Rifampin

Symposium on Antimicrobial Therapy

Rifampin Barry Farr, M.D., * and Gerald L. Mandell, M.D.t

Rifampin is a semisynthetic dcrivative of rifamycin B, onc of a group of macrocyclic antibiotic compounds produccd by the mold Streptomyces mediterranei. This mold was cultivated from the soil at a French pine forest, and the rifamycins were first isolated from a fermentation culture in 1957 at the Lepetit Laboratory of Milan, Italy.'3' Whimsically named for a then current Italian movie, "Le Riffi,"1l5 the rifamycins were found to have a broad antimicrobial spectrum and marked structural diversity with over 750 derivatives being studied. 68,114,127,131 Rifamycin B appeared to be the least toxic of the original compounds, and onc of its derivatives, rifamycin SV, was shown to have enhanced activity and solubility.'3l Rifampin, which is the 3-4-methylpiperazinyl-iminomethyl derivative of rifamycin SV, was shown by Maggi and associates to have greater antimicrobial activity and a longer in vivo half-life than the parent compound. 79 Rifampin is a zwitterion ("inner salt") with a molecular weight of 822 daltons. fiR It is soluble in acidic aqueous solutions but even more soluble in organic solvents with remarkable diffusion through lipids. "1,82 The rifamycins exert their antibiotic effect by inhibition of DNA-dependent RNA polymerase at the beta subunit, preventing chain initiation hut not elongation. Synthesis of RNA in mammalian mitochondria is not inhibited by concentrations achieved with conventional therapcutic doses.K2 During the first decade since its introduction in the United States, rifampin has been used principally in the therapy of tuberculosis, where it has proved valuable in permitting two-drug, short course (nine month) therapy with results comparable to three drug regimens of longer duration. 3o ,72,75,95,':!4,'35 Its use in antituberculous therapy will be covered in a separate article. This article will focus on the drug's activity and utility against other pathogens.

ANTIMICROBIAL SPECTRUM Rifampin inhibits and kills a wide variety of microorganisms (Table 1). It is the most active antibiotic known against staphylococci (both coagulase-positive and coagulase-negative strains).,z3 Against other gram-positive cocci, it has less in vitro activity than penicillin but more than erythromycin and the cephalosporins. KG

*Fellow, Di\'ision of l11fE~cti()lIs Diseases, University ofVirgillia School of ~ledidne, Charlottesville, Virginia tHead, Division of Infectiolls Diseases, University of Virgillia School of Medicine, Charlottcsville, Virginia

Medical Clinics of North America-Vo!. 66, No. I, January 1982

157

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BARBY FABH AND GEHALll

Table 1.

L.

MANDELL

Minimal Inhibitory Concentrations of Rifampin

OHGAN1SM

Clostridium difficile Enterobacter spp. Enterococcus spp. Escherichia coli Hemophilus influenzae Klebsiella spp. Legionella pneunwphila Mycobacterium avium/intracellulare Mycobacterium fortuitum Mycobacterium kansasii Mycobacterium marinum Mycobacterium tuberculosis Mycobacterium ulcerans Neisseria gonorrhoeae Neisseria meningitidis Proteus spp. Pseudomonas spp.

Staphylococcus aureus Staphylococcus epidermidis Streptococcus pneumoniae Streptococcus pyogenes

20 >20 0.1-1.0 0.64-2.5 0.005-0.2 0.005-0.2 0.02 0.1-0.8 5-50 5-,50 0.005-0.01 0.003-0.005 0,01 0,01-0.5

Among gram-negative bacteria, Neisseria meningitidis, Neisseria gonorrhoeae, and Hemophilus infiuenzae are the most sensitive species. 22 ,,>8,", It has less activity than tetracycline, chloramphenicol, and aminoglycosides against most gram-negative bacilli. 82,86, 131 Rifampin is the most active agent tested against Legionella pneumophila, being 200 times as active as erythromycin in plaque reduction in infected chick emhryo cell culture monolayers,·39.78.107.14o It is also effective in a whole embryo model against Legionella micdadei, the Pittsburgh pneumonia agent. 96 It is as effective as vancomycin and eotrimoxazole in vitro against Clostridium difficile, the putative causative agent of pseudomembranous colitis. J The rifamycins have demonstrated antiviral activity and possible antitumor activity but have not proved clinically effective at usual therapeutic levels.72 There is also activity against some chlamydia, including Chlamydia trachomatis (LGV and non-LGV) and C, psittaci.23.62.92 Almost all hacteria may rapidly develop resistance to rifampin in vitro or in vivo.32.86.'37 This rapid development of complete resistance to the drug appears to be due to a mutation altering DNA-dependent RNA polymerase. 28 Approximately one of every lO lD tubercle bacilli is a resistant mutant, leading to a very low incidence of rifampin resistance among untreated tuberculous patients. '37 This numher increases with rifampin monotherapy, as illustrated by one series of 11 patients in which three had developed resistance after 45 days and five had developed resistance after 90 days.8 The mutation rate to rifampin resistance among other bacteria seems to be somewhat higher than that for Mycobacterium tuherculosis (e.g., Staphylococcus aureus, 10- 7; Streptococcus spp., 10- 7; Meningococcus, 10- 7 ; and E. coli, 10 -8). 32.66.68,86

159

HIFAMI'IN

PROPHYLAXIS Meningococcal Meningitis The sccondary attack rate of meningocoeeal mcningitis in closcd populations has been estimated to be about 800 times that of the general population. Sulfadiazine has been used since 1941 to eradicate the carrier state, although this was never rigorously demonstrated to reduce the incidence of meningitis. 91 By 1971 about 68 pcr cent of meningococcal isolates were resistant to sulfa, and rifampin was shown to be about 90 per cent effective in carriage eradication. 12.26 ..38.14.; Minocycline was almost as effective·'2 but caused a much higher incidence of side effects, with up to 86 per ccnt developing vestibular symptoms in one controlled study.29.3.3.61 Rifampin prophylaxis is associated with few side effects in controlled studies and is therefore recommended as the drug of choice for meningococcal prophylaxis at a dosc of 600 mg BID for two days in adults or 10 mg pcr kg BID for two days in children. (~).H2.84

Meningitis due to Hemophilus injluenzae Several recent studies have shown that household, pre-school agc contacts of patients with meningitis due to Hemophilus injluenzae have a high incidence of developing the diseasc. The secondary attack rates for this group in two of these studics were 2.1 per cent and 2.3 per cent, yielding a relativc risk equal to that of meningococcal contacts.17.144 Rifampin has been shown to be effective in several small studics in climinating asymptomatic carriage in over 90 per cent of children treated with 20 mg per kg per day for four days."""O' 1.32.146 Administration of ampicillin or cotrimoxazole was less successful. 43,.'" Although reduction of the incidence of Hemophilus injluenzae meningitis by prophylactic treatment of contacts has not been documented, rifampin prophylaxis will probahly be approved using the same rationale as for meningococcal disease.

THERAPEUTIC USES Beeause of the unique efficacy of rifampin as an antituberculous agent, it has bcen argued that the drug should be reserved for treating tuberculosis, H6, llH It was suggested that widespread use for other infections might Icad to an increasing population of rifampin-resistant Mycobacterium tuberculosis, but there have been no reports substantiating this fcar in the countries where rifampin has been used for other purposes. llH As suggested by the higher mutation rates to rifampin resistance among nontuberculous pathogens, resistanee appears to develop faster and more frcquently during rifampin monotherapy of infections caused by these organisms,12,32.H1,l2,3,l41i Data from experimental staphylococcal infections show that the development of resistance can be prcvented by combination of rifampin with another drug active against the infecting organism. 81 Except for its short-term use in the prophylactic treatment of meningitis contacts, rifampin should not be used alone, Rifampin has been approved in thc United States for the prophylaxis of meningococcal meningitis, and its use has been studied in a variety of other infections during the past decade.

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BAHHY FAHH .\I\ll CEHALIJ

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MA~I)ELL

Endocarditis Rihmpin, in eombination with vaneomyein and gentamicin, has been reeoll1mended for the treatment of endocarditis due to Staphylococcus epidermidis or Corynebaeterium Spp.I26 It is also recommended in combination with vancomyein for endocarditis caused by tolerant strains of Staphylococcus aI/reus .I2h Sande and associatcs examined the efficacy of rihlmpin in experimental cases of endocarditis due to S. aureus and found that it yielded no improvement over penicillin alone, except that the combination sterilized renal tissue faster (one day versus two). In vitro testing suggested antagonism betwecn rifampin and penicillin, hut this was not evident in the experimental therapy. On the basis of this study, they recommend consideration of rifampin in eases of staphylocoeeal endocarditis when complicated by formation of myocardial, renal, or cerebral abscess. 12. Other workers have shown rifampin to act synergistically with nafcillin and with vancomycin against S. aureus in vitro. 141 Nine recent cases of staphylococcal endocarditis (five S. aureus, four S. epidermidis) were reported to be refractory to antibiotic thcrapy (two due to methicillin resistance and vancomyein tolerance) until the addition of rifampin."ID ..31i.II.H'.")K One ease of endocarditis due to psittacosis that was refractory to multiple other antibiotics was subsequently responsive to rifampin. 62 It has been suggested that rifampin may be one of the best antibiotics available for sterilization of infected prostheses. The four cases of endocarditis due to S. epidermidis cited above all involved prosthetic valves. Three responded to antibiotics alone and the fourth had no evidence of persistent infection at the time of valve replacement. :H·1.H.' Infected Cerebrospinal Fluid Shunts Three ease reports describe cerebrospinal fluid shunt infections due to S. epidermidis that were refractory to multiple antibiotic therapy before the addition of rifampin.:l l '" Another case of ventrkulojugular shunt infection by Corynebacterium bovis was also cured by a regimen that included rifampin after unsuccessful treatment with penicillin.

I.

Meningitis Enterococcal meningitis, a very rare cause of septic meningitis, was cured in one penicillin-allergic patient by a combination of rifampin and vancomycin after unsuccessful regimens of chloramphenicol and vancomycin. 121 Rifampin was also used successfully in three eases of neonatal meningitis due to Flavobacteria meningosepticum, which was resistant to aminoglycosides, ampicillin, and chloramphenicol. (;9 Rifampin has been evaluated in an experimental model of meningitis due to Listeria in rabbits after it was reported to be 200 times more effective than arnpkillin or penicillin in treating intraperitoneal murine listeriosis. HJ Rifampin was less rapidly bactericidal in the meningitis model than ampicillin or penkillin; ampicillin plus gentamicin was the most effective combination. I2K Gram-Negative Bacteremia in Infancy Rihuupin has been used successfully by Naveh to treat infants with serious gram-negative infections resistant to most other antibiotics. These have included cases of Klebsiella, E. coli, Shigella, and Enterobacter sepsis. 97 .9" Osteomyelitis and Septic Arthritis Experimental data hy Norden and his associates suggest that rifampin combined with cephalothin and sisomyein may he the best regimen in the therapy of S. aureus osteomyelitis. 102 An oral combination

HIFA\!I'IN

161

of rifampin and trimethoprill1 was also evaluated in experimentally induced infections ~l\1d was shown to he less effective. 10\ Controlled trials arc necessary to confirm these data in human infection. One ease of osteomyelitis due to Enterohacter in an inhl11t was treated successfully with rifampin and chloramphenicol.'lH Rifampin is not part of the usual regimen f()]. staphylococcal arthritis, hut when one case provcd refractory to nafcillin therapy, rihllnpin was added and the response was immediate. It was speculated that the organisms had been sequestered in some intrailrtieular focus, perhaps inside cells inaccessible to nafcillin. 11

Tolerant Staphylococci As mentioned in relation to endocarditis above, some staphylococci may become tolerant to nakillin or vancomycin (or both), with minimal bactericidal concentration (MBC) much greater than minimal inhibitory concentration (N1IC), leading to persistence of the infection. 12" Because of synergy between rifampin and either of these two antibioties,ll1 addition of rifampin has led to the successful treatment of such infections. 8!i.];la Furunculosis Onc study has shown a marked reduction in the rate of staphylococcal nasal colonization during rifampin therapy. 12., '\1andell and Sande (unpublished observations) have used cloxacillin with rifampin to eradicate nasal carriage and interrupt the course of recurrent furunculosis. Fungal Infections Rifampin, though ineflective alone against fungi, has been shown to enhance the fungicidal effect of amphotericin B, miconazole, and miconazoic nitrate" against various species of Candida in vitro. :31."8 This has been extended to show synergy in the treatment of murine histoplasmosis and blastomyeosis"5 and in the topical therapy of experimental Candida keratitis. )J6 Clinical experience is still sparse, though one case of esophageal obstruction due to histoplasmosis'" and another case of Candida endophthalmitis 77 have been cured with rifampin and amphotericin B. Legionella Both Legionella pnellmophila and the Pittsburgh Pneumonia Agent appear to be sensitive to rifampin. "".107 It has been recommended that rifampin be added to erythromycin in Legionnaire's disease when the illness does not respond to erythromycin alone. )aH Brucellosis Rifampin has been shown to be superior to tetracycline in the therapy of experimental brucellosis in mice and guinea pigs. There have been several case reports of successful therapy in human infections, but clinical trials are laeking. lll Leprosy Rifampin oflers an alternative that may be as good or better than conventional therapy with dapsone. Experience is limited, but rifampin seems to kill the organisms faster. 72 . 117 lfused, it should be combined with dapsone to prevent the development of resistance. Genitourinary Infections

Conorrhea, nongonococcal urethritis due to

Chlamydia trachomatis, and lymphogranuloma venereum have all been treated suc-

cessfully with rifampin. 21 . 2:1.92 Rifampin is not the drug of choice, however, for any of these infections, since penicillin is more eflective against gonorrhea2J and tetracycline is a more reliable treatment for nongonococcal urethritis and lymphogran-

162

Ihl1Hr FAflH Ar\1l CICILlI.Il

L. 1'vL\"IlELL

uloma venereum. 21 .;)" Hifampin dol's not inhibit Treponema pallidll1n and has little activity against Ureaplasma urealyticl11n (one of the causes of 110ngonococcal urethritis). Chlamydiae rapidly develop resistance to rihllllpin in egg culture.

Infection Occurring in Patients with Chronic Granulomatous Disease of Childhood RihllTlpin has been demonstrated to kill living intracellular staph-

ylococci. 31. 71 .-':3 Onc patient with chronic granulomatous disease and a staphylococcal abscess responded dramatically to rihunpin within days aftcr unsuccesshd therapy for months with vancomycin, nafcillin, and gentamicin. 7<;

PHARMACOKINETICS Rifampin is availahle in the United States as a capsule of orange-red powdcr and as a pediatric suspension, both of which are almost completely ahsorbed from the gastrointestinal tract. H2 ~lean peak plasma concentrations of about 7 fLg pcr ml (range, 4 to 32) are achieved within one to four hours after ingestion of a 600 mg tablet in adults or 10 mg per kg in children. 24,," An intravenous preparation has been licensed in several foreign countries and is being investigated in the United States. The drug is 75 per cent protein-bound in serum and distributes into a volume calculated to be 160 per cent of body weight, perhaps reflecting intracellular concentration.6:l Plasma clearance is chiefly through hepatic uptake, deacetylation (to an active metabolite), and biliary excretion. Deacetylation diminishes reabsorption and increascs fecal excretion, though there is significant enterohepatic circulation. The half-life is initially 1. 5 to 5 hours and decreases by 40 per ecnt during the first two weeks of therapy due to enhanced biliary exeretion. H2 From (:; to 30 per cent of a dose is excreted in the urine, but dosage adjustment is not necessary in renal failure as it is with hcpatic dysfunction. (;1.<>H.k2 Aminosalicylic acid interferes with absorption. 111 Food also interferes with absorption, lowering and delaying peak blood levels. '2 One report suggested a doubling of rifampin levels by probenecid, hut this was not confirmed by a larger study.:ll.Ol Slow acetylators of isoniazid appear to have an accelerated clearance of rifampin. S2 Rifampin effectively penclrates almost all body tissues.'" Perhaps beeause of its great lipid solubility, it is the only antituberculous drug capable of penetrating and sterilizing semisolid caseous materia!.') It achieves eoncentrations in lung, liver, bile, cholecystic wall, and urine that exceed peak blood levels. 10 The concentration in tcars is similar to that in serum, and salivary concentrations are ahout 20 per eent of those of serum. 27.SS It also achieves therapeutic levels in pleural exudate, ascites, cavity fluid, milk, urinary bladder wall, and soft tissues (Table 2).40 It penetrates bone, with higher levels being reached in the prescnce of ostcomyelitis.,IO·lo3 Levels in cerebrospinal fluid of 0 to 0.5 fLg pcr ml have hecn recorded in normal individuals, but levels are higher with meningitis and may exeeed 1. 3 fLg per ml after standard oral doses (600 mg per day).12k Hifampin has been shown to he more efficacious than penicillin or methicillin in the treatment of experimental staphylocoecal abscesses. 71 This may relate in part to better penetration of abscess fluid but may also stem from rifampin's unique ability to enter phagocytic cells. When studied with 17 other antihiotics, rifampin alone was demonstrated to actually enter the phagocyte and kill bacteria. HO It has been shown to kill viable baeteria in neutrophils from normal hosts and patients

163

HIF\MI'IN

Table 2.

Concentrations of Hifampin Achiened after {[ Single Oral Dose (150 to 450 mg)*

OHCA\L nSSUE, OR I'Ll1ID

Ll1l1g

Cavity Hllid

Pleural exudate (:crclnospinal fluid Ascitic HuiJ Liver Bilc Chole,ystic wall Appendix

jJ.C/C~1

4.08 1.80 0.14

0.8.3 0.45 36.0

.538 ..5 10.0 2.10

OH j..lCi!\1 L

ORCA:'\!, TlSSL", OR FLl'IJ)

son

tiSSIlCS

BOIl('

Kidncy Bladdcr wall Urill('

Milk TearshH SalivaHH

J..lCiC~t

OR

~(;/\I

L

2.58 2.20 :3.9.5 0.45 700.0 0.49 7.0 1.0

*Adapted from FlIrcsz, S.: Chemical amI biological properties of rii:unpicill. Antibiot. CIll'lIlother., 16:31(;-:3.51. 1970.

with chronic granulomatous disease and in macrophages from pcritoneal exudate. One recent study, however, showed no killing of staphylococci ingested by peritoneal macrophages harvested from un stimulated mice. 110

ADVERSE EFFECTS Short-term daily therapy for meningitis prophylaxis is associated with very few side effects other than red urine and permanent staining of soft eontaet lenses in some patients. 78 Chronie daily therapy is associated with a mild, usually self~liJl1ited rash in 1 to 5 per cent, gastrointestinal complaints in 1 to 2 per cent (which can be reduced by administration with meals, which also reduces reahsorption), asymptomatic elevation ofliver enzymes in up to 14 per cent, hepatitis in less than 1 per cent (usually mild and self~limitcd with drug cessation), and purpura very rarely.'b.,!(I.'''" Seven cases of acute renal failure during daily therapy have heen reported, with three of these requiring dialysis. II:J Most patients receiving rifampin develop light-chain proteinuria without apparent ill effcct:19 Intermittent administration (less than twice per week) and high individual dosages (~1200 mg) have been associated with an increased incidence of side efft~cts. A flu-like syndrome with fever, chills, and myalgias develops in up to 20 per cent, beginning after several months of intermittent therapy and correlates well with the presence of antirifampin antihodies. 16 Some of these patients develop eosinophilia, 70. iOl tubulointerstitial nephritis (about 60 reported cases)'",·1l3.l20 and, more rarely, thrombocytopenia,53 hemolytic anemia, and even shoek.'h Various effects on the central nervous system have been reported, with rare progression to an organic brain syndrome. H2.112 Rihunpin has been incriminated by some as being associated with pseudomembranous colitis, though dear causality has not been proven. I .".12.f)1 Pancreatitis has also he en reported in rare instances to be possibly related to rifampin. IOU Patients have survived suicidal overdoses of up to 12 gm but may turn "lobster red" ftlr several days. "'.lIl0 Rifampin causes a significant increase in serum bile acids ll hut does not alter serum bilirubin concentrations at therapeutic levels in the absence of hepatitis. "" It competitively inhibits the hepatic uptake of several compoLlnds such as eholeeys-

164

BARRY FARI\ Ar-;]) GERALD

L.

MANDELL

tografin and Bromsulphalein. H2 Addition of isoniazid to rifampin increases the risk of hepatitis only slightly, making the combination safe in the absence of prior liver disease. H2 Rifampin is one of the most potent inducing agents for microsomal enzymes (greater than antipyrine or phenobarbital), 1041Q.5.139 leading to a decreased half-life for a number of compounds, including steroids such as prednisone and norethisterone, digitoxin, and the sulfonylureas. 5.142 These effects have been reported to cause decreased efficacy of oral contraceptives along with increased intermenstrual and breakthrough bleeding.'u 6 One patient with heart failure controlled by digitoxin decompensated after addition of rifampin. 15 A patient with nephrotic syndrome was refractory to steroid therapy until rifampin was stopped. 54 Patients on tolbutamide and chlorpropamide have had poorer diabetic control when also on rifampin. 130 It also reduces the efficacy of warfarin, causing a reduction in prothrombin time in patients anticoagulated with warfarin. 114 Rifampin causes a reduction in 25-hydroxycholecalciferollevels without changing levels of 1,25-dihydroxycholecalciferol or parathyroid hormone, and there are unconfirmed reports of osteomalacia with long-term treatment. 17 .1H It causes increased deiodination and biliary clearance of thyroxine; the serum concentration of thyroxine is lowered but serum concentration of triiodothyronine remains normal. 106 Immunosuppression has been alleged to be one of rifampin's side effects. Diminished primary antibody responses to sheep red blood cells and keyhole limpet hemocyanin and a decreased anamnestic response to Salmonella typhi vaccine have been reported. 13.49 Others have found normal antibody responses to E. coli, tetanus toxoid, pneumococcal vaccine, and sheep red blood cells. 48 •56 Some workers have suggested that rifampin blunted cell-mediated immunity with poor response to phytohemagglutinin in vitro,48 while others have shown no change in response in vitro to phytohemagglutinin, concanavalin A, pokeweed mitogen, or purified protein derivative and no change in purified protein derivative response in vivo. 48 .4!).56 No ill effect from this possible immunosuppression in the form of increased susceptibility to other infections or inability to heal tubcrculosis has been reported. 127 One recent study has suggested that rifampin at subinhibitory concentrations may actually enhance the serum susceptibility of certain organisms. 2

REFERENCES 1. Acocella, G., and Arioli, V.: Pseudomembranous colitis and rifampicin (letter). Lancet, 1:827-828, 1980. 2. Alexander. W. J., Cobbs, C. G .. and Curtiss, R: Modification of bacterial serum susceptibility by rifampin. Infect. Immun., 28:923--926, 1980. 3. Archer, G., Tenenbaum, M. J., and Haywood, H. B.: Rilampin therapy of S. epidermidis: Use in infections from indwelling artificial devices. J.A. M.A., 240:751-753, 1978. 4. Atlas, E., and Turek, M.: Laboratory and clinical evaluation ofrifampin. Am. J. ~[ed. Sd., 256:247-254, 1968. 5. Back, D. J., Breckenridge, A. M., Crawford, F. E., et al.: The elTect of rifampicin on the pharmacokinetics of ethynlestradiol in women. Contraception, 21:135--143, 1980. 6. Back, D. J., Breckenridge, A. M., Crawford, F., et al.: The cfkct of rifampicin on norethisterone pharmacokinetics. Em. J. Clin. Pharmacol., 15:193--197, 1979. 7. Banic, S., and Stropnik, Z.: Synergistic elTects of oleandomycin and rifamycin SV in experimental staphylococcal septicemia in rabbits. Infection, 2:16()--161. 1974. 8. Baronti, A., and Lukinovich, N.: A pilot trial of rifampicin in tuberculosis. Tubercle, 49:180--18,5,19689. Bassi, L., DiBernardino, L., Ariuli, V., et al.: Conditions for immunosuppression by rifampicin. J. Infect. Dis., 128:736, 1973. 10. Bayston, R: Rifampin for CSF shunt infection. J. Pediatr., 96:785--7H6, 1980. 11. Beam, T. R: Sequestration of Staphylococcus aureus at an inaccessible focus. Lancet, 2:227-228, 1979.

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12. Beam, W. E., Jr., Newberg, N. R., Devine, L. F., et al.: The effect ofrifampin on the nasopharyngeal carriage of Neisseria meningitidis in a military population. J. Infect. Dis., 124:3S--46, 1971. 13. Bellahsene, A., and Forsgren, A.: Effect of rifampin on the immune response in mice. Infect. Immun., 27:11>--20, 1980. 14. Bolton, W. K., Sande, M. A., Normansell, D. E., et a!.: Ventriculojugular shunt nephritis with Corynebacterium bovis. Am. J. Med., 59:417-423, 1975. 15. Boman, G., Eliasson, K., and Odar-Cederlof, I.: Acute cardiac failure during treatment with digitoxinAn interaction with rifampicin. Br. J. Clin. Pharmacol., 10:89-90, 1980. 16. Breckenridge, A., Back, D. J., Crawford, F. E., et a!.: Drug interactions with contraceptive steroids. In Estabrook, R. W., Lindenlaub, E., (eds.): The Induction of Drug Metabolism. Stuttgart, Schattauer, 1979, pp. 607--613. 17. Brodie, M. J., Boobi" A. R., Dollery, C. T., et a!.: Rifampicin and vitamin D metabolism. Clin. Pharmacol. Ther., 27:810-814, 1980. 18. Brodie, M. J., Boobis, A. R., and Dollery, C. T.: Rifampicin and vitamin D metabolism in man. Br. J. Clin. Pharmacol., 9:286p-287p, 1980. 19. Burman, N. D., Joffe, H. S., and Watson, c.: Oral antibiotic cure of staphylococcal endocarditis. Postgrad. Med. J., 49:920-922, 1973. 20. Bygbjerg, I. C., Knudsen, L., and Kieffer, M.: Failure of rifampin therapy to cure cutaneous leishmaniasis. Arch. Dermatol., 116:988, 1980. 21. Cobbold, R J. C., Morrison, G. D., and Willcox, R. R: Treatment of gonorrhea with single oral doses of rifampicin. Br. Med. J., 4:681-682,1968. 22. Cohn, H. D.: Clinical studies with a new rifamycin derivative. J. Clin. Pharm., 9:11~125, 1969. 23. Coufalik, E. D., Taylor-Robinson, D., and Csonka, G. W.: Treatment of non gonococcal urethritis with rifampicin as a means of defining the role of Ureaplasma urealyticum. Br. J. Vener. Dis., 55:36-43, 1979. 24. Council on Drugs, American Medical Association: Evaluation of a new antituberculus agent. J.A.M.A., 220:414-415, 1972. 25. Cross, F. S., Long, M. W., Banner, A. S., et a!.: Rifampin-isoniazid therapy of alcoholic and nonalcoholic tuberculous patients in a V.S. Public Health Service Cooperative Therapy Trial. Am. Rev. Respir. Dis., 122:349-353, 1980. 26. Deal, W. B., and Sanders, W. E., Jr.: Efficacy ofrifampin in treatment of meningococcal carriers. N. Engl. J. Med., 281:641-645, 1969. 27. Devine, L. F., Johnson, D. P., Hagerman, C. R., et al.: Rifampin levels in serum and saliva and effect on meningococcal carrier state. J.A.M.A., 214:1051>--1059, 1970. 28. di Mauro, D., Snyder, L., Marino, P., et al.: Rifampicin sensitivity of the components of DNAdependent RNA polymerase. Nature, 222:533--537, 1979. 29. Drew, T. M., Altman, R., Black, K, et a!.: Minocycline prophylaxis of infection with Neisseria meningitidis: High rate of side effects in recipients. J. Infect. 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