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 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 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 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 receiving injection. 2,3 While there is no commercially rifampin has been reported to produce available oral liquid formulation of rifampin, hepatotoxicity and hepatic encephalopathy. there are several extemporaneous formulations in Concurrent use of isoniazid and rif ampin may the literature. 2,21 also increase the likelihood of developing hepatotoxicity. This interaction may be more Summary pronounced in children under 2 years of age. Although the rapid emergence of resistance Close monitoring of liver function tests is limits its utility as monotherapy, rifampin has recommended. 2,3 been found to be useful in combination with other antimicro bials in a wide variety of bacterial Dosing infections. It is also serves an important role in A number of different rifampin regimens h ave postexposure prophylaxis for invasive bacterial been used for the treatment of tuberculosis in disease. While short -term use is generally well children. 4 A recent paper by Al -Dossary and tolerated, health care providers should be aware colleagues published in The Pediatric Infectious of the potential for rare but serious adverse Diseases Journal described their success with a effects and the numerous drug interactions that program consisting of 2 weeks of daily therapy may occur with rifampin. followed by twice weekly therapy for a total of 6 months. 20 Treatment consisted of rifampin at a References dose of 10 to 20 mg/kg and isoniazid with 1. Alsayyed B. Rifampin. Pediatr Rev 2004;25:216 -7. pyrazinamide for the first 6 weeks. Use of this 2. Rifampin. Drug Facts and Comparisons . Efacts [online]. 2004. Available from Wolters Kluwer Health, Inc. Accessed regimen allowed direct observation by health 9/17/04. ® care workers to ensure compliance. Th e program 3. Rifadin prescribing information. Aventis produced improvement in all 173 subjects and Pharmaceuticals Inc., August 2000. complete resolution of disease in 37% of the 4. American Academy of Pediatrics. Tuberculosis. In: children. Pickering LK, ed. Red Book: 2003 Report of the Committee on Infectious Diseases . 26 th ed. E lk Grove Village, IL: American Academy of Pediatrics; 2003: 642 -60. For the treatment of other susceptible bacterial 5. American Academy of Pediatrics. Diseases caused by strains, rifampin may be administered nontuberculous mycobacteria. In: Pickering LK, ed. Red intravenously or orally at a dose of 10 to 20 Book: 2003 Report of the Committee on Infectious Diseases . 26 th ed. Elk Grove Village, IL: American Academy of mg/kg/day, g iven as a single dose or divided in Pediatrics; 2003: 661 -6. two doses given every 12 hours. The maximum 6. American Academy of Pediatrics. Leprosy. In: Pickering recommended dose for most infections is the LK, ed. Red Book: 2003 Report of the Committee on th adult dose of 600 mg/day, although for severe Infectious Diseases . 26 ed. Elk Grove Village, IL: infections, doses up to 900 mg/day have been American Academy of Pediatrics; 20 03:401 -3. 2-16 7. American Academy of Pediatrics. Group A streptococcal used. infections. In: Pickering LK, ed. Red Book: 2003 Report of the Committee on Infectious Diseases . 26 th ed. Elk Grove Postexposure prophylaxis fo r Haemophilus Village, IL: American Academy of Pediatrics; 2003: 573 -84. influenzae type b typically consists of a rifampin 8. Ameri can Academy of Pediatrics. Staphylococcal 3. Several new products were added to the infections. In: Pickering LK, ed. Red Book: 2003 Report of Inpatient and Outpatient Formularies for the the Committee on Infectious Diseases . 26 th ed. Elk Grove Village, IL: American Academy of Pediatrics; 2003: 561 -73. treatment of patients with HIV -1 infection, 9. American Academy of Pediatrics. Ha emophilus influenzae including the combination of abacavir and infections. In: Pickering LK, ed. Red Book: 2003 Report of lamivudine (Epzicom ®), the combination of th the Committee on Infectious Diseases . 26 ed. Elk Grove emtricitabine and tenofovir disoproxil f umarate Village, IL: American Academy of Pediatrics; 2003:293 -301. ® ® 10. American Academy of Pediatrics. Brucellosis. In: (Truvada ), and enfuvirtide (Fuzeon ). These Pickering LK, ed. Red Book: 2003 Report of the Committee products are restricted to Category A for adults. on Infectious Diseases . 26 th ed. Elk Grove Village, IL: 4. (Tindamax ®) was added to the American Academy of Pediatrics; 2003: 222 -4. Inpatient and Outpatient Formularies for the 11. American Academy of Pediatrics. Legionella pneumophila infections. In: Pickering LK, ed. Red Book: treatment of trichomoniasis, giardiasis, and 2003 Report of the Committee on Infectious Diseases . 26 th intestinal amebias is in adults and children greater ed. Elk Grove Village, IL: American Academy of Pediatrics; than 3 years of age who are infected with 2003:397 -8. resistant organisms or who have failed or cannot 12. American Academy of Pediatrics. Cat -scratch disease. In: Pickering LK, ed. Red Book: 2003 Report of the Committ ee tolerate . on Infectious Diseases . 26 th ed. Elk Grove Village, IL: 5. The restrictions on the use of intravenous N - American Academy of Pediatrics; 2003: 232 -4. acetylcysteine were amended to include 13. American Academy of Pediatrics. Amebic prevention of contra st -dye induced renal failure meningoencephalitis and keratitis. In: Pickering LK, ed. Red in patients who are unable to take acetylcysteine Book: 2003 Report of the Committee on Infectio us Diseases . 26 th ed. Elk Grove Village, IL: American Academy of enterally. Pediatrics; 2003:194 -6. 6. Papain, urea debriding spray (Accuzyme ®) 14. Shama A, Patole SK, Whitehall JS. Intravenous rifampin and papain -urea -chlorophyllin copper complex in neonates with persistent staphylococcal bacteraemia. Acta debriding and deodorizing spray (Panafil ®) were Paediatr 2002;91:670 -3. 15. Singhal T, Baj pai A, Kalra V, et al. Successful treatment added to the Inpatient and Outpatient of Acanthamoeba meningitis with combination oral Formularies for the removal of necrotic tissue. antimicrobials. Pediatr Infect Dis J 2001;20:623 -7. 7. The combination of simvastatin and ezetimibe 16. Krause PJ, Corrow CL, Bakken JS. Successful treatment (Vytorin ®) was approved for the Outpatient of human granulocytic ehrlichiosis in children using rifampin. Pediatrics 2003;112(3):e252. Formulary for patients with dyslipidemias. 17. American Academy of Pediatrics. Meningococcal 8. Rosuvastatin (Crestor ®) was added to the infections. In: Pickering LK, ed. Red Book: 2003 Report of Outpatient Formu lary. th the Committee on Infectious Diseases . 26 ed. Elk Grove 9. Telithromycin (Ketek ®) was rejected. Village, IL: American Academy of Pediatrics; 2003:4 30 -6. 18. Fernandez M, Rench MA, Albanyan EA, et al. Failure of rifampin to eradicate group B streptococcal colonization in ** NOTICE TO READERS OUTSIDE OF infants. Pediatr Infect Dis J 2001;20:371 -6. THE UVA HEALTH SYSTEM************ 19. Zelunka EJ. Intravenous cyclosporine -rifampin We will be discontinuing our mail (print) service interaction in a pediatric bone marrow transplant recipient. Pharmacotherapy 2002;22:387 -90. to readers outside of the UVA Health System 20. Al -Dossary FS, Ong LT, Correa AG, et al. Treatment of after December 2004. We will begin a new e - childhood tuberculosis with a six month directly observed mai l subscription service in January. If you regimen of only two weeks of daily therapy. Pediatr Infect would like to continue to receive the newsletter, Dis J 2002;21:91 -7. 21. Allen Jr LV, Erickson III MA. Stability of bethanechol please send a request, with your e -mail address, chloride, pyrazinamide, quinidine sulfate, rifampin, and to us at [email protected] . If you do not have tetracycline hydrochloride in extemporaneously compounded access to the internet, please contact us at 434 - oral liquids. Am J Health -Syst Pharm 1988;55:1804 -9. 982 -0921 to make other arrangements. This notice does not apply to UVA faculty, staff, or houseofficers. *************************** Formulary Update The foll owing actions were taken by the Contributing Editor:Marcia L. Buck, Pharm.D. Pharmacy and Therapeutics Committee at their Editorial Board: Kristi N. Hofer, Pharm.D. meeting on 10/22/04: Michelle W. McCarthy, Pharm.D. If you have comments or suggestions for future ® 1. Cinacalcet (Sensipar ) was added to the issues, please contact us at Box 800674, UVA Inpatient and Outpatient Formularies for the Health System, Charlottesville, VA 22908 or treatment of secondary hyperparathyroidism in by e -mail to [email protected] . This patients with chron ic kidney disease on dialysis newsletter is also available at and treatment of hypercalcemia in parathyroid www.healthsystem.virginia.edu/internet/pediatr carcinoma patients. ics/pharma -news/home.cfm 2. Intranasal influenza vaccine (FluMist ®) was added to both Inpatient and Outpatient Formularies for the immunization of healthy patients 5 to 49 years of age.