VA Class:AM500

AHFS Class:

• Antituberculosis Agents 8:16.04

Generic Name(s):

• Rifapentine

Chemical Name:

• 3-[[(4-Cyclopentyl-1-piperazinyl)imino]methyl]-rifamycin

Molecular Formula:

• C₄₇H₆₄N₄O₁₂

Rifapentine, a long-acting semisynthetic cyclopentylpiperazinyl derivative of rifamycin SV,1,11,12,13 is an ansamycin antituberculosis antibiotic.1,2,3,5,6,7,8,9,14,19,20

Tuberculosis

Active Tuberculosis

Rifapentine is used in conjunction with other antituberculosis agents in the treatment of clinical tuberculosis.

The American Thoracic Society (ATS), US Centers for Disease Control and Prevention (CDC), and Infectious Diseases Society of America (IDSA) currently recommend several possible multiple-drug regimens for the treatment of culture-positive pulmonary tuberculosis.14 These regimens have a minimum duration of 6 months (26 weeks), and consist of an initial intensive phase (2 months) and a continuation phase (usually either 4 or 7 months).14 Rifapentine is considered a first-line antituberculosis agent for use in intermittent regimens in patients with pulmonary tuberculosis.14 Although the manufacturer states that rifapentine can be used in both the initial and continuation phases of tuberculosis treatment,1 the ATS, CDC, and IDSA suggest that rifapentine not be used in the initial phase of treatment but can be used in certain patients for the continuation phase in a once-weekly regimen in conjunction with isoniazid.14 The ATS, CDC, and IDSA state that rifapentine can be used in patients with noncavitary pulmonary tuberculosis caused by susceptible Mycobacterium tuberculosis if sputum smears are negative at completion of the initial treatment phase, but the drug should not be used for the treatment of tuberculosis in individuals with human immunodeficiency virus (HIV) infection and, because of limited experience, should not be used in those with extrapulmonary tuberculosis.14 For information on general principles used in the treatment of tuberculosis, see the Antituberculosis Agents General Statement 8:16.04.

Clinical Experience

Safety and efficacy of rifapentine is based on a large, controlled international trial comparing the drug with rifampin in patients with pulmonary tuberculosis who received either drug concomitantly with at least one other antituberculosis agent in a regimen that consisted of an intensive phase for 2 months and a continuation phase for 4 subsequent months; all patients received pyridoxine (vitamin B₆) throughout the 6-month trial.1,19 The intensive phase of therapy included either rifapentine (600 mg twice weekly) or rifampin (450 or 600 mg daily depending on body weight) given in conjunction with isoniazid (300 mg daily), pyrazinamide (1.5 or 2 g daily depending on body weight), and ethambutol (800 mg or 1.2 g daily depending on body weight).1,19 The continuation phase of therapy (subsequent 4 months) evaluated a drug regimen consisting of rifapentine (600 mg once weekly) and isoniazid (600 or 900 mg once weekly depending on body weight) or a regimen of rifampin (450 or 600 mg twice weekly depending on body weight) and isoniazid (600 or 900 mg once weekly depending on body weight); pyrazinamide and ethambutol were discontinued.1,19 Sputum converted to negative in 87% of patients with tuberculosis receiving rifapentine-containing drug regimens and in 81% of patients receiving rifampin-containing regimens by the end of 6 months of therapy.1,19 Although rifapentine also has been studied in China and Hong Kong, the results of these studies were less than optimal since the oral formulation used produced low and variable bioavailability.4,19,22 Because rifapentine has a long half-life and can be administered intermittently (once weekly for the continuation phase or twice weekly for the intensive phase), some clinicians suggest that the drug may be particularly useful when patient compliance is a concern.1,4 In addition, intermittent rifapentine therapy may have operational advantages in implementing directly observed therapy.4 However, additional study and experience are needed to elucidate further the role of rifapentine vs. rifampin in multiple-drug regimens for the treatment of tuberculosis,21,22,23 particularly because of concerns about relapse.1,4,19,22

The rate of relapse (reactivation of clinical tuberculosis) was higher in patients receiving rifapentine versus rifampin combination therapy, principally as a result of a higher rate of patient noncompliance with daily concomitant therapies during the intensive phase in rifapentine-treated patients.1,4,19 Failure for sputum to convert to negative during the intensive phase of short-course therapy also was associated with a greater risk of relapse for either treatment regimen as was male gender.1,4,19 Relapse or treatment failure at 6 months1,4 of follow-up occurred in 10% of patients receiving the rifapentine-containing regimens and in 5% of those receiving the rifampin-containing regimens.1,19 A small proportion of patients relapsing had in vitro evidence of rifampin- and rifapentine-resistant (genetic differences from baseline strains based on restriction fragment length polymorphism) or multidrug-resistant strains of tuberculosis.1 However, relapses in patients receiving rifapentine were not associated with mono-resistance to rifampin.1,19

HIV-infected Individuals

Experience with rifapentine in patients with HIV infection and tuberculosis is limited,1,21 and the ATS, CDC, and IDSA state that use of the drug in antituberculosis regimens in such patients currently is not recommended.14,21 In an ongoing small clinical trial in patients with HIV infection and tuberculosis who were randomized to receive once-weekly rifapentine and daily isoniazid during the continuation phase (months 3-6) of therapy, the relapse rate was about twice that observed in HIV-negative patients with tuberculosis.1,19 Almost all (4 out of 5) cases of relapse in these HIV-infected patients who received rifapentine were associated with rifampin-resistant tuberculosis; relapse also was associated with late stages of HIV infection (e.g., lower CD4⁺ T-cell counts compared with those whose disease did not relapse), extrapulmonary tuberculosis, and concomitant therapy with an azole-derivative antifungal.1,19 As with other antituberculosis agents used in HIV-infected patients, if rifapentine is used, a more aggressive (i.e., more frequent dosing) rifapentine-containing regimen should be employed during the continuation phase of short-course therapy.1 Based on these limited findings, once-weekly rifapentine dosing during the continuation phase of therapy should not be employed in HIV-infected patients.1 In addition, the possibility that drug regimens may have to be altered because of clinically important pharmacokinetic interactions between rifapentine and other drugs commonly used in these patients (e.g., HIV protease inhibitors such as indinavir, nelfinavir, ritonavir, saquinavir; azole antifungals; reverse transcriptase inhibitors) should be considered.1 The manufacturer recommends that rifapentine be used with extreme caution, if at all, in patients who are receiving an HIV protease inhibitor.1 (See Drug Interactions: Antimycobacterial Agents, in Nelfinavir, Ritonavir, and Saquinavir 8:18.08.08.) Because the management of these patients is complex and must be individualized, experts in the management of mycobacterial infections in HIV-infected patients should be consulted.18

If tuberculosis is diagnosed in an HIV-infected patient in whom use of an HIV protease inhibitor is being considered but has not yet been initiated, a management strategy suggested by CDC is to complete the treatment of tuberculosis according to current ATS and CDC guidelines before adding the HIV protease inhibitor to the patient's antiretroviral regimen.18 In HIV-infected patients who already are receiving an HIV protease inhibitor when tuberculosis is diagnosed, the CDC has suggested several options for consideration.18 However, because the risks and benefits of these options are unknown, management decisions must be individualized on a case-by-case basis to provide optimal patient care.18 (See Initial Treatment of Tuberculosis: Active Tuberculosis in HIV-Infected Individuals, in the Antituberculosis Agents General Statement.)

Administration

Rifapentine is administered orally.1 Since the incidence of some adverse effects (e.g., vomiting, nausea, or GI upset) may be increased during fasting conditions, administration of rifapentine with food may be useful in patients with a history of such disorders.1 GI absorption of rifapentine is reduced (e.g., by 20-32% in the fasted state) in HIV-infected patients compared with healthy adults, but concomitant administration with food can increase the extent of GI absorption of the drug.1

Rifapentine usually is given once or twice weekly, and the manufacturer recommends an interval of not less than 3 days (72 hours) between doses.1

Dosage

Active Tuberculosis

In the treatment of clinical tuberculosis, rifapentine should not be given alone.1,14 The drug is considered a first-line agent for use in intermittent regimens in patients with pulmonary tuberculosis.14 Therapy for tuberculosis should be continued long enough to prevent relapse. The minimum duration of treatment currently recommended for patients with culture-positive pulmonary tuberculosis is 6 months (26 weeks), and recommended regimens consist of an initial intensive phase (2 months) and a continuation phase (usually either 4 or 7 months).14 However, completion of treatment is determined more accurately by the total number of doses and is not based solely on the duration of therapy.14 For information on general principles of antituberculosis therapy and recommendations regarding specific multiple-drug regimens and duration of therapy, see the Antituberculosis Agents General Statement 8:16.04.

The manufacturer states that the usual dosage of rifapentine for the treatment of pulmonary tuberculosis is an initial intensive phase of 600 mg of rifapentine twice weekly for 2 months in conjunction with other appropriated antituberculosis agents (e.g., isoniazid, pyrazinamide, ethambutol, streptomycin) followed by once-weekly administration of rifapentine (600 mg) and isoniazid for 4 additional months.1 The manufacturer also recommends concomitant administration of pyridoxine (vitamin B₆) in those who are malnourished, predisposed to neuropathy (e.g., alcoholics, diabetics), and in adolescents.1

The American Thoracic Society (ATS), US Centers for Disease Control and Prevention (CDC), and Infectious Diseases Society of America (IDSA) currently do not recommend use of rifapentine during the initial intensive phase of tuberculosis treatment.14 However, these experts suggest that patients with pulmonary tuberculosis who have negative sputum smears at completion of an initial phase of treatment may receive rifapentine in conjunction with isoniazid for the continuation phase.14 When this regimen is used, the ATS, CDC, and IDSA recommend that adults and children 15 years of age or older receive rifapentine in a dosage of 10 mg/kg (600 mg) once weekly in conjunction with isoniazid (15 mg/kg [900 mg] once weekly) for 4 months (18 weeks).14

Dosage in Renal and Hepatic Impairment

While the half-life of rifapentine is prolonged in patients with mild to severe hepatic impairment,9 accumulation of the drug in patients receiving intermittent dosing (recommended once or twice weekly dosing) is unlikely.9,12 Results of a pharmacokinetic study in patients with hepatic dysfunction indicate that no dosage adjustments appear to be necessary in these patients,9 and the manufacturer makes no specific recommendations.1

The effects of renal impairment on the elimination of rifapentine have not been evaluated.1 Studies using radiolabeled rifapentine indicate that 17% of a dose of the drug is excreted in urine, suggesting that renal impairment may not substantially affect elimination of the drug.1 The manufacturer makes no specific recommendations regarding dosage adjustments in patients with impaired renal function.1

Contraindications

Known hypersensitivity to rifapentine, other rifamycins (e.g., rifampin and rifabutin), or any ingredient in the formulation.1

Warnings/Precautions

Warnings

Hepatic and Hematologic Effects

Because multiple-drug antituberculosis regimens, including those that employ a rifamycin, can cause adverse hepatic and hematologic effects, liver function (hepatic enzymes, bilirubin) and hematologic status (complete blood cell and platelet counts) should be monitored at initiation of rifapentine therapy.1 Patients should be seen at least monthly during continued rifapentine therapy and questioned concerning adverse reactions; those reporting abnormalities should have follow-up, including laboratory monitoring, as necessary.1 Patients should be advised to contact their clinician immediately if they develop fever, loss of appetite, malaise, nausea and vomiting, darkened urine, yellowish discoloration of the skin and eyes, and/or pain or swelling of the joints during rifapentine therapy.1 Routine laboratory monitoring for drug-induced toxicity in patients with normal baseline tests generally is not necessary.1 However, if rifapentine is considered for use in patients with preexisting liver function abnormalities and/or liver disease, the drug should be used only if clinically necessary and with caution and close medical supervision; in addition to baseline tests, careful monitoring of liver function (particularly aminotransferases) should be repeated every 2-4 weeks during continued therapy.1 If signs or symptoms of liver disease develop or worsen, rifapentine should be discontinued.1 Hepatotoxicity of other antituberculosis agents that may be used in conjunction with rifapentine (e.g., isoniazid, pyrazinamide) should be considered.1

Diarrhea and Colitis

Clostridium difficile -associated diarrhea and colitis (also known as antibiotic-associated pseudomembranous colitis) has been reported rarely during or following discontinuance of therapy with other rifamycins, including rifampin, and should be considered in the differential diagnosis of patients who develop diarrhea (particularly if severe or persistent) in association with rifapentine.1,17 If C. difficile -associated diarrhea and colitis is suspected, rifapentine should be discontinued and the patient should be treated with supportive and specific treatment as indicated.1,24,25,26,27,28 Mild cases may respond to discontinuance of the drug alone, but diagnosis and management of moderate to severe cases should include appropriate bacteriologic and other (e.g., identification of clostridial toxins) studies, and treatment with fluid, electrolyte, and protein supplementation as indicated; sigmoidoscopy (or other appropriate endoscopic examination) usually is reserved for special situations.24,25,26,27,28 If colitis is moderate to severe or is not relieved by discontinuance of rifapentine, appropriate anti-infective therapy (e.g., oral metronidazole or vancomycin) should be administered.1,24,25,26,27,28 Isolation of the patient also may be advisable.25,26 Agents inhibiting peristalsis are contraindicated in these patients.1,24,25,26

Other Effects

The possibility that rifapentine may share the toxic profile of rifampin also should be considered.1 (See Cautions in Rifampin 8:16.04.)

General Precautions

Patients should be advised that rifapentine, like other rifamycins, may impart a red-orange color to urine, feces, sputum, sweat, saliva, CSF, tears, breast milk, and tongue; patients should be informed of this possibility.1,9,16,29 Contact lenses or dentures worn during rifapentine therapy may become permanently stained.1

Because of the ability of rifampin and possibly other rifamycins to induce various hepatic enzyme systems, including delta aminolevulinic acid synthetase, use of these drugs may be associated with an exacerbation of porphyria.1 Therefore, the manufacturer states that rifapentine should not be used in patients with porphyria.1

Specific Populations

Pregnancy

Category C.1 (See Users' Guide.)

Lactation

Not known whether rifapentine is distributed in milk; possibility of red-orange discoloration of breast milk exists because of known discoloration of other body fluids.1 (See Cautions: General Precautions.) Caution is advised if the drug is administered in nursing women.1

Pediatric Use

The safety and efficacy of rifapentine in pediatric patients younger than 12 years of age have not been established.1

Geriatric Use

Experience in those 65 years of age and older insufficient to determine whether they respond differently from younger adults.1 Careful titration of dosage is recommended because of the greater frequency of decreased hepatic, renal, and/or cardiac function and or concomitant disease and drug therapy in geriatric individuals.1

Drugs Affecting Hepatic Microsomal Enzymes

Rifapentine induces microsomal enzymes (i.e., cytochrome P-450 [CYP] 3A4 and 2C8/9 isoenzymes) responsible for the inactivation of a number of drugs including certain calcium-channel blocking agents (e.g., verapamil, diltiazem, nifedipine), certain antifungals (fluconazole, itraconazole, ketoconazole), opiate analgesics (e.g., methadone), oral antidiabetic agents (e.g., sulfonylureas), corticosteroids, cardiac glycosides, certain antiarrhythmic agents (e.g., disopyramide, mexiletine, quinidine, tocainide), certain anti-infectives (e.g., quinine, dapsone, chloramphenicol, clarithromycin, doxycycline, fluoroquinolones), certain reverse transcriptase inhibitors (e.g., delavirdine, zidovudine), certain immunosuppressants (e.g., cyclosporine, tacrolimus), and oral anticoagulants (e.g., warfarin).1 Concomitant use of rifapentine and any of these drugs may result in decreased plasma concentrations of the drugs, and dosage adjustments may be required.1 Concomitant use of rifapentine also may diminish the effects of barbiturates, anticonvulsants (e.g., phenytoin), benzodiazepines (e.g., diazepam), clofibrate [no longer commercially available in the US], theophylline, β-adrenergic blocking agents, haloperidol, levothyroxine, sildenafil, and tricyclic antidepressants (e.g., amitriptyline, nortriptyline); dosage adjustments of these agents also may be required.1

Induction of cytochrome P-450 hepatic microsomal enzymes by rifapentine generally occurs within 4 days after the first dose and returns to baseline levels 14 days after discontinuing the drug.1 The magnitude of hepatic microsomal enzyme induction by rifapentine is dose- and dosing frequency-dependent; less enzyme induction occurs when 600 mg of rifapentine is given once every 72 hours versus daily administration.1 In vitro and in vivo enzyme induction studies have suggested that rifapentine induction potential may be less than that of rifampin but greater than that of rifabutin.1

Antiretroviral Agents

Because rifapentine has been shown to increase metabolism of HIV protease inhibitors, which may result in subtherapeutic plasma concentrations of these antiretroviral agents, rifapentine should be used with extreme caution, if at all, in HIV-infected patients taking these drugs.1 (See Uses.)

Oral Contraceptives

Patients should be advised that the reliability of oral or other systemic hormonal contraceptives may be affected by concomitant rifapentine therapy, and consideration should be given to using alternative contraceptive measures.1

Antacids

In a large, international controlled trial, patients were advised to take the drug at least 1 hour before or 2 hours after ingestion of antacids.1 However, since no specific drug interaction studies have been performed, it is unknown whether an interaction between rifapentine and antacids exists.31

Description

Rifapentine, a long-acting semisynthetic cyclopentylpiperazinyl derivative of rifamycin SV,1,11,12,13 is an ansamycin antibiotic6 . Rifapentine is a lipophilic compound12,19 that is similar structurally and pharmacologically to rifampin and rifabutin.1,2,3,5,6,7,8,9,14,19,20

Rifapentine has an antibacterial spectrum of activity similar to that of rifampin;1,2,3,5,6,7,8,13,19,20 however, on a molar basis, rifapentine and its active 25-desacetyl metabolite generally are more active than rifampin against Mycobacterium tuberculosis 1,2,3,5,19,20 and more active than rifampin but less active than rifabutin against M. avium complex (MAC).5,19 The clinical relevance of activity of rifapentine against other mycobacterial species has not been established.1

Against nonmycobacterial organisms, rifapentine is active in vitro against some gram-negative bacteria such as Brucella species,13 Legionella species,7 Neisseria species,20 Haemophilus influenza ,20 Bordetella pertussis , and Bordetella parapertussis .6 The drug also has inhibitory activity against some gram-positive bacteria including streptococci,20 staphylococci,20 Corynebacterium pseudodiphtheriticum , Arcanobacterium haemolyticum (formerly Corynebacterium haemolyticum ), A. pyogenes , Listeria species, Turicella otitidis , Brevibacterium species, and Oerskovia species.8 Rifapentine generally was as active as or less active than rifampin against these bacteria.6,7,8,14,20 Like rifampin, rifapentine also is active in vitro against Chlamydia species but not against mycoplasma.20

Natural and acquired resistance to rifapentine have been observed in vitro and in vivo in strains of M. tuberculosis .1,3,4 A high level of cross-resistance has been demonstrated between rifampin and other rifamycin derivatives such as rifapentine.1,3,4,14 Cross resistance has not been demonstrated between rifapentine and non-rifamycin antimycobacterial agents such as isoniazid or streptomycin.1

Additional Information

Overview (see Users Guide). For additional information until a more detailed monograph is developed and published, the manufacturer's labeling should be consulted. It is essential that the manufacturer's labeling be consulted for more detailed information on usual cautions, precautions, contraindications, potential drug interactions, laboratory test interferences, and acute toxicity.

1. Aventis. Priftin^® (rifapentine) tablets prescribing information (dated Feb 2002). In: Physicians' desk reference. 57th ed. Montvale, NJ: Medical Economics Company Inc. 2003:763-6.

2. Mor N, Simon B, Mezo N et al. Comparison of activities of rifapentine and rifampin against Myocobacterium tuberculosis residing in human macrophages. Antimicrob Agents Chemother . 1995; 39:2073-7. [PubMedCentral][PubMed 8540718]

3. Moghazeh SL, Pan XI, Arain T et al. Comparative antimycobacterial activities of rifampin, rifapentine, and KRM-1648 against a collection of rifampin-resistant Mycobacterium tuberculosis isolates with a known rpoB mutations. Antimicrobial Agents cehmother . 1996; 40: 2655-7.

4. Tam CM, Chan SL, Lam CW et al. Rifapentine and isoniazid in the continuation phase of treating pulmonary tuberculosis. Am J Respir Crit Care Med . 1998; 157: 1726-33. [PubMed 9620898]

5. Heifets LB, Lindholm-Levy J, Flory MA. Bactericidal activity in vitro of various rifamycins against Myocbacterium avium and Mycobacterium tuberculosis . Am Rev Respir Dise . 1990; 141:626-30.

6. Hoppe JE, Bryskier A. In vitro susceptibilities of Bordetella pertussis and Bordetella parapertussis to two ketolides (HMR 3004 and HMR 3647), four macrolides (azithromycin, clarithromycin, erythromycinA, and roxithromycin), and two ansamycins (rifampin and rifapentine). Antimicrob Agents Chemother . 1998; 42:965-6. [PubMedCentral][PubMed 9559823]

7. Schulin T, Wennersten CB, Ferraro MJ et al. Susceptibilities of Legionella spp. to newer antimicrobials in vitro. Antimicrob Agents Chemother . 1998; 42:1520-3. [PubMedCentral][PubMed 9624509]

8. Soriano F, Fernandez-Roblas R, Calvo R et al. In vitro susceptibilities of aerobic and facultative non-spore-forming gram-positive bacilli to HMR 3647 (RU 66647) and 14 other antimicrobials. Antimicrob Agents Chemother . 1998; 42:1028-33. [PubMedCentral][PubMed 9593121]

9. Keung ACF, Eller MG, Weir SJ. Pharmacokinetics of rifapentine in patients with varying degrees of hepatic dysfunction. J Clin Pharmacol . 1998; 38: 517-24.

10. Keung ACF, Miller TD, Green VI et al. Bioavailability (BA) and food effects study of rifapentine in healthy adults. Pharm Res . 1995; 12(suppl):S419.

11. Reith K, Keung A, Toren PC et al. Disposition and metabolism of 14C-rifapentine in healthy volunteers. Drug Metab Dispos . 1998; 26:732-8. [PubMed 9698286]

12. Durand DV, Hampden C, Boobis AR et al. Induction of mixed function oxidase activity in man by rifapentine (MDL 473), a long-acting rifamycin derivative. Br J Clin Pharmac . 1986; 21:1-7.

13. Garcia-Rodriguez JA, Munoz-Bellido JL, Fresnadillo MJ et al. In vitro activities of new macrolides and rifapentine against Brucella spp. Antimicrobial Agents and Chemother . 1993; 37:911-3.

14. Centers for Disease Control and Prevention. Treatment of tuberculosis, American Thoracic Society, CDC, and Infectious Diseases Society of America. MMWR Morb Mortal Wkly Rep . 2003; 52(No. RR-11):1-77. [Fulltext MMWR][PubMed 12549898]

15. US Centers for Disease Control and Prevention. Initial therapy for tuberculosis in the era of multidrug resistance. Recommendations of the Advisory Council for the Elimination of Tuberculosis. MMWR Morb Mortal Wkly Rep . 1993; 42(RR-7):1-8. [Fulltext MMWR][PubMed 8418395]

16. Bolan G, Laurie RE, Broome CV. Red man syndrome: inadvertent administration of an excessive dose of rifampin to children in a day-care center. Pediatrics . 1986; 77:633-5. [PubMed 3486402]

17. Hoechst Marion Roussel. Rifadin^® (rifampin capsules) and Rifadin^® I.V. (rifampin for injection) prescribing information (dated 1995 May). In: Physicians' desk reference. 51st ed. Montvale, NJ: Medical Economics Company Inc; 1997:1276-8.

18. Centers for Disease Control. Clinical update: impact of HIV protease inhibitors on the treatment of HIV-infected tuberculosis patients with rifampin. MMWR Morb Mortal Wkly Rep . 1996; 45:921-5. [PubMed 8927017]

19. Jarvis B, Lamb HM. Rifapentine. Drugs . 1998; 56:607-16. [PubMed 9806107]

20. Felmingham D, Robbins MJ, Clark S et al. The in vitro activity of rifampicin and rifapentine against recent clinical bacterial isolates. Abstracts of the 37th Interscience Conference on Antimicrobial Agents and Chemotherapy (ICAAC). Washington, DC: American Society for Microbiology. 1997:152. Abstract No. F-35.

21. Centers for Disease Control and Prevention. Prevention and treatment of tuberculosis among patients infected with human immunodeficiency virus: principles of therapy and revised recommendations. MMWR Morb Mortal Wkly Rep . 1998; 47(No. RR-20):1-58. [Fulltext MMWR][PubMed 9450721]

22. Tam CM. Rifapentine: a viewpoint. Drugs . 1998; 56:617.

23. Chaulet P. Rifapentine: a viewpoint. Drugs . 1998; 56:617.

24. Johnson S, Gerding DN. Clostridium difficile -associated diarrhea. Clin Infect Dis . 1998; 26:1027-36. [PubMed 9597221]

25. Gerding DN, Johnson S, Peterson LR et al for the Society for Healthcare Epidemiology of American. Position paper on Clostridium difficile -associated diarrhea and colitis. Infect Control Hosp Epidemiol . 1995; 16:459-77. [PubMed 7594392]

26. Fekety R for the American College of Gastroenterology Practice Parameters Committee. Guidelines for the diagnosis and management of Clostridium difficile -associated diarrhea and colitis. Am J Gastroenterol . 1997; 92:739-50 (IDIS 386628) [PubMed 9149180]

27. American Society of Health-System Pharmacists Commission on Therapeutics. ASHP therapeutic position statement on the preferential use of metronidazole for the treatment of Clostridium difficile -associated disease. Am J Health-Syst Pharm . 1998; 55:1407-11. [PubMed 9659970]

28. Wilcox MH. Treatment of Clostridium difficile infection. J Antimicrob Chemother . 1998; 41(Suppl C):41-6. [PubMed 9630373]

29. Food and Drug Administration. Priftin (rifapentine) tablets [October 20, 2000: Aventis]. MedWatch drug labeling changes. Rockville, MD; October 2000. From FDA website. [Web]

31. Aventis Pharmaceuticals, Kansas City, MO: Personal communication.