INTERNATIONAL. JOURNAL. OF LEPROSY^ Volume 55, Number 4

Primed in the

Primary and Secondary Dapsone Resistance ofM. leprae in Martinique, Guadeloupe, New Caledonia,Tahiti, Senegal, and Paris Between 1980 and 1985 1

Clair-Cecile Guelpa-Lauras, Jean-Louis Cartel,Monique Constant-Desportes, Jacques Milian, Pierre Bobin,

Claude Guidi, Gilles Brucker, Beatrice Flageul, Jean-Claude Guillaume,Christian Pichet, Jean-Charles Remy, and Jacques H. Grosset"

The resistance of .1/Ivo/woe/him u'to diaminodiphenylsullone (dapsone, DDS)was first reported by Pettit and Rees in 1964( 8 ) less than 4 years after the developmentby Shepard of the mouse foot pad model("'). Since then, there have been many sub-sequent reports of acquired and primarydapsone resistance from different parts ofthe world, of which a well-documented re-view has been made recently by Ji C). Sec-ondary dapsone resistance appears com-mon among patients who relapse after long-term (5 years or more) dapsone mono-therapy, and is usually of high degree (I -7 ).Conversely, primary dapsone resistance thatis observed in untreated patients is usuallyof low degree ('' "). Because .1/. /eprae strainswith a high degree of dapsone resistance areable to grow in the presence of a dapsoneconcentration that corresponds to the serumlevel achieved in patients treated with 100mg dapsone per day, the resistance of thesestrains is highly significant from a thera-peutic point of view.

' Received l'or publication on 30 March 1987: ac-cepted for publication in revised limn on 22 July 1987.

C.-C. Guelpa-Lauras, M.D.: C. Pichet, INSERMTechnician: J.-C. Remy. M.D.. and J. H. Grosset, M.D..Departement de Bacteriologie-Virologie. FacuIle deN'Uecine Pitie-Salpetriere, 91 Boulevard de 116pital,75634 Paris Codex 13. France. J.-L. Cartel, M.D.. In-stitut Pasteur de la Guadeloupe, Guadeloupe. M. Con-stant-Desportes, M.D., Service de Dermatologie,I lOpital (lame. Fort de France, Martinique. J. Milian.M.D.. Institut de Leprologie Appliquee, Dakar, Sen-egal. P. Bobin, M.D.. Centre Hospiudier Territorial,Noumea, New Caledonia. C. Guidi, M.D.. Institut LouisMalarde, Papeete, Tahiti. G. Brucker, Nil).. Departe-ment de Parasitologie. HOpital Pitié-Salpetriere, Paris,France. 13. Flageul, M.D., Service de Dermatologie,HOpital St. Louis. Paris, France. J.-C. Guillaume. Nl.D.,Service de Dermatologie. HOpital Henri Mondor, Cre-tell. France.

Although .11. hprae strains with low-de-gree dapsone resistance are definitely dif-ferent from fully sensitive strains (''), thereare doubts about the therapeutic signifi-cance of their resistance. A patient harbor-ing such a strain is likely to respond favor-ably to a 100 mg daily dose of dapsone butthe favorable response could well be shortlived

This paper provides information on dap-sone resistance observed between 1980 and1985 in .11. /epare strains isolated from pa-tients of the French West Indies (Marti-nique and Guadeloupe), New Caledonia,Tahiti. Senegal, and also from overseas pa-tients hospitalized in Paris. It confirms whathas been observed in other parts oldie world,and indicates that dapsone resistance, es-pecially primary resistance, is a threateningworldwide problem.

MATERIALS AND METHODSFrom 1 January 1980 onward it was de-

cided that all patients with active multi-bacillary leprosy, either new cases or re-lapses, from Martinique and Guadeloupeshould be biopsied and their biopsies sentby air freight in special wet-ice containersto Paris for dapsone-sensitivity testing bymouse loot pad inoculation according toShepard's technique ('"). Thereafter, biop-sies from patients from New Caledonia andTahiti were also received in Paris, as wellas biopsies from overseas patients hospi-talized in Paris. Furthermore, during theyears 1983-1985 a survey of primary dap-sone resistance was conducted in the CapVert area of Senegal.

Table 1 gives the type (new cases or re-lapses) and the geographical distribution of

672

55, 4^Guelpa-Lauras, et al.: Dapsone Resistance ofM. leprae^673

the patients whose biopsies were receivedin the Paris laboratory from 1980 to 1985.A total of 415 biopsies was received, 280inoculated and only 234 infective. Amongthe latter, 133 were from new cases and 101from relapsed cases of leprosy. A relapsecase of multibacillary leprosy was definedas clinically and bacteriologically acti ve lep-rosy in a patient who is on prescribed dap-sone therapy for at least 5 years. Other pa-tients, mainly totally untreated cases, wereconsidered as new cases.

Epidemiological data are available fromGuadeloupe patients. The 31 biopsies fromnew cases were taken from the 56 new casesof lepromatous leprosy detected between1980 and 1985. The 33 biopsies from re-lapsed cases were taken from the 41 relapsesthat occurred from the average 663 lepro-matous patients who had been treated forat least 5 years and who were still living.Some patients eligible for biopsy were notbiopsied because they had been put undertreatment with combined chemotherapywith ri fampin before a biopsy could be tak-en.

To limit as much as possible the numberof mouse inoculations followed by nogrowth. biopsies received in Paris were notinoculated when: a) <5 x 1W acid-fast ba-cilli (AFB) per ml were recovered. b) themorphological index (MI) was <10%, ande) the length of time elapsed between thecollection of the biopsy and its receipt inParis was more than 14 days.

The mouse foot pad inoculation for dap-sone-sensitivity testing was pertbrmed di-rectly from all biopsies according to stan-dard procedure ( 7 "'). In brief, 5 x 10 3 AFBwere inoculated into the left hind foot padof four groups of eight mice. The first groupacted as an untreated control, being fed adrug-free diet, and the other three groupswere administered diets containing dapsonein concentrations of 0.0001. 0.001, and 0.01dapsone per 100 g, respectively. Harvestsfrom drug-treated mice were always per-formed immediately alter harvests from un-treated control mice had yielded unmistak-able evidence that the organisms hadmultiplied (10' AFI3 or more per foot pad).Therefore, groups of three control mice hadto be harvested first at month 7 and, if therewas no evidence of multiplication at the first

TABLE 1. Number of biopsies receiveclfivm1980 to 1985 in Paris laboratory for tootpad inoculation. inoculated. and JOund in-fective.

Place

lhopsies

Re- Inocu-ceived^lated

I n 1 ect ve

New cases

Guadeloupe 31 31 29Martinique 32 21 20New Caledonia 30 26 19Senegal 50 41 39Paris 23 18 19Tahiti I0 6 2Others 5 5 5

Subtotal 181 148 133

Relapse cases

(ivadcloupe 33 29 18Martinique 131 71 58New Caledonia 18 14 10Senegal 7 5 5Paris 25 II 8Tahiti II 0Others 9 2

Subtotal 234 132 101

Totals 415 280 234

harvest, at month 10 and, if no evidence ofmultiplication at the second harvest, atmonth 12. However, due to the increasedworkload in the laboratory, the first harvestwas frequently done at month 10 or evenlater (Tables 5 and 7). The possible conse-quences of the late harvests will be discussedlater. If there was evidence of multiplica-tion, five mice from each treated group ofmice were harvested, beginning with thosetreated with the lowest concentration ofdapsone. 1f there was no multiplication inthe control mice, ;11. leprae Were consideredto have been nonintective for the mouse. Astrain oil/. leprae was considered resistantto a given concentration of dapsone whenat least one mouse fed with that concentra-tion yielded at least 10' AFB per foot pad.

RESULTSDapsone resistance in relapse cases. From

relapsed cases of lepromatous leprosy, 101infective strains were isolated. Table 2 showsthe results of dapsone-susceptibility testingof these strains according to the patients'geographical distribution. Among them. 18(17.8%) were fully sensitive to dapsone, sug-

674^ International .lournal of Leprosy^ 1987

TABLE 2. Dap.s .one susceptibility q/ . M. leprac isolated from relapse cases.

Susceptibility to dapsone

Place^Total infectiveSensitive

Resistant to (g % in diet)

0.0001 0.001 0.01

GuadeloupeMartiniqueNew CaledoniaParisOthers

185810

87

I()

3

46

513

829

5

3Total^

101^

18^

14^

47100%^

17.8%^

13.9%^

21.8%^

46.5%

Besting that in these cases the relapses weredue to patient noncompliance in taking pre-scribed dapsone therapy. Of the remaining83 strains, 14 (13.9% of total infectivestrains) were of low-degree, 22 (21.8%) wereof intermediate-degree, and 47 (46.5%) wereof high-degree dapsone resistance. There-fore, the majority (68.3%) of the strains iso-lated from relapsed cases were of interme-diate- or high-degree dapsone resistance, asalready pointed out by many other workers(1_7)

•

Since biopsies from New Caledonia, Paris.and other places were limited in 111.1111ber,

only the biopsies from Guadeloupe andMartiniq Lie may be taken for analysis of thedifferences related to geographical origin. Nosignificant differences were observed in dap-sone susceptibility between Guadeloupe andMartinique.

Table 3 gives the distribution of the .1/.leprae strains according to their degree ofdapsone resistance and the duration of dap-sone therapy prescribed for the patients.Since all of the patients were treated onlywith dapsone monotherapy, the duration of

TABLE 3. Dapsone susceptibility of M.leprae in relapse cases of multibacillar• lep-rosy according to duration ofpreviously pre-scribed dapsone therapy.

Duration of

Total^dapsone therapy

<15 yrs >15 yrs

Sensitive 18 6 12Resistant to 0.0001% 14 6 8Resistant to 0.001% 22 8 14Resistant to 0.01% 47 8 39"

Total 101 28 73

p < 0.05.

prescribed dapsone therapy corresponds tothe length of time that elapsed between thecommencement of treatment and the de-tection of relapse. Data presented in Table3 suggest that the longer the prescribed dap-sone therapy, the more frequent the high-degree dapsonc resistance. However, fullydapsone-sensitive strains were isolated from12 out of 73 patients having had >15 yearsof prescribed dapsone therapy.

The reason for the strains having kept fullsensitivity or having a low degree of resis-tance to dapsone despite long-term pre-scribed dapsone therapy is unclear, al-though very irregular treatment is the mostprobable explanation. However, the changesin dapsone resistance of two strains succes-sively isolated from two different patients,sum marized in Table 4, deserve careful at-tention. Patient no. 1, who was prescribeddapsonc for >32 years belbre the occur-rence of relapse, had at the time of relapsein March 1982 a strain with low-degree dap-sone resistance. Because he refused initialhospitalization and multidrug therapy, hewas again given daily 100 mg dapsone alone.Three years later, his condition deterioratedand a M. leprae strain with high-degree dap-sone resistance was isolated. Patient no. 2was also prescribed >30 years of dapsonealone before he relapsed in January 1984with a fully dapsone-sensitive strain. Be-cause he. too, refused initial hospitalizationand multidrug therapy, he was given dap-sone alone. One year later, in April 1985,his condition had not improved and a strainof low-degree dapsonc resistance was iso-lated. In both of these patients, one wonderswhether the increase in dapsone resistancebetween the first and second biopsies is dueto the selection of more resistant organisms

Susceptibility todapsone (g (%)

55, 4^GueIpa-Lauras, et al.: Dapsone Resistance of M. leprae^675

TABLE 4. Detailed results of susceptibilit y testing of M. leprae isolated . from two success-ive biopsies of two (11//('rent patients.

Patient^Date ofno.^biopsy

AF13/mg(MI)

No. AF13inocu-lated

No. AFII harvested/lbot pad

Date ControlsD DS

0.0001 % 0.001% 0.01°A)

Mar. 7x 4x 10 2 Feb. 1^x^10' <2 x 10' <2 x 10 4 <2 x^10 4

1982 (25%) 1983 2^x^It)' 8 x 10' <2 x 1 0 4 <2 x^10 4

3 x^10' 2 x 10' <2 x 10 4 <2 x^10 4

5 x 10' <2 x 10 1 <2 x^10 4

9 x 10' <2 x 10' <2 x^10 4

.11111e 9 x^10' 5 x HP Apr. 5 x^10' 2 x 10' <2 x^10 4

1985 (23%) 1986 7 x^10' 3 x 10' 8 x^10'9 x^10' 6 x 10' 2 x^10'

7 x 10' 3 x^10'7 x 10' 4 x^10'

Jan. 8 x^10' 5 x 10 2 Nov. 2 x^10' <2 x 10 , ND ND1984 (26%) 1984 5 x^10' <2 x 10 4

6 x^10' x 104

<", x 10 ,

<2 x 10 1

Apr. 3 x^10" 5 x 10 2 Mar. 5 x^10' I^x 10' <2 x 10 1 ND1985 (59%) 1986 I^x^IO" 2 x 10' <2 x 10 4

2 x 2 x 10' x 10'2 x 10' <2 x 10 4

7 x 10' <2 x 10 4

ND = not done.

or to a better adaptation of the strain to growin the presence of dapsone in the sensitivitytesting. If the latter hypothesis is correct,the strain kept the same dapsone suscepti-bility but the results of the sensitivity testwere different because of a better multipli-cation of M. leprae in dapsone-treated miceor a later harvest. To assess the possible roleola later harvest, the results of all dapsone-sensitivity tests performed on leprae frompreviously treated patients were examinedin relation to the time of harvests. As shownin Table 5. the dapsone-susceptibility re-sults obtained when harvests were per-formed earlier than 11 months after inoc-ulation were not significantly different fromthose obtained when harvests were per-formed on month 11 or later from the strainsclassified as dapsone sensitive or for thosestrains of low-, intermediate, or high-degreedapsone resistance (x = test used).

Available epidemiological data providethe yearly incidence of secondary dapsoneresistance in Guadeloupe. Of the 41 relapsesdiagnosed between 1980 and 1985 amongthe mean number of 663 lepromatous pa-tients on prescribed dapsone therapy for >5years, 33 were biopsied. Four biopsies con-

tained <5 x 10 4 bacilli and were not in-oculated into the mouse foot pad. Eleventhat contained enough bacilli were not in-fective. The 18 biopsies that were infectiveyielded 1 dapsone-sensitive strain and 17dapsone-resistant strains. The 15 biopsiesthat failed to yield growth in the mouse footpad or that were not inoculated because oftoo low a number of AFI3 may be assumedto contain fully dapsone-sensitive .11. lep-rae. Therefore, from the 33 biopsies we canestimate that 17 (52%) contained dapsone-resistant and 16 (48%) dapsone-sensitiveleprae. If the proportion of dapsone-resis-taut and dapsone-sensitive strains was sim-ilar among the remaining 8 relapse casesthat were not biopsied, 5 additional strainsof dapsone-resistant M. leprae should beadded to the 17 that were isolated, giving atotal of 22 dapsone-resistant strains in 6years (1980-1985) from a mean number of663 lepromatous patients. Therefore, theyearly incidence of secondary dapsone re-sistance in Guadeloupe can be estimated tobe

2 2 x 100

6 x 663= 0.55%.

676^ International .lournal (il Lepros•^ 1987

TABLE 5. Dapsone slivceptibility^leprac harre.vicil Iron; previottvly treated patientsin relation to time of harvest.

Ilarvest time^'total strainsSusceptibility to dapsone

SensitiveResistant to (g9 in diet)

(mos.)^No.0.0001 0.001 0.01

7^2_8^2_

1_-.,_ 1

9^7 7 510^40 39 7 7 9 17H^15 15 3 5 512^29 29 4 3 4 1813^6 6 1 1 3 1

Total^101 100 18 14 47Mean (mos.) = 10.7 •^0.3

Primary dapsone resistance. From newcases of leprosy, 133 infective strains wereisolated. Table 6 shows the results of dap-sone-susceptibility testing of these strainsaccording to the patients' geographical dis-tribution. Among them. 81 (61 0/u) were fullysusceptible and 52 (39%) harbored some de-gree of dapsone resistance: 37 (28%) beingof low-, 8 (6%) of intermediate-, and 7 (5%)of high-degree dapsone resistance. Dapsoneresistance of II. /cprac isolated from pa-tients considered as previously untreatedwas evenly distributed at a similar rate. anda low degree of dapsone resistance wasprominent in all of the places. None of thestrains isolated from untreated patients fromGuadeloupe and Martinique were of high-degree dapsone resistance: whereas somestrains with such high resistance were iso-lated from all other places. Since the pa-tients from Guadeloupe and Martiniquewere those with the most precise clinicalhistory, one may suppose that some so-called"untreated — patients from places other than

Guadeloupe and Martinique had, in fact,received prior dapsone treatment. This couldhave occurred. in particular, for several pa-tients in Paris who came from overseas. De-spite that possibility, the proportion of re-sistant cases among new cases of leprosywas significantly lower than among the re-lapsed cases. and the grade of resistance wasalso quite lower. The survey on primarydapsone resistance conducted (luring 1983-1985 in the Cap Vert area of - Senegal yieldeda prevalence rate of primary dapsone resis-tance at least as high as in other places, em-phasizing the worldwide problem of pri-mary dapsone resistance, whatever theprevailing network of leprosy control.

Finally, the results of primary dapsoneresistance were examined in relation to thetime when harvests were performed. Asshown in Table 7 1„ when harvests were per-formed before 11 months, the results weresignificantly different from those obtainedwhen harvests were perlbrmed on month11 or later. The differences are significant

TABLE 6. Dapsone susceptibility of M. leprac strains isolated 1 .roin new cases.

Place Total^infec-tive

Susceptibility to dapsone

SensitiveResistant to (g °/0 in diet)

0.0001 0.001 0.01

(ivadeloupe 29 19 I 0 0 0Martinique 20 8 10 0New Caledonia 19 14 1

Senegal 39 27 7 3Paris 19 9 5 2 3Others 7 4 3 0 0

Total 133 81 37 8 7100% 6104 28 (14) 6% 503

55. 4^(hie/pa-/.auras, et al.: 1)ap.volie Resistance of M. leprae^677

TABLE 7. nap.s .one susceptibility of M. leprae //arrested from wareated patients inr(laIion 10 time of harvest.

Ilarvest time Total strainsSusceptibiloy to dapsone

SensitiveResistant to (g % in diet)

(mos.) No. ')/00.0001 0.001 0.01

8 7 5 59 10 8 8 1

10 51 38 39 7 3II 35 26 20 8 412 25 19 $ 1413 5 4 1 4

Total 133 81 37 8 7Mean (mos.) 10.6^0.'

I -or the distribution of the strains as dapsonesensitive or resistant as well as for the dis-tribution of the dapsone-resistant strains asof low or of higher degrees of resistance (X.'test used). They tend to indicate either thatprimary dapsone-resistant leprae strainsmultiplied more slowly in mice ICd with adiet containing dapsone than a dapsonc- freediet, or that they contained a mixture ofdapsone-sensitive and dapsone-resistantorganisms.

DISCUSSIONThe most important findings reported in

this paper are that 82% of patients who re-lapsed when on prescribed long-term dap-sone monotherapy harbored dapsone-resis-tant /eprae which were mainly of highdegree. and that 39% of patients with newlydiscovered lepromatous leprosy also har-bored dapsone-resistant .1/. leprae' whichwere, in contrast, mainly of low degree. Thehigh frequency ofdapsone resistance did notresult from a bias in the selection of patientsbecause all eligible cases, at least in Guade-loupe and Martinique, were biopsied withthe only exception of those who were, byerror, put on combined treatment with ri-fampin before a biopsy could be taken. Sincethe results observed in Guadeloupe andMartinique were similar to those from Sen-egal. New Caledonia, Tahiti, and Paris,where a bias in the selection of patients can-not be excluded, the high frequency of dap-sone resistance is likely to reflect the actualsituation. The !het that our data were con-sistent with all data from other places in theworld (`) is also indirect evidence of theirvalue.

One possibility of error in our results couldbe the concentration ofdapsone in the mousediet. If the actual concentration of dapsonewas lower than indicated, some sensitivestrains could have grown in the mice led adapsone-containing diet and he consideredas resistant. In fact_ all batches of the dap-sone-containing diets were not systemati-cally controlled for their dapsone contentbut the dapsone levels in the blood of micewere always, when measured. in the normalrange ( 2 ). Thus, our data on dapsone resis-tance can be considered as accurately re-flecting the actual situation in those placeswhere the study was conducted.

A point of - concern is the precise meaningof reported data on secondary dapsone re-sistance. Secondary dapsone resistance wasbeing studied yearly in Guadeloupe amongall patients who had clinical and bacterio-logical relapse. In studies conducted by oth-er workers secondary dapsone resis-tance was mainly studied for a limitedduration of time among all, or a sample of,smear-positive patients with and withoutclinically active disease. Comparison is,therefore, difficult between data from Gua-deloupe and data from other parts of theworld. with the exception adata giving theannual incidence of secondary resistance,the range of which being 0.1% to 3% (').With the relatively low incidence of 0.55%,Guadeloupe can be considered in an inter-mediate position. An interesting finding isthe positive relationship between the degreeof dapsone resistance and the length of pre-scribed dapsone therapy. a finding that in-directly supports the commonly acceptedview ( 3 ) of step-wise dapsone resistance. It

678^ International Journal of Leprosy^ 1987

also indirectly supports the commonly ac-cepted view concerning primary dapsoneresistance, which would result from the in-fection of naive subjects by ,11. /eprac frompatients who have relapsed 10-15 years ago.Because those who relapsed first were thosewho had acquired low-degree dapsone re-sistance. in relation to low-dosage dapsonetreatment and poor compliance ('), the firstdapsone-resistant /eprae to be transmit-ted should have been those with low-degreedapsone resistance. If that is actually thecase, an increase in the degree of primarydapsone resistance could occur in the future,unless standard combined chemotherapy isapplied as recommended by internationalorganizations (").

All of the data we have collected in the 6years of this study do not give an answer tothe question of the clinical and biologicalmeaning of - primary dapsone resistance. Be-cause of the usual low degree of primarydapsone resistance, it is likely that the ma-jority ofstrains of primary resistance as wellas totally sensitive strains will respond todapsone given at full dosage. But it is alsopossible that some strains that appear tohave low-degree dapsone resistance do notrespond well to dapsone treatment becausethey are not as sensitive as they seem to be.That possibility is not fully hypotheticalwhen we consider the strains isolated fromour two patients who relapsed after morethan 30 years of prescribed dapsone thera-py. These strains appeared much less resis-tant at first isolation than at second isolationa few months later. Between both isolations.the patients were given dapsone alone whichcould have been responsible for a rapid in-crease of the degree of Of course,these strains were isolated from alreadytreated patients and not from newly diag-nosed ones, and it may not be possible tocompare strains with primary resistance tostrains with secondary strains.

Our findings that the later the harvest themore frequent the dapsone resistance amongM. leprae strains isolated from untreatedpatients raises a number ofquestions. Is thatphenomenon due to a slower growth of pri-mary dapsone-resistant strains in the pres-ence of dapsone because these strains havenot yet recovered their full capacity to ex-press their resistance, or because they con-tained a mixture of dapsone-sensitive and

dapsone-resistant organisms? It is not pos-sible to decide whether one of the two orboth explanations are correct. That the pro-portion of sensitivity tests with partial re-sistance (only some of the live mice har-vested were positive) has been similar amongstrains from previously treated patients anduntreated patients, and because there wasno relation between time of harvest and fre-quency of resistance with strains isolatedfrom previously treated patients, tend to in-dicate that the right explanation may not bea mixture of sensitive and resistant organ-isms.

11 primary dapsone - resistant strains growat first isolation, less well in the presence of'dapsone than in the absence oldapsone, onemay fear that the prevalence and the degreeof primary dapsone resistance are still higherthan those observed when dapsone-suscep-tibility testing is done according to the of-ficial which indicate that the harvestshould be made as soon as control mice arepositive. That hypothesis could be easilytested by repeating the dapsone-sensitivitytesting of ,11. /eprac isolated from untreatedpatients and harvested from mice with thehighest dapsone concentration that permitsgrowth.

In practice, it should be emphasized thatthe time of harvests should be strictly stan-dardized, as already pointed out by spe-cialists ( 3 ), in order to compare data fromdifferent laboratories. As Fur as we are con-cerned, we are now working to have the firstharvest done on month 7 and in case of nogrowth, the second on month 10.

SUMMARYPrimary and secondary dapsone resis-

tance were studied among lepromatous pa-tients living in Martinique, Guadeloupe,New Caledonia. Tahiti, Senegal, and Paris.Four hundred fifteen biopsies were takenfrom clinically active and bacteriologicallypositive (bacterial index > 2) patients in the6-year period of 1980-1985. Among these,280 biopsies that contained 5 x 10 -I acid-last bacilli per ml with a morphological in-dex of at least 0.10 were inoculated intothe mouse foot pad, and 229 harbored in-fective Mycobacterium leprae. Among the129 infective Al. leprae isolated from newcases. 54% had some degree of dapsone re-sistance, a low degree being prominent in

55, 4^(;ut,Ipa-Lauras, et al.: Dapsone Resistance of M. lcprae^679

all cases. Among the 100 infective Al. lepracisolated from relapsed cases, 79% had a highor an intermediate degree of dapsone resis-tance. The annual incidence of secondarydapsone resistance was estimated to be about0.55% in Guadeloupe.

RESUMENSc estudiô la rcsistencia primaria y sccundaria a la

dapsona entre los pacientcs de Ia Martinica. Guada-

lupe, Nucsa Caledonia. Taal, Senegal y Pans. Durante

el period() de 6 aims comprendido entre 1980 y 1985,Sc tomaron 41) biopsitts de pacientes clinicam•nte ac-

ti vos y bactenolOgicamente positivos (indict bacteno-

!Ogle() 2). Entre estas, 280 hiopsias que contenian

5 x IW bacilos por ml y Lin indict mort0lOgico de

cuando MenOS 0.1, lueron inoculados en la almohadilla

plantar del ratan. Doscientos veintinueve casos tuvie-

ron M ycohacterium leprae iniectivos. Entre las 129

muestras con .1/. leprae infectivos, aislados de casos

nuevos, el 54% mostro algUn grado de resistencia a la

dapsona, predominando un hzijo grado de resistenciaen todos los casos. Entre las 100 muestras inlecti vasde I/. /eprac aisladas de casos recaidas, el 79%mostrO un grado alto o intermedio de resistencia a ladapsona. En la Isla de Guadalupe, la incidencia anual

de resistencia sccundaria a la dapsona Sc estimO cer-cana al 0.05%.

RESUME

On a et oche Ia resistance primaire et Ia resistancesecondaire A la dapsone clic/ des malades lepromateux

vivant en Martinique, A Ia Guadeloupe. en Nouvelle-

Caledonie. a Tahiti. an Senegal et a Paris. On a preleve415 biopsies clic/ des malades chniquement actil's et

bactenologiquemcnt positik (index bacterml 2)•pendant one periode de 6 ans s'etendant de 1980 A1985. Parini ces biopsies, on cn a choisi 280 qui come-

nment 5 x 10' hacilles acido-rj2sistants par nil. avec

un index morphologique d'au moins 0,10. Ces biopsies

ant etc alors inoculees dans le coussinct plantaire dc

la souris. On a constate que 229 de ces biopsies conte-naient des AI ycobacterium leprae infectils. Parini les129 souches de .1/. leprae isolees A partir de nouveauxcas, 54% presentaient un certain degre de resistance

faible A la dapsone. Parmi 100 souches in fectieuses deleprae, isolees de recidives, 79% presentaient un

degre eleve 00 intermediaire de resistance A la dapsone.L'incidence annuelle de resistance secondaire a Ia dap-

sone a etc estimee a 0.55% en ( uadeloupe.

Acknowledgments. The authors thank Evelyne Pe-ram and Corinne Beoletto I -or their dedicated work,and are indebted to Dr. Ji 13aohong. Secretary of . 11-1E-LEP, WHO. Geneva, for providing help and advice inthe preparation of the manuscript.

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