120^ International Journal of Leprosy^ 1985

of the drug intake. What has been necessaryto establish the present concept itself shouldbe used to challenge it.

—J. Grosset, M.D.—L. Levy, M.D., Ph.D.—R. J. W. Rees, M.D.—C. C. Shepard, M.D.

Genera, Switzerland

REFERENCEI. CANETTI, G., Fox, W., KliostENko, A., MAHLER,

H. T., MLNoN, N. K., MI icilisoN, D. A., Risr, N.and SMEITV, N. A. Advances in techniques of test-ing mycobacterial drug sensitivity, and the use ofsensitivity tests in tuberculosis control pro-grammes. Bull. WHO 41 (1969) 21-43.

Response to Dr. Grosset, et al.

To THE EDITOR:We thank the correspondents for their in-

terest in our papers, and are happy to notethat they do not dispute those of our find-ings of most practical importance. Our pop-ulation-based study in an established lep-rosy control program directly observeddapsone resistance in a leprosy-endemicarea. Previous estimates had relied on clin-ic- or hospital-based studies.

One thousand out of 1224 lepromatousand borderline lepromatous patients ondapsone monotherapy in the 1320 km' areaof Gudiyatham Taluk, India, were found tohave been smear negative for three years ormore. Smear negativity was found to indi-cate a markedly reduced risk of dapsone(DDS)-resistant infection. Seventy-six pa-tients, a very small group, remained con-tinuously smear positive despite treatment,and only this group had a high prevalenceof DDS-resistant infection.

This small "high-risk" group that emergesduring dapsone monotherapy deserves thefullest possible concentration of - efforts andresources. Theoretical predictions that dap-sone-resistant infections would threatenevery "multibacillary" patient are not sup-ported by evidence from leprosy controlprograms in endemic areas. On the con-trary, data showing the continuing efficacyof dapsone monotherapy, after two decades,were presented by independent investi-gators from Polambakkam, Chingleput, andSalur (all in South India) at the biennialconference of the Indian Association ofLeprologists in November 1983.

The correspondents seem to feel thatmouse test drug resistance is equivalent to

clinical drug resistance in patients. In ourview this is not supported by the evidencewhich, in fact, comes from several sources.Pearson, et al. (4) found patients who re-sponded for over 53 months (41/2 years) toDDS monotherapy, after the mouse foot padtest had grown high-grade DDS-resistantMycobacterium leprae. Jacobson ( 3 ) ob-served that patients diagnosed by the mousefoot pad test to harbor primary dapsone-resistant AI. leprae, and treated initially withDDS monotherapy, showed a response thatwas "completely normal as measured by allthe usual criteria." Warndorlf-van Diepen( 6 ) showed that after even "high-grade" dap-sone-resistant M. leprae grew in mice, pa-tients yielding such organisms attainedsmear negativity and clinical inactivity de-spite continuing on dapsone monotherapy.

It seems to us that the mouse foot padtest for drug resistance has suffered from theomission of a control group of patients.While patients deteriorating on DDS mono-therapy invariably yielded dapsone-resis-tant M. leprae in mice, it was assumed thatpatients responding favorably to DDSmonotherapy would not do so. No "con-trol" group of responding patients was evertested. Such a control group has now be-come available from our study, and 5 outof 6 responding patients yielded M. lepraeresistant to high-dosage dapsone (0.01%w/w) in the mouse diet.

The mouse foot pad test for drug resis-tance, as described by Pettit and Rees ( 5 ),seems exquisitely sensitive to the presenceof a few drug-resistant M. leprae in predom-inantly drug-sensitive strains. We have sub-sequently demonstrated that strains of M.

53, I^ Correspondence^ 121

leprae with only 1 in 1000 bacilli drug re-sistant can grow drug-resistant Al. leprae inthe mouse foot pad test ('). It is likely thatthe more carefully and expertly the mousetest is performed, the more exquisitely sen-sitive will it prove to minute proportions ofdrug-resistant Al. leprae. In order that a dis-tinction be made between predominantlydrug-resistant and predominantly drug-sen-sitive strains, the "drug-resistant propor-tion" test ( 2) has now been described. Thetechnique previously described by Pettit andRees ( 5) required that harvests be done "atintervals of six to ten months from the dayof inoculation." The reliability of that tech-nique is likely to be enhanced by the "drug-resistant proportion" test ( 2), where harvestsare performed before the plateau of bacil-lary growth is reached in untreated mice.

Theoretical predictions are often contra-dicted by practical experience. However, theevidence in this case comes over a long pe-riod, and from several independent sources.We feel that a more realistic view ofdapsoneresistance in leprosy is required.

—J. G. Almeida, M.B., B.S.—C. J. G. Chacko, M.D., Ph.D.

Schielklin Leprosy Researchand Training Center

Karigiri 632106. South India

REFERENCESI. ALMEIDA, J. G., JosiTii, P. S., SARANGAPANI, G. and

CIIACKO, C. J. G. The mouse loot-pad test—sen-sitive to small proportions of drug-resistant bacilliin a sample of M. leprae. Indian J. Lepr. 56 (1984)10-14.

2. ALMEIDA, J. G., JosH , 0, P. S., SARANGAPANI, G. andIACKO, C. J. G. "Drug-resistant proportion test"

for M. leprae to quantify the proportion of drug-resistant M. leprae in a sample using the mouse footpad. Int. J. Lepr. 52 (1984) 468-470.

3. JAcolisoN, R. R. The effectiveness of dapsone inpatients with primary dapsone-resistant leprosy. In-dian J. Lepr. 56 Stipp!. (1984) abstract no. 111/162(A).

4. PEARSON, J. M. H., HAILE, G. S., BARNETSON, R.ST. C. and RHis, R. J. W. Dapsone-resistant leprosyin Ethiopia. Lepr. Rev. 51 (1980) 315-319.

5. PETTIT, J. H. S. and RHis, R. J. W. Sulphone re-sistance in leprosy. An experimental and clinicalstudy. Lancet 2 (1964) 673-674.

6. WARNDORFI-VAN DIEPEN, T., AREDATii, S. P. andMENOISTI/, G. Dapsone resistant leprosy in AddisAbaba: A progress report. Lepr. Rev. 55 (1984) 143-147.