SummaryThe bactericidal activity for Mycobacterium lep rae in mice of a range of dietary concentrations of clofazimine and ethionamide was studied by the proportional bactericidal technique. The 2 highest concentrations of clofazimine studied, 0·0 I % and 0·003 % were respectively 99·6 ± O· 2 % and 98 ± 1·0% bactericidal. Though less killing was afforded by 0·00 1 % and 0·000 1 % clofazi mine, even the latter concentration retained significant bactericidal activity (84 ± 10% bactericidal). The minimal bact e ricidal dietary concentration of ethionamide was fo und to be approximately 0·02% (68 ± 13% bactericidal). Higher concentrations of ethionamide , 0·05% and greater, were consistently more active, at least 95 ± 3% bactericidal. It is noteworthy in these studies that significant bactericidal activity of both clofazimine and ethionamide was retained at lower dietary concentrations than had been demonstrated previously.Actual bactericidal activity against Mycobacterium leprae appears critical in the therapy of lepromatous leprosy. Recently results' were presented quantifying the killing of M. leprae in mice by a wide range of dietary concentrations of dapsone and rifampicin. Previous work2 in this regard had evaluated only high dietary concentrations of these and other agents which yield steady state levels corresponding to peak levels experienced by patients undergoing therapy. The evaluation of the killing of M. leprae by lower dietary concentrations that result in levels that are also experienced by patients had not previously been evaluated by these same methods. Since clofazimine and ethionamide are the only other antimicrobial agents that are widely used to treat leprosy,3 we studied these 2 antimicrobial agents in a similar manner.Both clofazimine and ethionamide have been demonstrated to be bactericidal for M. leprae infected mice at high dietary levels. Clofazimine 0·003% and 0·01 % in mouse food was previously fo und to be respectively 96-99% and 98% bactericidal,2 while ethionamide 0· 1 % and 0·2% was fo und respectively 98·6% and 97·4% bactericidal.2 Clofazimine accumulates in skin, resulting in a dose-related red-black discolouration which makes the drug unacceptable to some patients. If the dosage of clofazimine could be reduced without loss of significant antimicrobial potency, this would certainly be advantageous. Ethionamide is not well tolerated in a significant number of patients because of dose-dependent gastrointestinal intolerance, is hepatoxic, especially when combined

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Summary Our studies indicate that the patient with leprosy is at risk for developing keratoconjunctivitis sicca. The cause of keratoconjunctivitis sicca in our patients suggests that the aqueous layer of the tear film may be decreased as a result of a decrease in secretion of tears from the accessory lacrimal gland of the conjunctiva although it could also be decreased due to a diseased afferent arc to the lacrimal gland or to a diseased lacrimal gland both resulting in decreased aqueous production. In addition the stability of the precorneal tear film is probably affected due to a decrease in corneal sensation and to lagophthalmos both of which result in decreased blinking, as well as fa ilure of the lid to resurface the tears because of irregularity of the conjunctiva or cornea.Our results suggest that patients with leprosy should be fo llowed closely for keratoconjunctivitis sicca and that treatment directed towards this problem should be initiated early.Absence of the precorneal tear film is a potentially seri o us problem in ocular leprosy, and this combined with corneal exposure is a major cause of blindness in these patients. In an effort to identify the individual components of keratoconjunctivitis sicca which might lead to corneal damage, we have carried out complete ocular examinations on 73 consecutive patients with biopsy proven leprosy who were seen at the Hansen's Disease Clinic in the San Francisco Bay Area. In the study we fo und a significant number with a decrease in the precorneal tear film.Leprosy commonly affects the eyes. Moreover, ffytche has stated that leprosy affects the eyes more frequently than any other systemic disease.' Estimates of ocular complications in leprosy vary from 6% to 93%2.3 and of the I ()"" 15 million who suffer from the disease4 possibly 5% are blind.5 The periocular structures including the skin as well as the anterior segment of the eye are most freq uently involved in leprosy, but the greatest threats to vision arise from lagophthalmos, chronic iridocyclitis, and keratitis. In our studies we therefore directed much of our attention toward determining the severity and frequency of exposure keratitis and loss of the precorneal tear film. The various parameters we studied included: the Schirmer tear test, tear lysozyme, corneal sensation, 0305-751 8/87/0584.13 + 05 SO 1.00

Prior to the landmark discovery in 1960 of ' The Experimental disease that fo llows the injection of human leprosy bacilli into fo otpads of mice,' 1 the only means of searching for drugs active against human disease was to conduct clinical trials. Because clinical improvement of lepromatous patients is both very slow and variable, because the number of AFB (BI) in the skin fa lls extraordinarily slowly despite adequate therapy, and because the viability of solid-staining bacilli (MI) was not appreciated, early short-term clinical trials were difficult to conduct and the results even harder to interpret. Of the earlier studies on dapsone only the study of Lowe2 fo llowed a stable population until bacteriological negativity, finding 32 of 39 (83%) negative at 5 years, 31 of 35 (89%) negative at 6 years, and 34 of 35 (97%) smear-negative at 7 years.The earliest studies on the effect of antimicrobial agents on My cobacterium leprae-infected mice utilized primarily drugs known to be effective against M. tuberculosis. These first studies utilized constant treatment from the time of mouse fo otpad infection, generally with 5 x 103 M. lepraejfootpad, either by incorporation of drug into mouse chow or daily (actually usually five times weekly) intraperitoneal injections. By these means Shepard3 fo und dapsone, clofazimine, isoniazid, para-aminosalicylic acid, streptomycin, and cycloserine active and ethambutal and pyrizinamide inactive. By similar means Gaugas4 in 1967 fo und the same drugs active, and notably, as well, rifampicin and cephaloridine. This method of drug testing, termed the 'continuous method', does not distinguish between purely bacteriostatic and bactericidal activity. Since it has been well established in bacterial endocarditis and a number of other infectious diseases where protective local or systemic host defence mechanisms are inadequate (osteomylitis, meningitis, and Gram negative bacteremia in the neutropenic patient) that bactericidal therapy is crucial to a salutary outcome and that the key to effective short-course chemotherapy for pulmonary tuberculosis is the inclusion of two or more bactericidal agents,5 actual bactericidal activity against M. leprae is likely to be similarly important in the therapy oflepromatous 0305-75 1 8/86/057137S + 12 $0 1 .00

The killing potential of various aminoglycoside antibiotics for Myco bacterium leprae infection of the mouse fo ot-pad was studied, utilizing daily intraperitoneal therapy. Kanamycin (100 mg/kg), streptomycin (150 mg/kg), and amikacin (100 mg/kg) resulted in impressive killing of bacilli (99• 7%, 97% and 96% bactericidal, respectively). Gentamicin (20 mg/kg) and tobramycin (20 mg/kg) were much less active (60% and 37% bactericidal). The bactericidal activity of these very high doses of kanamycin, streptomycin and amikacin compared favourably with those of other agents previously studied in a similar manner at relatively lower dosage levels. Aminoglycoside antibiotics have received only limited experimental and/or clinical attention for their potential role in the therapy of leprosy. 1-9 In 1964 the first study8 on the activity of streptomycin in the treatment of experimental My cobacterium leprae infection of the mouse fo ot-pad was reported. In this study, 2 mg of streptomycin injected subcutaneously 5 times weekly, con tinuously fr om the time of infection, prevented multiplication of M. leprae fo r the 15!-month study duration. In a later study (1968)7 M. leprae-infected mice were treated by the 'kinetic method' with 2 mg of streptomycin 3 times a week fr om day 30 to 86 fo llowing infection. The growth of M. leprae was fo und to be inhibited during the period of drug administration but resumed promptly when therapy was discontinued, suggesting that streptomycin was purely bacteriostatic. More