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Drugs used in tuberculosis and leprosy
C.J. Ellis
31
Drugs used in tuberculosis and leprosy
DRUGS USED IN TUBERCULOSIS (SED-
11, 633; SEDA-12, 255) Introduction Even in a field where most of the drugs are as familar as they are where tuberculosis is concerned, the literature continues to throw new light on risks in particular situations, including the use of new combinations of drugs, exposure of particular populations and the treatment of particularly susceptible patients. Papers within the recent past have included an overview of the risks in a Japanese population (1 R) and new evidence of risks in populations with a high incidence of hemoglobin E trait (discussed below). In 1976 standard antituberculous therapy consisted of daily treatment with rifampicin and isoniazid for 9 months supplemented by ethambutol or streptomycin during the first two. By 1984 it was clear that the total duration could be reduced to 6 months if, in addition, pyrazinamide were added for the first two (2). The trend is now towards a 3-drug regime once again but with pyrazinamide instead of ethambutol or streptomycin in the first phase. Increasing clinical experience makes it likely that this will soon be regarded as standard therapy, and one trial, carried out in Singapore, has formally demonstrated its efficacy (3). All 3 drugs have been in use for many years and it is unlikely that clear causal relationships have yet to be demonstrated between this combination and significant side effects, except, possibly, in patients with AIDS. On the other hand, communities in which HIV infection is prevalent are certain to see an increase in the incidence of human tuberculosis, not only in patients with AIDS, but
9 1989 Elsevier Science Publishers B.V. (Biomedical Division)
Side Effects of Drugs Annual 13 M.N.G. Dukes and L, Beeley, editors
probably also in individuals who are otherwise asymptomatic HIV carriers. The frequency of allergic drug reactions in AIDS patients may make therapy in this group both difficult and inefficient. Thus the present consensus that sensitive M. tuberculosis infection should be treated with 6 months of rifampicin and isoniazid with pyrazinamide given for the first 2 months will, like any other antimicrobial regime, need to be kept under constant review and may have to be susperseded by different regimes with which specialists will have to become familiar if serious toxic effects are to be avoided. The fact is that unwanted effects of antituberculous therapy are frequent but are seldom serious because they are spotted early. Emphatically, tuberculosis and leprosy should only be treated by physicians who are using antimycobacterial drugs regularly. Adverse effects in the treatment of tuberculous meningitis The rifampicin, isoniazid and pyrazinamide regime, is, at the moment, probably the best for tuberculous meningitis also. It was used in conventional dosage (together with streptomycin which penetrates the CSF poorly) in 28 adult patients in Thailand (4e). Only 2 patients died, both of whom were comatose at the start of treatment. One patient developed erythema multiforme necessitating cessation of pyrazinamide. Six patients showed the common, benign elevation of liver enzymes during early weeks of treatment, but in all this subsided without alteration of medication. The commonest adverse effect recorded was asymptomatic hyperuricemia noted in half the patients. This settled after the end of the first 2 months during which pyrazinamide was given. A series of 33 young children (median age 25 months) with tuberculous meningitis were reported from South Africa (5c) in whom the 3 'standard' drugs were used in comparatively
260 high dosage (INH 20 m g / k g / d , rifampicin 20 m g / k g / d , pyrazinamide 40 mg/kg/d). Ethionamide 0 5 m g / k d / d ) was also given. Liver enzymes were monitored at least fortnightly for the first 12 weeks and the typical elevation was seen during the first 8 weeks, higher levels being noted in patients with more advanced disease. Jaundice did not develop, except in one child with hepatitis A, and in all children the enzyme levels were falling or were normal at the end of this period.
Hepatotoxicity and multidrug therapy Even among those physicians who regularly prescribe antituberculosis drugs the risk of hepatic reactions appears to be insufficiently appreciated. In 1988 the Federal German Health authorities found it necessary to impose a specific warning to the effect that a combination product containing isoniazid, prothionamide and dapsone, indicated for the treatment of mycobacterial lesions, should bear the warning that hepatic disturbances, occasionally life-threatening, could occur. Monitoring of liver function was recommended at least monthly, and it was advised that treatment be discontinued if clinical or biochemical evidence of dysfunction were detected (6r). The official steps in the Federal Republic appear to have followed some reports of extremely severe hepatic effects, including one of hepatic necrosis, where the hepatotoxicity of prothionamide may have been potentiated by oral contraception (7c). Almost simultaneously with it, other German workers produced further evidence of the particular risk of liver damage in patients with a history of alcohol-induced liver changes
(8CR).
Very exceptionally, fulminant hepatitis develops despite careful monitoring with withdrawal of antituberculous therapy at the first sign of progressive liver damage. A 10-yearold girl developed fulminant hepatitis while being treated with rifampicin, pyrazinamide and ethambutol (9c). Initial therapy with rifampicin, isoniazid and ethambutol was stopped after 2 weeks because of 'gastrointestinal tract disturbances' and elevated liver enzymes. Bilirubin levels were not reported although they are believed to be a useful pointer to potentially progressive hepatitis. Tile girl recovered within 2 weeks and therapy was then recommenced using pyrazinamide in-
Chapter 31
C.J. Ellis
stead of isoniazid. Six weeks later she developed fever, dermatitis and hepatitis. Drug treatment was stopped within a few days, but the hepatitis progressed and she died 12 days after the start of the terminal illness. There was no evidence of coincident viral infection and a skin biopsy showed allergic vasculitis. The authors caution against adding any drug known to be hepatotoxic, even idiosyncratically, to the drug regime of a patient in whom hepatoxicity has occurred. The inexorably fulminating course after the start of the second course strongly suggests sensitization by the first.
Identification of causal drugs in multiple therapy As pointed out below when discussing a case relating to pyrazinamide, it is not always easy (and sometimes quite impossible) to determine which of a series of a drugs in a antituberculous regimen has caused a particular reaction; the fact that some of these drugs have side effects in common and that one may consider it irresponsible to follow a normal withdrawal-and-rechallenge technique leave some mysteries unsolved, as in a recent report of erythema elevatum diutinum in a patient on multidrug therapy (rifampicin, pyrazinamide, isoniazid and streptomycin); the patient reacted well to treatment with dapsone 50 mg daily but died before rechallenge could be performed (10c). Ethambutol (SED-11, 639; SEDA-12, 256) Special senses After very many years, the scope and severity of the eye disorders induced by ethambutol remain a recurrent topic, though serious damage is not likely if dosage is properly chosen. Campbell and Ormerod, relying primarily on British (and English language) evidence, traced 4 cases of ethambutol-induced blindness over a period of 24 years of intensive use (11 R) though some supplementary evidence may have been missed (12r). Meyler's Side Effects of Drugs (SEDI l, 640) currently adheres to the conclusion at a 15 mg/kg daily dose levels ocular toxicity will develop only in 1.6~ of cases but stresses the dose-dependence of the risk. The most important step is to identify and employ the right monitoring methods to detect early changes in ocular function, e.g. involving the use of Stil-
Drugs used in tuberculosis and leprosy Chapter 31
261
l i n g - Verhage's '65' plates for testing color vision (SEDA-12, 256), and perhaps newer methods such as the pattern electroretinogram and visual-evoked cortical potential (13 C, 14c). In spite of the fact that the problem is known, permanent damage to vision is still being reported, a further tragic case from Canada almost co-inciding with Campbell and Ormerod's review.
pyrazinamide pyrexia has been reported but not quantified (SED-11, 641). Even prednisone can cause fever on withdrawal, and high doses of atropine can have the same effect. In this particular case, rifampicin and then pyrazinamide were withdrawn; removal of the latter resulted in rapid termination of the fever. Rechallenge was not attempted because of the potential risk.
Isoniazid (SED-11, 634; SEDA-12, 257)
Thromboeytopenia Effects on the platelet
A single case-report from Australia brings to 6 the number of cases of pure red cell hypoplasia attributed to isoniazid (16c). Recovery after cessation of therapy is remarkably rapid, regeneration being evident in bone marrow aspirate after only 4 days in this case. The mechanism is unknown. The wide availability of isoniazid in many parts of the world and its isoniazid has led to repeated reports of overdosage, resulting either from attempted suicides or accidents (17c); one such report relates to no less than 6 attempted suicides in South-East Asian refugee women, with metabolic acidosis and seizures as prominent features (18c); one aspect of overdosage may be rhabdomyolysis, as suggested by 5 new reports, which could explain the prominence of renal failure (19c). The recent literature, however, in general confirms the well-established picture defined by Ellenhorn and Barceloux in a companion volume to this series (20 R) and the success of the therapeutic approaches to isoniazid poisoning presented by these same authors.
Pyrazinamide (SED-11, 641) Drug fever The attribution of adverse effects to a particular drug can be difficult during multiple drug therapy. In a thoughtful paper from 1986 not previously discussed in these volumes, Van Dijke and Mudde describe how, in a patient with tuberculous choroidoretinitis who was receiving prednisone, isoniazid, rifampicin, pyrazinamide and topical dexamethasone and atropine, marked fever developed (21r Of the antituberculous drugs which were being given, all are known to be capable of producing drug fever; the incidence for rifampicin has been cited as 0.5% (22r), that for isoniazid as 0.3% (23r) while with
count do not seem to have been documented prior to the publication in 1988 of a paper by Jain et al. describing severe thrombocytopenia and bleeding in a man of 27 who was taking pyrazinamide as part of a multidrug scheme of treatment which had twice been changed, pyrazinamide having been interrupted for a time. Ten days after it was restarted, clinical evidence of thrombocytopenia appeared. It receded after all drugs were withdrawn, remained absent when isoniazid and ethambutol were restarted but reappeared in severe form when pyrazinamide was given again for only 3 days. The cause - effect relationship here must be considered entirely clear (15c).
Rifampiein (SED-II, 637; SEDA-12, 258) Rifampicin has long been known to be a potent inducer of liver microsomal enzymes resulting in acceleration of its own deacetylation over the first 6 days of treatment. The enzyme induction can lead to important interactions and also have other consequences. The catabolism of corticosteroids, estrogens, warfarin and digoxin may all be increased during the initial stages of rifampicin therapy with clinically significant consequences. Incipient adrenal insufficiency may be unmasked. Recent case-reports on this topic include one from Spain (24C) and a particularly worrying case in which the complication appears to have occurred in a patient already suffering from AIDS (25c). Rejection of a kidney transplant started 7 weeks after initiation of rifampicin (26c). The ability of rifampicin to undermine essential corticosteroid therapy has certainly often been underestimated. Some recent reports describe how the drug led to an exacerbation of prednisone-treated dermatomyositis in 2 patients (27 C) and of prednisolone-treated pemphigus in another (28c); interpreting such
Chapter 31 C.J. Ellis
262 reports, however, one has to recall the fact that rifampicin itself can induce a series of dermatological complications, pemphigus for example being one of them (SED-11,638). More recently, the plasma level of orally-administered verapamil has been shown to be reduced in patients receiving rifampicin (29c). When verapamil was given intravenously there was no change in plasma levels. Yet other recent reports show rifampicin significantly reducing the serum levels of the antibiotic chloramphenicol in 2 children being treated for acute infections (30c), probably undermining the control of blood pressure with enalapril in an adult (31c), rendering ineffective the treatment of a Blastomyces dermatidis infection with ketoconazole (32c), paradoxically raising the serum of levels of phenytoin in a very old man (33c), delaying elimination of theophylline (though in a man also receiving isoniazid) (34c) and increasing plasma concentrations of warfarin (again in the presence of isoniazid) (35c). The only general rule which a physician can bear in mind is that rifampicin can interfere with the metabolism or elimination of a great many drugs, that not all these interactions are yet known, and that they can sometimes go in unexpected ways, especially where several antituberculous drugs are being given. Whenever
rifampicin is to be used alongside any other essential form o f therapy, careful monitoring for interactions is essential. Respiratory
The only respiratory problem sometimes associated with rifampicin is the 'flu-like' syndrome described in various cases (SED-I l, 31), but it is not impossible that the drug was responsible for a case of pulmonary fibrosis described in 1988. The patient was a man of 79 who received rifampicin, isoniazid and ethambutol to good effect, but developed fever and dyspnea after 3 months of treatment. The findings on lung biopsy and with other methods were consistent with bilateral pulmonary fibrosis. The drugs were discontinued and prednisolone administered. Later he was treated with isoniazid and ethambutol alone without problems, suggesting that rifampicin had been the causal agent (36c).
Skin and appendages
The ability of rifampicin to produce a range of dermatological
complications (SED-11,638) has been recalled above in dealing with the corticosteroid interaction. Pruritus, rashes, urticaria, acne, porphyria cutanea tarda, and various forms of pemphigus have all been reported. Fairly recent literature adds to the known range a case of exfoliative dermatitis in an elderly man. It arose shortly after starting treatment and when the drug was withdrawn after 6 months the condition improved considerably within 2 months; there was no rechallenge (37c). Rifampicin appeared t o precipitate toxic epidermal necrolysis in a 20-year-old woman who had been on corticosteroid therapy for systemic lupus erythematosus (SLE) for 6 years when she was commenced on rifampicin, isoniazid and ethambutol for suspected tuberculosis (38c). Her physicians considered the reaction to be unconnected with her SLE and it subsided promptly when rifampicin was stopped.
DRUGS USED tN LEPROSY (SED-I1,
643; SEDA-12, 258) Introduction Multiple drug therapy has been standard for all classes of leprosy since the WHO formulated protocols using rifampicin, dapsone and clofazimine in 1982. Paucibacillary (tuberculoid) disease, (patients with few skin lesions but with a liability to mononeuritis multiplex as a result of delayed-type hypersensitivity to antigen in peripheral nerves) is treated with dapsone and rifampicin for 6 - 12 months while bacilliferous patients (i.e. those with the multiple skin lesions of lepromatous leprosy) receive all 3 drugs until they have become skin-smear negative. It should be noted that the high cost of rifampicin may be prohibitive in countries where leprosy is endemic, but it remains an effective component of multiple drug regimens even if given as a single dose once a month. Intermittent rifampicin therapy has been associated with the "flu" syndrome which consists of headache, malaise and bone pain starting 1 - 2 hours after a dose and a subsiding within 12 hours. Many affected patients develop circulating antibodies to rifampicin. The phenomenon was seen most frequently in patients receiving higher doses (1200 mg or more) once a week in trials in patients with tuberculosis conducted in Hong
Drugs used in tuberculosis and leprosy Chapter 31 Kong and Singapore. Curiously, it is very rare in patients receiving a similar dosage for leprosy. Possibly there is a racial, i.e. genetic, element.
Clofazimine (SED-11, 645; SEDA-12, 258) An extensive review of clofazimine side effects in 514 leprosy patients concludes that the drug is very safe in usual doses (100 mg/d) (39c). Reddish-brown pigmentation of skin was usual (and is well-known) while the potentially more dangerous gastrointestinal side effects occurred in only 4o7o of patients (i.e. 20). In this group jejunal biopsies were normal although clofazimine crystals were seen in the lamina propria of one. A review of the literature suggests that significant diarrhea, weight loss and/or abdominal pain is only likely to occur in patients receiving higher doses for several months or years and would therefore not be expected in patients treated according to the current WHO protocols who would only receive higher doses if they were to develop erythema nodosum leprosum.
Dapsone (SED-11, 644; SEDA-12, 258) Hemolytic anemia is the most common problem with dapsone, occurring in virtually every patient on full doses, e.g. 2 0 0 - 3 0 0 mg/d (SED-11,345). It can however occur at much lower doses in susceptible patients. Lachant and Tanaka have described a Cambodian woman of 28 with a 4-year history of leprosy, treated for the last l0 months with 50 mg/d dapsone as well as with rifampicin and clofazimine. During the 9th month of treatment she developed severe hemolytic anemia (hemoglobin 7.1 g/dl, erythrocytes 2.92 x 1012/1). The peripheral blood showed microcytosis and rare target cells. Heinz bodies were seen and she proved to have a hemoglobin E trait. This is relatively common in the Cambodian population. The drugs were discontinued and she recovered (40C). The conclusion could well be that individuals with hemoglobin E trait are at greater risk of developing a Heinz body hemolytic anemia when they are exposed to oxidant
263 medications, the risk perhaps being even higher where there is an underlying infection. This is a matter of real importance since dapsone is likely to be used in some populations where hemoglobin E trait is relatively common.
Dapsone syndrome The 'dapsone syndrome' is one name for a condition which may be provoked by the drug (SED-11,644), particularly in malnourished patients and has been regarded as a form of exacerbation of lepromatous leprosy; it resembles mononucleosis, and as a rule occurs on full-dose therapy. In most of these respects a case presented by Grayson and others in 1988 is therefore unusual, since the syndrome occurred in an Australian woman in good physical condition who was taking onceweekly doses of 100 mg dapsone (with chloroquine and pyrimethamine) for malaria prophylaxis when visiting the tropics. After 4 weeks of prophylaxis she developed pyrexia with joint and muscle pain, rash, and then lymphadenopathy and tonsillitis. Severe atypical lymphocytosis was found, but the condition was not infectious mononucleosis, the Paul-Bunnell test being negative. Returning to Australia she was successfully treated, and on a subsequent visit to the tropics tolerated chloroquine given alone for prophylactic purposes (41c). Hypersensitivity Various forms of skin condition have in the past been assumed to represent the main hypersensitivity reactions to dapsone (SED-11, 644) though some workers have the impression that the problem of dapsone hypersensitivity has either been underestimated or is genuinely increasing because of the widespread use of the drug, e.g. in low doses for malaria prophylaxis (42R). In this connection an unusual case of photosensitivity may be noted (43 C) in which an allergic dermatitis with photosensitivity (conjunctivitis with exfoliation on exposed areas of the skin) seems to have been admixed with an erythema nodosum leprosum.
ACKNOWLEDGEMENT I acknowledge the help of Dr. J.A. Innes in the preparation of this chapter.
264
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REFERENCES 1. Yamanaka M, Kobayashi T, Sakurai H (1988) Review on side-effects of anti-tuberculosis drugs. Kekkaku, 63, 11. 2. British Thoracic Society (1984) A controlled trial of 6 months chemotherapy in pulmonary tuberculosis. Br. J. Dis. Chest, 78, 330. 3. Singapore Tuberculosis Service/British MRC (1988) Clinical trial of three 6-month regimens of chemotherapy given intermittently in the continuation phase in the treatment of pulmonary tuberculosis. Am. Rev. Respir. Dis., 137, 1147. 4. Phuapradit P, Vejjajiva A (1987) Treatment of tuberculous meningitis: role of short-course chemotherapy. Q. J. Med., 239, 249. 5. Donald PR, Schoeman JF, O'Kennedy A (1987) Hepatic toxicity during chemotherapy for severe tuberculous meningitis. Am. J. Dis. Child., 141, 741. 6. Anonymous (1988) Isoniazid/protionamide/ dapsone: hepatic toxicity. WHO Drug Inform., 2(3), 142. 7. Musch E, Lelbach WK, Stiens R (1987) Fulminantes Leberversagen unter tuberkulostatischer Therapie: ein Beitrag zur Klinik und Pharmakokinetik. Z. Gastroenterol., 25, 756. 8. Gellert J, Pfannkuch B, Teschke R (1988) Liver damage in combination therapy with antitubercular agents in patients with high and low alcohol consumption (in German). Atemwegs- u. Lungenkrankh., 13, 249. 9. Van Aalderen WMC, Knoester H, Knol K (1987) Fulminant hepatitis during treatment with rifampicin, pyrazinamide and ethambutol. Eur. J. Pediatr., 146, 290. 10. Mohamed KN (1988) Int. J. Dermatol., 27, 277. 11. Campbell IA, Ormerod LP (1988) Ethambutol and the eye. Lancet, 2, 113. 12. Kahana LM (1988) Ethambutol and the eye. Lancet, 2, 627. 13. Kakisu Y, Adachi-Usami E, Mizota A (1988) Pattern electroretinogram and visual evoked cortical potential in ethambutol optic neuropathy. Doc. OphthalmoL, 67, 327. 14. Petrera JE, Fledelius HC, Trojaborg W (1988) Serial pattern evoked potential recording in a case of toxic optic neuropathy due to ethambutol. Electroencephalogr. Clin. Neurophysiol., 71, 146. 15. Jain VK, Vardhan H, Prakash OM (1988) Pyrazinamide induced thrombocytopenia. Tubercle, 69, 217. 16. Lewis CR, Manoharan A (1987) Pure red cell hypoplasia secondary to isoniazid. Postgrad Med., J., 63, 309. 17. Orlowski JP, Paganini EP, Pippenger CE (1988) Treatment of a potentially lethal dose iso-
niazid ingestion. Ann. Emerg. Med., 17, 73. 18. Nolan CM, Elarth AM, Barr HW (1988) Intentional isoniazid overdosage in young Southeast Asian women. Chest, 93, 803. 19. Tamayo JG, Guzman RR (1987) Acute renal filure in isoniazid poisoning: is it due to rhabdomyolysis? Philipp. J. Intern. Med., 25, 287. 20. Ellenhorn M J, Barceloux DG (1988) Medical Toxicology, p. 366. Elsevier, Amsterdam. 21. Van Dijke CPH, Mudde AH (1986) Koorts door een geneesmiddel? Ned. Tijdschr. Geneeskd., 130, 1873. 22. Girling DJ (1977) Adverse reactions to rifampicin in antituberculosis regimens. J. Antimicrob. Chemother., 3, 115. 23. Van der Meer JWM, Haak A (1974) Koorts door INH. Ned. Tijdschr. Geneeskd., 118, 1945. 24. San Jos6 A, Simo R, Cierco P e t al (1988) An attack of suprarenal insufficiency after treatment with rifampicin (in Spanish). Med. Clln., 89, 397. 25. Ediger SK, Isley WL (1988) Rifampicin-induced adrenal insufficiency in the acquired immunodeficiency syndrome: difficulties in diagnosis and treatment. Postgrad. Med. J., 64, 405. 26. Pallardo L, Moreno R, Garcia Martinez J e t al (1987) Rechado agudo tardio del injerto renal inducido por rifampicina. Nefrologia 7, 93. 27. Camus JP, Koeger AC, Nahoul K et al (1987) Ann. Mdd. Interne, 138, 524. 28. Honeybourne D, Longworth S, Shaffer J (1987) Rifampicin causing an exacerbation of pemphigus. Br. J. Clin. Pract., 412, 937. 29. Mooy J, Bohm R, Van Baak Met al (1987) The influence of antituberculous drugs on the plasma level of verapamil. Eur. J. Clin. PharmacoL, 32, 107. 30. Kelly WH, Couch RC, Davis RL et al (1988) J. Pediatr., 12, 817. 31. Kandiah D, Penny WJ, Fraser AG et al (1988) A possible drug interaction between rifampicin and enalapril. Eur. J. Clin. PharmacoL, 35, 431. 32. Abadie-Kemmerly S, Pankey GA, Dalvisio JR (1988) Failure of ketoconazole treatment of Blastomyces dermatidis due to interaction of isoniazid and rifampicin. Ann. Intern. Med., 109, 844. 33. Abajo FJ (1988) Phenytoin interaction with rifampicin. Br. Med. J., 297, 1048. 34. Dal Negro R, Turco P, Trevisan F et al (1988) Rifampicin-isoniazid and delayed elimination of theophylline: a case report. Int. J. Clin. Pharmacol. Res., 8, 275. 35. Almog S, Martinowitz U, Halkin H et al (1988) Complex interaction of rifampicin and warfarin. Southern Med. J., 81, 1304. 36. Umeki S (1988) Rifampicin and pulmonary fibrosis. Arch. Intern. Med., 148, 1663.
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37. Goldin HM, Schweitzer W J, Bronson DM (1987) Ann. Int. Med., 107, 769. 38. Okano M, Kitano Y, Igarashi T (1987) Toxic epidermal necrolysis due to rifampicin. J. Am. Acad. DermatoL, 17, 303. 39. Kumar B, Kaur S, Kaur 1 (1987) More about clofazimine - 3 years experience and review of literature. Indian J. Lepr., 59, 63. 40. Lachant NA, Tanaka KR (1987) Case report: dapsone-associated Heinz body hemolytic anemia
265 in a Cambodian woman with hemoglobin E trait. Am. J. Med. Sci., 294, 364. 41. Grayson ML, Yung AP, Doherty RR (1988) Severe dapsone syndrome due to weekly Maloprim. Lancet, 1, 531. 42. Smith WCS (1988) Are hypersensitivity reactions to dapsone becoming more frequent? Leprosy Rev., 59, 53. 43. Joseph MS (1987) Photodermatitis provoked by dapsone: a case report. Leprosy Rev., 58, 425.
31
Drugs used in tuberculosis and leprosy
DRUGS USED IN TUBERCULOSIS (SED-
11, 633; SEDA-12, 255) Introduction Even in a field where most of the drugs are as familar as they are where tuberculosis is concerned, the literature continues to throw new light on risks in particular situations, including the use of new combinations of drugs, exposure of particular populations and the treatment of particularly susceptible patients. Papers within the recent past have included an overview of the risks in a Japanese population (1 R) and new evidence of risks in populations with a high incidence of hemoglobin E trait (discussed below). In 1976 standard antituberculous therapy consisted of daily treatment with rifampicin and isoniazid for 9 months supplemented by ethambutol or streptomycin during the first two. By 1984 it was clear that the total duration could be reduced to 6 months if, in addition, pyrazinamide were added for the first two (2). The trend is now towards a 3-drug regime once again but with pyrazinamide instead of ethambutol or streptomycin in the first phase. Increasing clinical experience makes it likely that this will soon be regarded as standard therapy, and one trial, carried out in Singapore, has formally demonstrated its efficacy (3). All 3 drugs have been in use for many years and it is unlikely that clear causal relationships have yet to be demonstrated between this combination and significant side effects, except, possibly, in patients with AIDS. On the other hand, communities in which HIV infection is prevalent are certain to see an increase in the incidence of human tuberculosis, not only in patients with AIDS, but
9 1989 Elsevier Science Publishers B.V. (Biomedical Division)
Side Effects of Drugs Annual 13 M.N.G. Dukes and L, Beeley, editors
probably also in individuals who are otherwise asymptomatic HIV carriers. The frequency of allergic drug reactions in AIDS patients may make therapy in this group both difficult and inefficient. Thus the present consensus that sensitive M. tuberculosis infection should be treated with 6 months of rifampicin and isoniazid with pyrazinamide given for the first 2 months will, like any other antimicrobial regime, need to be kept under constant review and may have to be susperseded by different regimes with which specialists will have to become familiar if serious toxic effects are to be avoided. The fact is that unwanted effects of antituberculous therapy are frequent but are seldom serious because they are spotted early. Emphatically, tuberculosis and leprosy should only be treated by physicians who are using antimycobacterial drugs regularly. Adverse effects in the treatment of tuberculous meningitis The rifampicin, isoniazid and pyrazinamide regime, is, at the moment, probably the best for tuberculous meningitis also. It was used in conventional dosage (together with streptomycin which penetrates the CSF poorly) in 28 adult patients in Thailand (4e). Only 2 patients died, both of whom were comatose at the start of treatment. One patient developed erythema multiforme necessitating cessation of pyrazinamide. Six patients showed the common, benign elevation of liver enzymes during early weeks of treatment, but in all this subsided without alteration of medication. The commonest adverse effect recorded was asymptomatic hyperuricemia noted in half the patients. This settled after the end of the first 2 months during which pyrazinamide was given. A series of 33 young children (median age 25 months) with tuberculous meningitis were reported from South Africa (5c) in whom the 3 'standard' drugs were used in comparatively
260 high dosage (INH 20 m g / k g / d , rifampicin 20 m g / k g / d , pyrazinamide 40 mg/kg/d). Ethionamide 0 5 m g / k d / d ) was also given. Liver enzymes were monitored at least fortnightly for the first 12 weeks and the typical elevation was seen during the first 8 weeks, higher levels being noted in patients with more advanced disease. Jaundice did not develop, except in one child with hepatitis A, and in all children the enzyme levels were falling or were normal at the end of this period.
Hepatotoxicity and multidrug therapy Even among those physicians who regularly prescribe antituberculosis drugs the risk of hepatic reactions appears to be insufficiently appreciated. In 1988 the Federal German Health authorities found it necessary to impose a specific warning to the effect that a combination product containing isoniazid, prothionamide and dapsone, indicated for the treatment of mycobacterial lesions, should bear the warning that hepatic disturbances, occasionally life-threatening, could occur. Monitoring of liver function was recommended at least monthly, and it was advised that treatment be discontinued if clinical or biochemical evidence of dysfunction were detected (6r). The official steps in the Federal Republic appear to have followed some reports of extremely severe hepatic effects, including one of hepatic necrosis, where the hepatotoxicity of prothionamide may have been potentiated by oral contraception (7c). Almost simultaneously with it, other German workers produced further evidence of the particular risk of liver damage in patients with a history of alcohol-induced liver changes
(8CR).
Very exceptionally, fulminant hepatitis develops despite careful monitoring with withdrawal of antituberculous therapy at the first sign of progressive liver damage. A 10-yearold girl developed fulminant hepatitis while being treated with rifampicin, pyrazinamide and ethambutol (9c). Initial therapy with rifampicin, isoniazid and ethambutol was stopped after 2 weeks because of 'gastrointestinal tract disturbances' and elevated liver enzymes. Bilirubin levels were not reported although they are believed to be a useful pointer to potentially progressive hepatitis. Tile girl recovered within 2 weeks and therapy was then recommenced using pyrazinamide in-
Chapter 31
C.J. Ellis
stead of isoniazid. Six weeks later she developed fever, dermatitis and hepatitis. Drug treatment was stopped within a few days, but the hepatitis progressed and she died 12 days after the start of the terminal illness. There was no evidence of coincident viral infection and a skin biopsy showed allergic vasculitis. The authors caution against adding any drug known to be hepatotoxic, even idiosyncratically, to the drug regime of a patient in whom hepatoxicity has occurred. The inexorably fulminating course after the start of the second course strongly suggests sensitization by the first.
Identification of causal drugs in multiple therapy As pointed out below when discussing a case relating to pyrazinamide, it is not always easy (and sometimes quite impossible) to determine which of a series of a drugs in a antituberculous regimen has caused a particular reaction; the fact that some of these drugs have side effects in common and that one may consider it irresponsible to follow a normal withdrawal-and-rechallenge technique leave some mysteries unsolved, as in a recent report of erythema elevatum diutinum in a patient on multidrug therapy (rifampicin, pyrazinamide, isoniazid and streptomycin); the patient reacted well to treatment with dapsone 50 mg daily but died before rechallenge could be performed (10c). Ethambutol (SED-11, 639; SEDA-12, 256) Special senses After very many years, the scope and severity of the eye disorders induced by ethambutol remain a recurrent topic, though serious damage is not likely if dosage is properly chosen. Campbell and Ormerod, relying primarily on British (and English language) evidence, traced 4 cases of ethambutol-induced blindness over a period of 24 years of intensive use (11 R) though some supplementary evidence may have been missed (12r). Meyler's Side Effects of Drugs (SEDI l, 640) currently adheres to the conclusion at a 15 mg/kg daily dose levels ocular toxicity will develop only in 1.6~ of cases but stresses the dose-dependence of the risk. The most important step is to identify and employ the right monitoring methods to detect early changes in ocular function, e.g. involving the use of Stil-
Drugs used in tuberculosis and leprosy Chapter 31
261
l i n g - Verhage's '65' plates for testing color vision (SEDA-12, 256), and perhaps newer methods such as the pattern electroretinogram and visual-evoked cortical potential (13 C, 14c). In spite of the fact that the problem is known, permanent damage to vision is still being reported, a further tragic case from Canada almost co-inciding with Campbell and Ormerod's review.
pyrazinamide pyrexia has been reported but not quantified (SED-11, 641). Even prednisone can cause fever on withdrawal, and high doses of atropine can have the same effect. In this particular case, rifampicin and then pyrazinamide were withdrawn; removal of the latter resulted in rapid termination of the fever. Rechallenge was not attempted because of the potential risk.
Isoniazid (SED-11, 634; SEDA-12, 257)
Thromboeytopenia Effects on the platelet
A single case-report from Australia brings to 6 the number of cases of pure red cell hypoplasia attributed to isoniazid (16c). Recovery after cessation of therapy is remarkably rapid, regeneration being evident in bone marrow aspirate after only 4 days in this case. The mechanism is unknown. The wide availability of isoniazid in many parts of the world and its isoniazid has led to repeated reports of overdosage, resulting either from attempted suicides or accidents (17c); one such report relates to no less than 6 attempted suicides in South-East Asian refugee women, with metabolic acidosis and seizures as prominent features (18c); one aspect of overdosage may be rhabdomyolysis, as suggested by 5 new reports, which could explain the prominence of renal failure (19c). The recent literature, however, in general confirms the well-established picture defined by Ellenhorn and Barceloux in a companion volume to this series (20 R) and the success of the therapeutic approaches to isoniazid poisoning presented by these same authors.
Pyrazinamide (SED-11, 641) Drug fever The attribution of adverse effects to a particular drug can be difficult during multiple drug therapy. In a thoughtful paper from 1986 not previously discussed in these volumes, Van Dijke and Mudde describe how, in a patient with tuberculous choroidoretinitis who was receiving prednisone, isoniazid, rifampicin, pyrazinamide and topical dexamethasone and atropine, marked fever developed (21r Of the antituberculous drugs which were being given, all are known to be capable of producing drug fever; the incidence for rifampicin has been cited as 0.5% (22r), that for isoniazid as 0.3% (23r) while with
count do not seem to have been documented prior to the publication in 1988 of a paper by Jain et al. describing severe thrombocytopenia and bleeding in a man of 27 who was taking pyrazinamide as part of a multidrug scheme of treatment which had twice been changed, pyrazinamide having been interrupted for a time. Ten days after it was restarted, clinical evidence of thrombocytopenia appeared. It receded after all drugs were withdrawn, remained absent when isoniazid and ethambutol were restarted but reappeared in severe form when pyrazinamide was given again for only 3 days. The cause - effect relationship here must be considered entirely clear (15c).
Rifampiein (SED-II, 637; SEDA-12, 258) Rifampicin has long been known to be a potent inducer of liver microsomal enzymes resulting in acceleration of its own deacetylation over the first 6 days of treatment. The enzyme induction can lead to important interactions and also have other consequences. The catabolism of corticosteroids, estrogens, warfarin and digoxin may all be increased during the initial stages of rifampicin therapy with clinically significant consequences. Incipient adrenal insufficiency may be unmasked. Recent case-reports on this topic include one from Spain (24C) and a particularly worrying case in which the complication appears to have occurred in a patient already suffering from AIDS (25c). Rejection of a kidney transplant started 7 weeks after initiation of rifampicin (26c). The ability of rifampicin to undermine essential corticosteroid therapy has certainly often been underestimated. Some recent reports describe how the drug led to an exacerbation of prednisone-treated dermatomyositis in 2 patients (27 C) and of prednisolone-treated pemphigus in another (28c); interpreting such
Chapter 31 C.J. Ellis
262 reports, however, one has to recall the fact that rifampicin itself can induce a series of dermatological complications, pemphigus for example being one of them (SED-11,638). More recently, the plasma level of orally-administered verapamil has been shown to be reduced in patients receiving rifampicin (29c). When verapamil was given intravenously there was no change in plasma levels. Yet other recent reports show rifampicin significantly reducing the serum levels of the antibiotic chloramphenicol in 2 children being treated for acute infections (30c), probably undermining the control of blood pressure with enalapril in an adult (31c), rendering ineffective the treatment of a Blastomyces dermatidis infection with ketoconazole (32c), paradoxically raising the serum of levels of phenytoin in a very old man (33c), delaying elimination of theophylline (though in a man also receiving isoniazid) (34c) and increasing plasma concentrations of warfarin (again in the presence of isoniazid) (35c). The only general rule which a physician can bear in mind is that rifampicin can interfere with the metabolism or elimination of a great many drugs, that not all these interactions are yet known, and that they can sometimes go in unexpected ways, especially where several antituberculous drugs are being given. Whenever
rifampicin is to be used alongside any other essential form o f therapy, careful monitoring for interactions is essential. Respiratory
The only respiratory problem sometimes associated with rifampicin is the 'flu-like' syndrome described in various cases (SED-I l, 31), but it is not impossible that the drug was responsible for a case of pulmonary fibrosis described in 1988. The patient was a man of 79 who received rifampicin, isoniazid and ethambutol to good effect, but developed fever and dyspnea after 3 months of treatment. The findings on lung biopsy and with other methods were consistent with bilateral pulmonary fibrosis. The drugs were discontinued and prednisolone administered. Later he was treated with isoniazid and ethambutol alone without problems, suggesting that rifampicin had been the causal agent (36c).
Skin and appendages
The ability of rifampicin to produce a range of dermatological
complications (SED-11,638) has been recalled above in dealing with the corticosteroid interaction. Pruritus, rashes, urticaria, acne, porphyria cutanea tarda, and various forms of pemphigus have all been reported. Fairly recent literature adds to the known range a case of exfoliative dermatitis in an elderly man. It arose shortly after starting treatment and when the drug was withdrawn after 6 months the condition improved considerably within 2 months; there was no rechallenge (37c). Rifampicin appeared t o precipitate toxic epidermal necrolysis in a 20-year-old woman who had been on corticosteroid therapy for systemic lupus erythematosus (SLE) for 6 years when she was commenced on rifampicin, isoniazid and ethambutol for suspected tuberculosis (38c). Her physicians considered the reaction to be unconnected with her SLE and it subsided promptly when rifampicin was stopped.
DRUGS USED tN LEPROSY (SED-I1,
643; SEDA-12, 258) Introduction Multiple drug therapy has been standard for all classes of leprosy since the WHO formulated protocols using rifampicin, dapsone and clofazimine in 1982. Paucibacillary (tuberculoid) disease, (patients with few skin lesions but with a liability to mononeuritis multiplex as a result of delayed-type hypersensitivity to antigen in peripheral nerves) is treated with dapsone and rifampicin for 6 - 12 months while bacilliferous patients (i.e. those with the multiple skin lesions of lepromatous leprosy) receive all 3 drugs until they have become skin-smear negative. It should be noted that the high cost of rifampicin may be prohibitive in countries where leprosy is endemic, but it remains an effective component of multiple drug regimens even if given as a single dose once a month. Intermittent rifampicin therapy has been associated with the "flu" syndrome which consists of headache, malaise and bone pain starting 1 - 2 hours after a dose and a subsiding within 12 hours. Many affected patients develop circulating antibodies to rifampicin. The phenomenon was seen most frequently in patients receiving higher doses (1200 mg or more) once a week in trials in patients with tuberculosis conducted in Hong
Drugs used in tuberculosis and leprosy Chapter 31 Kong and Singapore. Curiously, it is very rare in patients receiving a similar dosage for leprosy. Possibly there is a racial, i.e. genetic, element.
Clofazimine (SED-11, 645; SEDA-12, 258) An extensive review of clofazimine side effects in 514 leprosy patients concludes that the drug is very safe in usual doses (100 mg/d) (39c). Reddish-brown pigmentation of skin was usual (and is well-known) while the potentially more dangerous gastrointestinal side effects occurred in only 4o7o of patients (i.e. 20). In this group jejunal biopsies were normal although clofazimine crystals were seen in the lamina propria of one. A review of the literature suggests that significant diarrhea, weight loss and/or abdominal pain is only likely to occur in patients receiving higher doses for several months or years and would therefore not be expected in patients treated according to the current WHO protocols who would only receive higher doses if they were to develop erythema nodosum leprosum.
Dapsone (SED-11, 644; SEDA-12, 258) Hemolytic anemia is the most common problem with dapsone, occurring in virtually every patient on full doses, e.g. 2 0 0 - 3 0 0 mg/d (SED-11,345). It can however occur at much lower doses in susceptible patients. Lachant and Tanaka have described a Cambodian woman of 28 with a 4-year history of leprosy, treated for the last l0 months with 50 mg/d dapsone as well as with rifampicin and clofazimine. During the 9th month of treatment she developed severe hemolytic anemia (hemoglobin 7.1 g/dl, erythrocytes 2.92 x 1012/1). The peripheral blood showed microcytosis and rare target cells. Heinz bodies were seen and she proved to have a hemoglobin E trait. This is relatively common in the Cambodian population. The drugs were discontinued and she recovered (40C). The conclusion could well be that individuals with hemoglobin E trait are at greater risk of developing a Heinz body hemolytic anemia when they are exposed to oxidant
263 medications, the risk perhaps being even higher where there is an underlying infection. This is a matter of real importance since dapsone is likely to be used in some populations where hemoglobin E trait is relatively common.
Dapsone syndrome The 'dapsone syndrome' is one name for a condition which may be provoked by the drug (SED-11,644), particularly in malnourished patients and has been regarded as a form of exacerbation of lepromatous leprosy; it resembles mononucleosis, and as a rule occurs on full-dose therapy. In most of these respects a case presented by Grayson and others in 1988 is therefore unusual, since the syndrome occurred in an Australian woman in good physical condition who was taking onceweekly doses of 100 mg dapsone (with chloroquine and pyrimethamine) for malaria prophylaxis when visiting the tropics. After 4 weeks of prophylaxis she developed pyrexia with joint and muscle pain, rash, and then lymphadenopathy and tonsillitis. Severe atypical lymphocytosis was found, but the condition was not infectious mononucleosis, the Paul-Bunnell test being negative. Returning to Australia she was successfully treated, and on a subsequent visit to the tropics tolerated chloroquine given alone for prophylactic purposes (41c). Hypersensitivity Various forms of skin condition have in the past been assumed to represent the main hypersensitivity reactions to dapsone (SED-11, 644) though some workers have the impression that the problem of dapsone hypersensitivity has either been underestimated or is genuinely increasing because of the widespread use of the drug, e.g. in low doses for malaria prophylaxis (42R). In this connection an unusual case of photosensitivity may be noted (43 C) in which an allergic dermatitis with photosensitivity (conjunctivitis with exfoliation on exposed areas of the skin) seems to have been admixed with an erythema nodosum leprosum.
ACKNOWLEDGEMENT I acknowledge the help of Dr. J.A. Innes in the preparation of this chapter.
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