How effective Is monthly Rifampin? Response to the letter to the editor by Dr. J. G. Almeida
To the Editor:
I write in response to the Letter to the Editor by Dr. J. G. Almeida, entitled "How effective is monthly rifampin?"(1), in which he concludes that daily administration is many times more effective than monthly administration. Dr. Almeida's argument is flawed in that he draws conclusions with respect to the activity of the drug against Mycobacterium leprae in man from data obtained from work in mice. That rifampin is less active against M. leprae in the mouse than in man has been reported previously by Grosset (2,4), among others. Dr. Almeida's extrapolation of the initial rates of bacterial killing in mice leads him to the outlandish conclusion that patients treated with monthly rifampin harbor at least 108-fold more viable M. leprae after treatment for 14 weeks than do those treated with daily rifampin. In fact, the available data (3,6-9) demonstrate that the rate at which M. leprae are killed in man decreases abruptly, after the number of viable organisms has been reduced 1000-10,000-fold, at which time the population of "persisters" is unmasked (10). The decrease of the rate of bacterial killing and the size of the population of M. leprae surviving after the initial kill are indistinguishable in patients treated by a variety of rifampin-containing regimens (3,9).
One cannot be entirely confident that monthly rifampin is as effective as daily rifampin. Were I to become ill with multibacillary leprosy, I would very likely prefer my rifampin daily rather than monthly. However, the difference of effectiveness cannot be great, and administering the drug monthly both "stretches" the supply and permits supervision of drug administration.
Moreover, there is room for serious argument with respect to the antimicrobial activity of rifampin against M. leprae. None of us is comfortable with the discrepancy between man and mouse. In fact, as Grosset has pointed out (1,5), the pharmacokinetic behavior of rifampin is more favorable in the mouse than in man, a fact that is inconsistent with the apparently greater efficacy of the drug in man. Is the discrepancy between mouse and man the result of crossing species barriers-i.e., one demonstrates the viability of M. leprae by inoculating mice, whether the organisms have been recovered from mice or man? Or is it possible that shipment of the specimen, often if not always required when organisms are to be recovered from human lesions and inoculated into mice, and rarely if ever required when organisms are to be transferred from mouse to mouse, is injurious, particularly to M. leprae that have been exposed to rifampin? On the other hand, the available data appear to be "all of a piece" -i.e., internally consistent, and consistent with what we know about other drugs. Finally, the accumulating data attesting to the efficacy of the World Health Organization multidrug therapy (WHO MDT) arc entirely reassuring.
- Louis Levy, M.D., Ph.D.
Visiting Professor
Department of Dermatology
Hadassah Medical Organization
P.O. Box 12000
il-91120 Jerusalem. Israel
REFERENCES
1. ALMEIDA, J. G. How effective is monthly rifampin? Int. J. Lepr. 60(1992)81-82.
2. GUELPA-LAURAS, C.-C, GROSSET, J., TRUFFOTPER-NOT, C. and GIROIR, A. M. Activite bactericide comparee de la rifampicine seule sur M. tuberculosis et sur M. leprae. Acta Leprol. 86-87(1982)69-75.
3. GELBER, R. H. and LEVY L. Detection of persisting Mycobacterium leprae by inoculation of the neonatally thymectomi/cd rat. Int. .1. Lepr. 55(1987)872-878.
4. GROSSET. J. H. and GUELPA-LAURAS, C.-C. Activity of rifampin in infections of normal mice with M. leprae. Int. J. Lepr. 55(1987)847-851.
5. GROSSET,J.,TRUFFOT-PERNOT, C, BISMUTH, R. and LECOEUR, H. Recent results of chemotherapy in experimental tuberculosis of the mouse. Bull. I.U.A.T. 58(1983)90-96.
6. LEVY, L., SIIEPARD. C. C. and FASAL, P. The bactericidal effect of rifampicin on M. leprae in man: a) single doses of 600. 900 and 1200 mg; and b) daily doses of 300 mg. Int. J. Lepr. 44(1976)183-187.
7. SHEPARD, C. C, LEVY. L. and FASAL, P. Rapid bactericidal effect of rifampin on Mycobacterium leprae. Am. J. Trop. Med. Hyg. 21(1972)446-449.
8. SHEPARD, C. C., LEVY, L. and FASAL, P. Further experience with the rapid bactericidal effect of rifampin on Mycobacterium leprae. Am. J. Trop. Med. Hyg. 23(1974)1120-1124.
9. Subcommittee on Clinical Trials of the Chemotherapy of Leprosy (THELEP) Scientific Working Group of the UNDP/World Bank/WHO Special Programme for Research and Training in Tropical Diseases. Persisting Mycobacterium leprae among THELEP trial patients in Bamako and Chingleput. Lepr. Rev. 58(1987)325-337.
10. TOMAN, K. Bacterial persistence in leprosy. Int. J. Lepr. 49(1981)205-217.