RIFAMPIN IN DERMATOLOGY

REVIEW

RIFAMPIN IN DERMATOLOGY \

NIKOLAI K. TSANKOV, M.D., PH.D., AND JIVKO A. KAMARASHEV, M.D.

Rifampin (Rp) was first introduced in medical practice in 1966^ and has since proven to be very effective against mycobacteria and gram-positive microorganisms. It belongs to the group of rifamycins, macrocyclic antibiotics containing a chromophobic naphthohydroquinone system, which is spanned by a long aliphatic bridge. The parent compound of the commonly used semisynthetic rifamycins is rifamycin B, which is produced by Streptomyces mediterranei through fermentation. Rp is the most widely used representative of the group, because of its satisfactory intestinal absorption. Peak plasma levels are achieved in 2 to 4 hours after application.^ Its tissue distribution and penetration are excellent, and it gets concentrated in the bile, by which it is mainly excreted.^

intracellulare are sensitive to the same concentrations of Rp as polymerases of sensitive species.^ Acquired resistance in certain bacteria is due to diminished affinity of the drug to RNA polymerase as a result of conformational changes in the enzyme or substitution of a single aminoacid in the P-subunit. Bacterial selection often is the cause of resistance. DRUG INTERACTIONS

Absorption of Rp in the gastrointestinal tract diminishes when it is applied together with aminosalicylic acid. A synergism exists between Rp and lincomycin and an antagonism between Rp and p-lactam antibiotics. Rifampin is a potent inducer of the hepatic microsomal system that causes clinically important interactions with other drugs. This phenomenon is observed when doses of around 10 mg/kg/day or more are applied and reaches its maximum in a period of 3 weeks. After discontinuation of Rp therapy, this phenomenon could persist for a period of 1 to 4 weeks. Rp can thus diminish the therapeutic effects of anticoagulants, p-blocking drugs, barbiturates, cimetidine, chloramphenicol, cortisone, cyclosporine, digitoxin, ketoconazole, oral contraceptives (when applied while the patient is on Rp therapy there is a risk of ineffective contraception, phenytoin, and verapamil.^ Toxicity may occur with the combination of Rp and isoniazid, especially when it is given together with barbiturates, which may occur in patients undergoing general anesthesia. Contraindications are hypersensitivity to Rp, hepatitis, hepatal insufficiency, porphyria, renal failure, and pregnancy and lactation.

Rifampin, like certain cephalosporins, contains an O-acetyl group, which is hydrolyzed by an esterase. By the third hour some 50% of the antibiotic in the bile is deacetylated, and by the sixth hour almost 100% is deacetylated. The activity of the deacetylated form against M. tuberculosis is similar to that of the parent compound, but its gastrointestinal absorption is poor."* This bioconversion, therefore, ensures the effective elimination of the antibiotic and prevents maintenance of high plasma levels, which could result in toxicity. Rifampin given in small doses exerts a bactericidal action on mycobacteria and gram-positive organisms. When applied in higher doses it is effective against certain gram-negative microorganisms, e.g., N. gonorrhoeae.^ The target of the antibiotic action of Rp is the DNA dependent RNA polymerase in the cytoplasm.** The medication forms a stable complex with the enzyme RNA dependent DNA polymerase, by interacting with its psubunit. Rp damages the ribosomes and thus inhibits protein synthesis. In mycobacteria it inhibits the incorporation of sulfate in lipids and that of sulfur in proteins. Resistance to Rp can be intrinsic or acquired. Some mycobacteria and gram-negative organisms are intrinsically resistant. They have low permeability to the antibiotic, which is proven by the fact that polymerases isolated from resistant £. coli, S. typhi murium, or M.

Methods of Application Rifampin is applied mainly per os but can also be administered parenterally or locally. The capsules are of 150 mg and of 300 mg. The standard dose is 8—12 mg/kg daily, usually 450-600 mg taken in the morning at once. INDICATIONS

From the Department of Dermatology and Venereology, Sofia Faculty of Medicine, Sofia, Bulgaria

Cutaneous Tuberculosis This is a primary indication for Rp therapy. Because of its solubility in lipids, Rp penetrates quickly into cells. It is markedly bactericidal to M. tuberculosis:, nevertheless, Rp is never used on its own, because of the risk of

Address for correspondence: Nikolai K. Tsankov, M.D., Ph.D., Department of Dermatology, Sofia Faculty of Medicine, 1, Georgi Sofiiski St., Sofia 1431, Bulgaria. 401

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Pyoderma

development of resistance as a one-step process. The three-drug regimens, very popular in the past, are now being reconsidered. Three antituberculous drug combinations were tested in 90 patients with cutaneous tuberculosis in India.' The patients were divided into three groups. The first two drug regimens included Rp, isoniazid, and either pyrazinamide or thiacetazone, and the third regimen consisted only of Rp and isoniazid. The clinical trial demonstrated that lupus vulgaris and tuberculosis cutis verrucosa were equally well managed by all three regimens, with the disease subsiding after 4 months of therapy in the localized forms and after 5 to 6 months in the more widespread forms. Patients with scrofuloderma responded similarly to two-drug and to three-drug regimens. The cutaneous lesions disappeared in 6 months, the lymph nodes regressed in 7 months in the localized and in 9 months in the widespread forms. In order to achieve the same results with the two-drug combination, all patients with disseminated scrofuloderma and one third of those with localized forms required 10 months of therapy. No relapses were observed in the patients who were followed-up for 3.5 years. This gives support to the idea that two drug regimens are as effective in cutaneous tuberculosis as threedrug ones. Lupus vulgaris is the sole form of cutaneous tuberculosis that can be managed with just one drug, isoniazid. There is always the possibility that there might be another focus of the infection in the visceral organs, for instance, so the combination of Rp and isoniazid should be preferred even in these cases. Papulonecrotic cutaneous tuberculosis requires a two-drug combination of isoniazid and 8 to 12 mg/kg Rp daily. The tuberculous lesions begin diminishing on the second month of therapy and disappear completely in 6 to 12 months, leaving atrophic and hyperpigmented cicatrices.

As Rp is bactericidal to gram-positive cocci, it could be used in the treatment of pyodermas. The availability of other effective agents against these bacteria, as well as the major role of Rp in antituberculous therapy, are factors that limit the use of Rp in pyodermas to only those caused by staphylococci resistant to other antibiotics.'^'" Cutaneous Leishmaniasis This disease responds well to Rp treatment. Joshi et al.'^ conducted a clinical trial in Saudi Arabia. A good response was achieved in 12 (80%) of the 15 patients treated with Rp for 2 to 12 weeks. Cutaneous leishmaniasis is a self-healing disease; however, Rp seems to be effective with the fewest side effects and warrants its place in the management of this disease. It is believed, that because it is lipid soluble, Rp easily penetrates the cell membrane and attacks intracellular pathogens. In spite of the encouraging results, further studies are needed to confirm the favorable response of dermal leishmaniasis to Rp. Rhinoscleroma Twenty-five patients with rhinoscleroma were treated with Rp."' Rp was administered per os to one group of 15 patients. The other group consisted of 10 patients treated locally with Rp in the form of ointment. Electron microscopic study of the pathologic changes in the lesions showed that Rp is effective, both systemically and locally in the treatment of rhinoscleroma. Pruritus Pruritus in primary biliary cirrhosis is common while not fully understood. The metabolic basis for this phenomenon has been the subject of a great deal of scientific research but has remained rather elusive. The traditional idea that itching correlates directly to the level of serum bile salts has been challenged.'^ According to this hypothesis, the high concentrations of bile salts accumulating in the liver during cholestasis have a direct damaging effect on the hepatocyte plasma membranes as a result of which a non-bile salt pruritogen is released. On the grounds of this hypothesis, Ghent'^ predicted that drugs which decreased the hepatocyte uptake of bile salts would relieve itching regardless of the serum bile salts level. They then went on to conduct a clinical experiment using Rp, which proved as much. Eight of the nine patients subjected to this randomized double-blind study reported reduced itching while being given Rp, and no significant placebo response was observed. The antipruritic effect of Rp became manifest after 4 to 5 days of treatment and persisted for about 1 week after its discontinuation.

Leprosy This is another important indication for Rp treatment. Rp is the only product bactericidal to M. leprae up to now. It kills 99.98% of the leprous bacteria in just a few days'" and quickly prevents the patient from spreading the disease. Twenty-five mg/kg daily Rp has the same effect as 100 mg daily dapsone administered for two months. In 15 to 30 days no leprous bacteria can be found. Its effect is much more rapid than that of dapsone. The usual dose is 600 mg daily—two capsules of 300 mg. Even minimal doses, though, have excellent effect, so that a single dose of 600 mg monthly can be applied." This, however, does not shorten the duration of therapy, and it has to be continued with dapsone'^ for two main reasons: Rp is relatively expensive and the lack of appropriate effect of Rp after 6 months of application.'-^ 402

Rifampin Tsankov and Kamarashev

In another recent study,"* 14 patients were treated with Rp. Eleven of them reported that itching disappeared completely, and three patients reported partial improvement. Six patients with a prior poor or no response to cholestyramine improved with Rp. After this short-term study, the same authors conducted a longterm open one. Rp was administered over a period of 8 months, and the relief of pruritus was maintained. It is considered that Rp not only inhibits bile acid uptake by hepatocytes but may contribute to detoxification of hepatic bile acids by stimulation of mixed-function oxidases in the liver." Tsankov and Krasteva^" observed a good therapeutic response in patients with severe forms of psoriasis after treatment with Rp. An interesting point in this study is the suppression of pruritus by Rp therapy, reported by them. The patients evaluated the gravity of their pruritus on a 10 point scale and were accordingly divided into three groups: no pruritus or mild pruritus (pruritus rating 1-4); moderate pruritus (pruritus rating 5-8); severe pruritus (pruritus rating 9-10) (Table 1). A similar mechanism to this in patients with biliary cirrhosis is hardly implicated in psoriasis. Nevertheless these results seem to justify further studies on the antipruritic effect of Rp.

Local Application Locally, Rp is indicated in the treatment and prevention of cutaneous infections (wounds, burns, eschars, impetigo, infected dermatoses, abscesses, fistulas), as well as in the treatment of postoperation wounds. Rp possesses great bactericidal power and reaches high local concentrations, at which it demonstrates a broad spectrum antibacterial activity. The high local concentration of the antibiotic permits it to remain active in the presence of necrotic material in the treated site and regardless of the local pH, without leading on the other hand to cytotoxicity. On the contrary, there is data that locally applied Rp stimulates the healing process.^^ The local application of Rp does not interfere with the systemic use of this and other similar antibiotics. Rp is apphed on the skin in the form of 5% solution. In the field of ophthalmology, Rp is used in the form of 1% solution. The eye-drops and the ophthalmic unguent are characterized by bactericidal activity in regard to a great number of gram-positive and gram-negative bacterial species. Cross-resistance has not been reported. Rp is indicated in the treatment of eye infections caused by microorganisms sensitive to it: acute, subacute, or chronic bacterial conjunctivitis, infectious blepharitis, dacryocystitis. Rifampin could be applied locally on the serous membranes, in cases of peritonitis, pleuritis, as well as on the mucous membranes. It could be administered with caution into the dura mater and into the joints.

Psoriasis In 1982 Rosenberg et al.^' suggested that psoriasis is a generalized inflammatory disorder initiated by yeast, gram-negative, or streptococcal induced activation of the alternative complement pathway. Antibiotic therapy including penicillin-Rp and erythromycin-Rp combinations has been applied successfully in patients with streptococcal-associated psoriasis.^^ Tsankov and Krasteva-*^ report on a series of 10 patients with severe forms of psoriasis (psoriatic erythroderma, pustular psoriasis, psoriatic arthritis), most of whom responded well to monotherapy with Rp. An interesting point is that not all patients who experienced benefit from Rp therapy had clinical or microbiologic evidence of streptococcal carriage. According to the authors, Rp treatment could be considered in the severe forms of psoriasis, when contraindications to other systemic therapeutic methods exist. A probable explanation of the favorable response of patients with psoriasis to Rp could be found in the fact that the latter suppresses humoral, as well as cellular immunity.^^"^^ Eurther studies will shed light on the mechanism of action of Rp in psoriasis.

SIDE EEEECTS

Rifampin is considered to be an antibiotic seldom producing untoward effects. Various side effects relating to different organs have been reported over the years of its application. Cutaneous This is the group of the most commonly encountered side effects of Rp.^*' Eive percent of the patients submitted to Rp treatment develop skin eruptions, which are usually mild and transitory. Elushing of the face and neck, itching, or eruptions are usually observed. Acute exudative conjunctivitis as well as Stevens-Johnson syndrome have also been observed.•^''^'' The appearance of skin vasculitis after therapy with Rp has recently been reported." This idiosyncratic reaction developed on reintroduction of Rp after it had been stopped for 4 weeks, and disappeared after the antibiotic was discontinued. The two-drug regimen of isoniazid and streptomycin, which was later used, did not lead to recurrence of the vasculitis. Occasional cases of allergic shock have been reported.^^ Drug-induced pemphigus may resuh from Rp therapy."""" The eruption appears after a considerable peri-

Tahle 1. Pruritus Rating on the 10 Point Scale Pruritus Rating (mean ± SD) At Admission

At Discharge

6 + 2.75

1.8±1.14 P< 0.001

Complete suppression of itch in 6 parients. 403

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Hepatotoxicity

od of continuous Rp administration (8 to 10 months). Direct immunofluorescence studies were conducted in one case and demonstrated depositions of IgC and complement in intercellular areas of the epidermis. Circulating antibodies to intercellular substance were also present. The course of the disease is benign, and the lesions disappear soon after the discontinuation of Rp. Ogawa et al.-*^ established the existence of many SH-free residual proteins on the membrane or in the intercellular areas and suggested that the free SHgroups in the antigenic sites of the membrane might be essential for their ability to bind the possible pemphigus antibodies. According to Lee et al.,^'' it is possible that Rp may bind the SH-groups of the epidermis in vivo and modify the structure of the antigenic sites thus being able to produce the antibody, especially in individuals with an underlying immunologic susceptibility to it.

This is one of the earliest reported complications of Rp therapy. Hepatic impairment most commonly occurs during the first 5 weeks of Rp administration.''^ Liver biopsy specimens usually point to hepatitis, which in the greatest part of cases is mild.''^ It is now believed that the fulminate forms, which are rarely observed, are due to drug combinations of Rp with isoniazid and aminosalicylic acid, which have demonstrated a pronounced hepatotoxicity. One study has indicated a substantial incidence of hepatitis virus infections in children who developed acute hepatotoxic reactions in the course of antituberculous therapy with Rp and isoniazid.''^ Hepatitis A virus (HAV) was confirmed by IgM antibodies in 7.5%, and hepatitis B virus (HBV) in 35% of all patients. Non-A non-B infection was suspected in at least some of the other children. The study gives serious basis for contemplating the role of hepatitis-virus infection as a risk factor for the development of acute hepatotoxic reactions during antituberculous therapy and explains the greater incidence of such reactions in the developing countries. The risk for alcoholics to develop a drug-induced hepatitis while undergoing antituberculous therapy does not exceed the risk for nonalcoholics and encouraged the completion of standard therapy for such patients.'"* It has been reported that liver protection is provided in mice by tocopherol acetate (an antioxidant) and piracetam, riboxin, and pyriditol (antihypoxic agents) when the liver is affected by antituberculous drugs.'"

Antibodies to Rifampin Circulating antibodies to Rp were first discovered in sera of patients with thrombocytopenia and/or flu-like syndrome.^^ IgG and IgM have been established.^^ Acute hemolytic anemia and acute renal failure with circulating antibodies to Rp as a result of long-term therapy have been reported.""^ Bassi et al.'" have demonstrated human IgE antibodies to Rp by means of histamine release from passively sensitized peritoneal mast cells. They were obtained from patients showing side effects to Rp therapy. The clinical presentation of Rp antibodies may be that of flu-like syndrome, thrombocytopenia, hemolytic anemia, or renal failure. The risk of "immunization" is greater when higher doses are applied (1200 mg/ daily), or when the antibiotic is given intermittently, once or twice.''^ In all of these cases, discontinuation of the drug is obligatory, despite the fact that as far as the flu-like syndrome is concerned, a more appropriate dosage might prove to be sufficient to solve the problem."*^ The prevention of these immunoallergic reactions requires strict abidance by the recommended doses and way of administration.

Renal The most common renal complications of Rp therapy are acute interstitial nephritis and acute tubular necrosis, but cases of hemoglobinuria due to hemolysis, renal cortical necrosis, and proliferative glomerulonephritis have also been reported. Acute renal failure and interstitial nephritis, as well as the flu-like syndrome, which they found associated in all their patients, are characteristic side effects of intermittent rather than continuous Rp treatment.^"

Gastrointestinal Nausea and mild abdominal pain are common in patients undergoing Rp treatment. Occasionally, vomiting and diarrhea are observed. Like most other antibiotics, Rp has been incriminated in the etiology of pseudomembanous colitis. Miller et al.'''' report impairment of the small intestines, which in the case reported by them was complicated by jejunal perforation. Small intestine impairment might prove to be more common than it is thought, because of the imperfection of the diagnostic methods available.

Cardiovascular Deep venous thrombosis can occur in 3.4% of all patients with tuberculosis treated with regimens including Rp." A retrospective study of a large number of patients showed a relative risk for patients who received Rp in comparison with those who did not. This complication is more common in the winter months and usually appears during the first 2 weeks of therapy. 404

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Hematologic

5. 6.

Thrombocytopenia, though rare, is a serious side effect of Rp. It is more common when Rp is administered intermittently, especially in patients with leprosy, who receive large doses monthly.-'^

7.

8.

Pulmonary Recently, a case of a man who developed pulmonary fibrosis while undergoing antituberculous treatment was reported.^^ Fvolution of the disease was prevented by withdrawal of therapy. It did not progress after reintroduction of isoniazid and etambutol.

9.

10.

Brown SG. Mycobacterial diseases: leprosy. In: Fitzpatrick TB, Eisen AZ, Wolff K, et al., eds. Dermatology in general medicine. New York: McGraw-Hill, 1987: 2180.

11.

Baker H. Antileprotics. In: Rook A, Wilkinson DS, Ebling FJG, eds. Textbook of dermatology. 3rd Ed. Oxford: Blackwell, 1979:2275. Aron-Brunetiere R. Guide de therapeutique dermatologique. Paris: Masson, 1982. Bonafe JL. Antibiotiques en pathologie cutanee. Rev Med Toulouse 1983; 19:29-37. Arndt KA. Manual of dermatologic therapeutics. Boston: Little Brown, 1991. Joshi RK, Nambiar PMK. Dermal leishmaniasis and rifampicin. Int J Dermatol 1989; 28:612-614. Gamea AM, El-Tatawi FA. The effect of rifampicin on rhinoscleroma: an electron microscopic study. J Laryngol Otol 1990; 104:772-777. Ghent CN. Pruritus of cholestasis is related to effects of bile salts on the liver, not the skin. Am J Gastroenterol 1987; 82:117-118. Podesta A, Lopez P, Terg R, et al. Treatment of pruritus of primary biliary cirrhosis with rifampin. Dig Dis Sci 1991; 36:216-220.

Immunologic Rifampin suppresses humoral, as well as cellular immune responses.-^^"^^ This fact is proved by many studies, but so far no clinical equivalent of this phenomenon has been observed. Calal et al.^^ discuss the possibility that Rp might impair heavy-chain synthesis, which could also explain the light-chain proteinuria.

12. 13. 14.

Ocular Toxicity 15. Some cases of ocular toxicity due to Rp have been reported. 54

16.

17.

CONCLUSIONS

Rifampin is an antimicrobial agent, whose application is limited mainly to mycobacterial infections (tuberculosis and leprosy), the modern treatment of which is impossible to imagine without it. The satisfactory results it produces in the treatment of staphylococcal infections render it useful in pyodermas. The observations of positive therapeutic response of leishmaniasis, rhinoscleroma, and psoriasis need further confirmation in larger number of patients. The reports of its antipruritic effect in biliary cirrhosis and other hepatic disorders also arouse great interest. They require more detailed study, as does its antipruritic effect in skin diseases.

18.

19. 20. 21. 22.

23.

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Kaposi's Sarcoma In its classic, "European" or chronic form, KS is an uncommon neoplasm that usually affects persons older than 50 years of age with a distinct male predominance. A racial predisposition is recorded, with an increased incidence in Ashkenazic Jews and individuals of Mediterranean descent. A significant percentage of these elderly patients, up to one third in some reports, are at risk for a subsequent second primary neoplasm, often of hematopoietic origin. Cutaneous lesions typically evolve in stages, evidenced as violaceous patches, plaques, and nodules on the distal lower extremities. The initial involvement may be unilateral or bilateral. The lesions gradually coalesce, spread proximally, and may in time, ulcerate. Upper extremity lesions may develop with time, or occasionally, may be the site of presentation. The clinical course is usually indolent. Some lesions may regress while others progress and, in a single patient, clinical lesions of varying stage are typical. In equatorial Africa, in contrast to Europe, KS is a common neoplasm, accounting for 9% of malignant tumors in Ugandan males and up to 10% of registered cancers in other areas. There is an overwhelming male predominance. The disease affects a younger population than the classic European variant, with the difference averaging a decade in most reports and also presenting in children. From Chor PJ, Santa Cruz DJ. Kaposi's sarcoma. J Cutan Pathol 1992; 19:6-20. 406