with or without rash), stomach upset, anorexia, protease inhibitors na usea, vomiting, diarrhea, hyperbilirubinemia, propafenone quinidine dose of 20 mg/kg given orally once daily for 4 quinine days. For patients less than 1 month of age, a sulfapyridine dose of 10 mg/kg/day may be used. 7 For sulfonylureas postexposure prophylaxis or eradication of theophylline meningococcal or streptococcal carriage, tocainide children less than 1 month of age should receive tricyclic antidepressants a rifampin dose of 5 mg/kg orally every 12 hours verapamil for 2 days Children one month of age or older warfarin should receive 10 mg/kg, up to the 600 mg adult zidovudine dose, every 12 hours for 2 days. 17 Oral doses zolpidem 2,3,19 should be given on an empty stomach (1 hour before or 2 hours after a meal) with a full glass of Concomitant administration of aminosalicylic water. Patients unable to take oral rifampin may acid or azole antifungals may decrease rifampin be given the drug intravenously, using the same serum concentrations to subtherapeutic levels. dose. Rifampin cannot be administered Administration of protease inhibitors with intramus cularly or subcutaneously. 2,3 rifampin may decrease the rate of rifampin metabolism and lead to ele vated serum Availability concentrations. These combinations should be Rifampin is available in brand (Rifadin ®, Aventis avoided whenever possible. 2,3 and Rimactane ®, Novartis) and generic forms as 150 and 300 mg capsules and a 60 mg/ml vial for Administration of halothane in patients