Hansen for ever...Hansen para siempre ??? Chapter II    Bibliographic refrences !!!

DATA-MEDICOS 
DERMAGIC/EXPRESS 2-(96) 
4 Octubre 2.000  4 October 2.000 
 
~ Hansen para Siempre...??? ~ 
~ Hansen forever...??? ~ 
 

EDITORIAL ESPANOL 
================= 
Hola amigos de la red, DERMAGIC con otro interesante tema: HANSEN PARA SIEMPRE ??? 
En el año 1.997 se registraron unos 690.000 casos nuevos de la enfermedad y se estimaba el total 
en unos 1.200.000 de casos. Para ese año (1.997) unas 2.100.000.000 de personas vivian donde 
existe una prevalencia de mas de 1 caso por cada 10.000 habitantes. Para comienzos de 1.998 el 
numero de casos se estimaba en 800.000. Para el año 2.000 el numero de casos remanentes de 
Lepra en el mundo se estima en unos 2.5 a 2.8 millones de pacientes. 

 Los paises mas afectados son India, Indonesia y Myanmar (sudeste Asiatico) los cuales tienen el 
70% del total de casos de Lepra. Africa la segunda region mas afectada y en Latinoamerica Brasil 
esta severamente afectado representando el 80% de los casos de nuestro continente. 

Enfermedad Biblica, ancestral y apocaliptica, el causante de la enfermedad Mycobacterium Leprae 
descubierto por Armauer Hansen en 1873 todavia se resiste a ser eliminado.el tratamiento inicial fue 
con el  aceite de Chalmoogra introducido por el egipcio Tortoulis Bey en 1894. Fue en los años 40 
cuando aparece la Dapsona como una alternativa terapeutica realmente eficaz contra la enfermedad, 
luego la rifampicina y el clofazimine constituyendose estas tres drogas (MTD) en el tratamiento 
oficial de la OMS.  En los años 70 se inicio la era de las (vacunas-inmunoterapia) contra la 
enfermedad (Venezuela, India). En 1997 se descubrio que antibioticos comunes como la minociclina 
y Ofloxacina, conjuntamente con rifampicina son altamente bactericidas contra el bacilo de Hansen y 
se instituyeron nuevos esquemas terapeuticos (ROM). Hoy en dia los Indues utilizan una vacuna 
(Mycobacterium  w) para detener el flagelo de la enfermedad en ese Continente. 
 
El 17 de marzo de 1.999 DERMAGIC/EXPRESS salio a la red con el tema; 
LA MINOCICLINA, LO BUENO, LO MALO Y LO FEO, donde se señalo el efecto beneficioso 
de este medicamento en la lepra e hice la siguiente pregunta: 
" .......realmente la minociclina se esta usando  en la lepra en nuestros paises, ??? " 
Este DERMAGIC EXPRESS fue publicado en la revista Chilena de DERMATOLOGIA, segun me 
comento la Dra Altanisia Ramuno (Venezuela). 
 
EL 11 de agosto de 1.999 DERMAGIC EXPRESS volvio a la red con el tema LEPRA Y 
VACUNAS 
donde en el editorial se escribio: 
....En la India NUEVA DELHI, se ha estado trabajando con 4 cepas, entre las que destacan 
Mycobacterium Habana y Mycobacterium w, este ultimo del cual segun ellos se pondra al mercado 
LA PRIMERA VACUNA contra la Lepra producida por Cadila Pharmaceuticals, porque NO ES 
PATOGENO. Pero si revisamos bien TODAS las referencias, NO SON VACUNAS 
PROPIAMENTE DICHAS, en el sentido estricto de la  PREVENCION de la infeccion,  puesto 
que se usan en combinacion con poliquimioterapia.  (MTD).  Recordemos tambien que la clasica 
vacuna BCG (bacillus Calmette-Guerin) , que protege conta la tuberculosis,  tambien protege contra 
la lepra..... 

En enero 26 del 2000 DERMAGIC/EXPRESS volvio a la red con otra revision:  LA LEPRA 2000 
AÑOS DESPUES... con 80 referencias bibliograficas... 

En el año 1.997 la Organizacion Mundial de la salud considero en base a un estudio multicentrico 
que UNA SOLA DOSIS rifampicina, ofloxacina y minociclina era una buena alternativa y de bajo 
costo para el tratamiento de la lepra pausibacilar (PB) con una sola lesion, y una dosis MENSUAL 
por 24 meses para lepra multibacilar (MB). Tambien se considero la disminucion del tratamiento 
CLASICO con MTD a 12 meses. 
 
En Junio de 1.999 en San Francisco se realizo una conferencia sobre lepra entre JAPON Y 
ESTADOS UNIDOS donde se reconocieron varios aspectos como: la aparicion de resistencia del 
Bacilo de Hansen a la DAPSONA, en los años 70, y actualmente a las fluoroquinolonas y al nuevo 
REGIMEN de tratamiento (ROM), rifampicina-ofloxacina-minociclina, determinandose las causas 
geneticas de tal resistencia. 
 
El año de 1.999 en Londres se realizo un estudio en ratones infectados con el Mycobacterium 
Leprae utilizandose una combinacion de rifampicina (RMP) con claritromicina (CLARI) y ofloxacina 
(OFLO) resultando en la muerte del bacilo en 3 semanas de tratamiento. La combinacion de 
Sparfloxacina (SPAR) mas rifampicina (RMP) tambien provoco el mismo efecto. Se concluyo que 
Esta combinacion de drogas: RMP, OFLO, o  (SPAR)-CLARI, con o sin minociclina (MINO) y 
cuya efectividad se observa en 4 SEMANAS puede ser administrada a pacientes por un periodo 
mas corto que el actual de 2 años (reducido a 1 año actualmente) con MTD. 
 
En el año 1.981 la OMS en base a evidencias cientificas considero que el tratamiento con MTD 
(rifampicina, dapsona y clofazimine) debia ser de 6 meses para la lepra paucibacilar (PB) y de 2 
años para la lepra multibacilar (MB) en la conferencia de 1.994 se ratifico este esquema de 
tratamiento por su alta efectividad, habiendose logrado la cura de unos 84. millones de pacientes. 
 
En la conferencia de 1.997 sobre lepra LA OMS considero una disminucion del tratamiento con 
MTD a 12 meses en la lepra multibacilar (MB) en base a algunos estudios realizados y 
principalmente el hecho de la aparicion de resistencia a las drogas utilizadas por el 
INCUMPLIMIENTO del tratamiento en las zonas de dificil acceso. 
 
En el año de 1.999 en la India se publicaron dos estudios para detectar bacilos viables en pacientes 
con lepra multibacilar despues de 6, 12, 24 y 36 meses de tratamiento clasico con MTD. SE 
DEMOSTRO que despues de 12 MESES DE TRATAMIENTO entre un 25% y 31% de los 
pacientes tenian bacilos viables. Despues de 2 años de tratamiento solo un 8%-12%. Despues de 3 
años de tratamiento un 4%, Y RECOMIENDAN TENER PRECAUCION CON LA 
DISMINUCION DEL TRATAMIENTO DE 24 A 12 MESES. 
 
En un estudio realizado en China y publicado en Diciembre de 1.999 sobre el seguimiento a 
pacientes con lepra paucibacilar (PB) y multibacilar (MB) despues de tratamiento clasico con MTD 
se llego a la conclusión de que a los pacientes con lepra paucibacilar hay que hacerles un 
seguimiento de 5 años y a los de lepra multibacilar de 10 años. 

En el año de 1.998 la FDA libera de nuevo la talidomida para su utilizacion en el eritema nodoso 
leproso (ELN) 

El 15 de noviembre de 1.999 la OMS lanzo una alianza global contra le lepra con el objetivo de 
eliminarla completamente del planeta tierra antes del año 2.005. 
 
India, indonesia y Brasil los paises mas efectados...para 1.998 
 
Cierro con varias preguntas para todos,,,, ??? 
 
No es una bomba de tiempo disminuir el clasico TRATAMIENTO CON MTD de 24 a 12 meses 
??? , no provocara esto una nueva ola de lepra a futuro ???,  pues ya se demostro que el numero de 
bacilos viables aumenta a medida que se disminuye el tiempo de tratamiento. 

Si ya se han curado mas de 84 milones de personas con el clasico tratamiento,,,, porque no 
continuarlo ???? 
 
Es realmente confiable la utilizacion del nuevo esquema ROM, ????  Si es realmente confiable, 
porque no se esta utilizando en nuestros paises ??? 
 
Un hecho interesante lo constituye nuestra hermana republica de Brasil, quien ocupa el 2do lugar en 
prevalencia de la enfermedad (1.998), y estando al lado de Venezuela, pais pionero en la lucha 
contra la enfermedad. Porque Brasil no implemento los esquemas de Venezuela, ??? 
 
Porque Venezuela y otros paises no prueban la vacuna en base a Mycobacterium w utilizada en la 
India ??? 
 
Si bien es cierto que hay que elogiar a los investigadores en TODO EL MUNDO, tambien hay que 
reconocer que para triunfar hay que unir esfuerzos y no andar dispersos haciendo cada quien lo que 
mejor le convenga  y si esta alianza quiere triunfar TODOS tienen COLABORAR, dejar de un lado 
INTERESES PERSONALES o comerciales y poner empeño para matar el bichito. 

En estas 70 referencias los hechos... 
 
Saludos a todos 
Dr. Jose Lapenta R. 

EDITORIAL ENGLISH 
================= 
Hello friends of the net, DERMAGIC with other interesting topic: HANSEN forever??? 
For the year of  1.997  they registered some 690.000 new cases of the illness and the total was 
considered in 1.200.000 cases. As of 1997 around 2 100 000 000 people live in countries where 
the prevalence of leprosy is more than one case per 10 000 population.At the beginning of 1998, the 
number of leprosy patients in the world was about 800 000. For the year 2.000 the remaining 
leprosy cases in the world  are currently estimated at 2.5–2.8 million. 

The countries but affected they are India Indonesia and Myanmar (Asian southeast) which have 70% 
of the total of cases of Leprosy. Africa the second region but affected and in Latinoamérica America 
Brasil this severely affected one representing 80% of the cases of our continent. 
 
Biblical, ancestral and apocalyptic illness, the causing of the illness Mycobacterium Leprae 
discovered by Armauer Hansen in 1873 he still resists to be eliminated. The initial treatment was with 
the oil of Chalmoogra introduced by the Egyptian Tortoulis Bey in 1894. It was in the forties when 
appears the Dapsone like an alternative therapeutic really effective against the illness, then the 
rifampicin and the clofazimine (1981) being constituted these three drugs (MTD) in the official 
treatment of the OMS.  In the seventies beginning the time of those (vaccine-inmunotherapy) against 
the illness (Venezuela, India). In 1997 he was discovered that common antibiotics as the minocycline 
and Ofloxacin, jointly with rifampicin they are highly germicides against the bacillus of Hansen and 
new therapeutic outlines were instituted (ROM). Today in day in the India they uses a vaccine 
(Mycobacterium w) to stop the illness in that Continent. 
 
March 17 of 1.999 DERMAGIC/EXPRESS  went out to the net with the topic; 
THE MINOCYCLINE, THE GOOD thing, THE BAD thing AND THE UGLY thing, where I 
points out the beneficial effect of this medication in the leprosy and I asked the following question: 
"...... .really the minocycline is it using in the leprosy in our countries???" 

This DERMAGIC EXPRESS was published in the Chilean magazine of DERMATOLOGY, as I 
comment myself the Dra Altanisia Ramuno (Venezuela). 
 
August 11 of 1.999 DERMAGIC EXPRESS  returned to the net with the topic LEPROSY AND 
VACCINES  where in the editorial it was written: 
"....in the India NEW DELHI,  has been working with 4 strains, among those are the 
Mycobacterium Habana and Mycobacterium w, this last of which will put on to the market THE 
FIRST VACCINE against the Leprosy produced by Cadila Pharmaceuticals,  according to them, 
because it IS NONPATHOGEN. But if we revise ALL the references well, they ARE NOT 
VACCINE PROPERLY, this in the strict sense of the PREVENTION of the infection, since they 
are used in combination with multidrugtherapy (MTD).  Let us also remember that the  classic 
VACCINE BCG (bacillus  Calmette-Guerin) that protects against the tuberculosis, it also protects 
against the leprosy.. " 
 
In January 26 of the 2000 DERMAGIC/EXPRESS it returned to the net with another revision: 
THE LEPROSY 2000 YEARS LATER... with 80 bibliographical references... 

 In the year 1.997 the World Organization of the health considers based on a Field trial  study 
that A SINGLE DOSE rifampicin, ofloxacin and minocycline were a good alternative and of low 
cost for the treatment of the paucibacillary leprosy (PB) with a single lesion, and a MONTHLY dose 
for 24 months for multibacillary   leprosy  (MB). The WHO also considers the decrease of the 
CLASSIC treatment with MTD to 12 months. 
 
In June of 1.999 in San Francisco carries out a meeting about leprosy between JAPAN AND 
UNITED STATES where several aspects were recognized like: the appearance of resistance of the 
Bacillus of Hansen to the DAPSONE, in the seventies, and at the moment to the fluoroquinolones 
and the new treatment RÉGIME (ROM), rifampicin-ofloxacin-minocycline, being determined the 
genetic causes of such a resistance. 
 
The year of 1.999 in London  carries out a study in mice infected with the Mycobacterium Leprae 
being used a rifampicin combination (RMP) with clarithromycin (CLARI) and ofloxacin (OFLO) 
being in the death of the bacillus in 3 weeks of treatment. The combination of Sparfloxacin (SPAR) 
plus rifampicina (RMP) I also cause the same effect. They concludes that 
This combination of drugs: RMP, OFLO, or (SPAR)-CLARI, with or without minocycline (MINO) 
and whose effectiveness is observed in 4 WEEKS it can be administered to patient by one period 
but I short  that the current of 2 years (reduced to 1 year at the moment) with MTD. 
 
In the year 1.981 the OMS based on evidences scientists considers that the treatment with MTD 
(rifampicin, dapsone and clofazimine)should be of 6 months for the paucibacillary leprosy  (PB) and 
of 2 years for the multibacillary leprosy (MB)  in the conference of 1.994 ratifies this treatment 
outline for their high effectiveness, there being achieved the cure of about 84. millions of patient. 
 
In the conference of 1.997 on leprosy THE OMS considers a decrease of the treatment with MTD 
to 12 months in the multibacillary leprosy  (MB) based on some carried out studies and mainly the 
fact of the resistance appearance to the drugs used by the NONFULFILMENT of the treatment in 
the areas of difficult access. 
 
In the year of 1.999 in the India two studies were published about  to detect viable bacilluses in 
patient with multibacillary leprosy after 6, 12, 24 and 36 months of classic treatment with MTD. It 
was DEMONSTRATED that after 12 MONTHS OF TREATMENT between 25% -31% of the 
patients had viable bacilluses. After 2 years of treatment alone 8%-12%.After 3 years of treatment 
4%. AND THEY RECOMMENDED TO HAVE CAUTION WITH THIS REDUCTION OF 
THE DURATION OF THE TREATMENT FROM 24 TO 12 MONTHS. 
 
In a study carried out in China and published in December of 1.999 on the pursuit to 
patient with leprosy paucibacilar (PB) and multibacilar (MB) after classic treatment with MTD 
they conclude that  is necessary to make them a ollow up for at least 5 years for paucibacillary (PB) 
and 10 years for MB patients after being released from WHO/MDT. 

In the year of 1.998 the FDA release again the thalidomide for the treatment the ELN (erythema 
nodosum leprosum.) 

November 15 1.999 the OMS throws a global alliance against leprosy with the objective of 
eliminating it completely of the planet earth before the year 2.005. 
 
India, indonesia and Brazil the countries but effected...for 1.998 
 
Do I close with several questions for all??? 
 
A bomb of time is not to diminish the classic TREATMENT WITH MTD from 24 to 12 months??? 
, didn't this cause a new leprosy wave in the future??? because it was already demonstrated that the 
one numbers of viable bacilluses it increases as diminishes the time of treatment. 

If they have already been treated but of 84 millionss of people with the classic treatment, because to 
not continue him???? 
 
Is the use of the new outline ROM really reliable????  If it is really reliable,why is not using in our 
countries??? 
 
An interesting fact constitutes it our sister republic of Brazil who occupies the 2do place in 
prevalence of the illness (1.998), and being beside Venezuela, pioneer country in the fight against the 
illness. Why Brazil doesn't implement the outlines of Venezuela??? 
 
Why Venezuela and other countries don't prove the vaccine based on Mycobacterium w used in the 
India??? 
 
Although it is certain that it is necessary to eulogize the investigators in the ENTIRE WORLD, it is 
also necessary to recognize that to triumph it is necessary to unite efforts and to not walk dispersed 
making each who that better it suits him and if this alliance wants to triumph ALL they have to 
COLLABORATE, to leave INTEREST PERSONAL or COMMERCIAL and to put zeal to kill 
the bug. 

In these 70 references the facts... 
 
Greetings to all 
 Dr. Jose Lapenta R.,,, 
================================================================== 
REFERENCIAS BIBLIOGRAFICAS / BIBLIOGRAPHICAL REFERENCES 
================================================================== 
============================================================= 
1.) Leprosy: the Disease 
2.) The Global Alliance for Elimination of Leprosy 
3.) Leprosy in a child of less than two months of age. 
4.) 7th WHO Expert Committee on leprosy June 1997 
5.) The US-Japan Joint Leprosy Research Program Meeting, San Francisco, June 28-30, 1999 
6.) Another View of the Therapy of Leprosy 
7.) Rifampicin/minocycline and ofloxacin (ROM) for single lesions--what is the evidence? 
8.) What are the new antileprosy drugs - ROM - now available for the treatment of leprosy? 
9.)What are the types of leprosy that can be treated by ROM ? 
10.)What is the reason for introducing single dose treatment for paucibacillary leprosy presenting 
with a single skin lesion? 
11.) What is the basis for the recommended alternative regimen for the treatment of paucibacillary 
leprosy presenting with a single skin lesion? 
12.)Does WHO recommend that all programmes should treat single lesion paucibacillary leprosy 
cases with one dose of ROM? 
13.) Efficacy of single dose multidrug therapy for the treatment of single-lesion paucibacillary 
leprosy. Single-lesion Multicentre Trial Group. 
14.) Minocycline in lepromatous leprosy. 
15.) Efficacy of minocycline in single dose and at 100 mg twice daily for lepromatous leprosy. 
16.) Field trial on efficacy of supervised monthly dose of 600 mg rifampin, 400 mg ofloxacin and 
100 mg minocycline for the treatment of leprosy; first results. 
17.) Bactericidal activity of a single-dose combination of ofloxacin plus minocycline, with or without 
rifampin, against Mycobacterium leprae in mice and in lepromatous patients. 
18.) Bactericidal activity of single dose of clarithromycin plus minocycline, with or without ofloxacin, 
against Mycobacterium leprae in patients. 
19.) WHO Expert Committee on Leprosy. 
20.) Experimental evaluation of possible new short-term drug regimens for 
treatment of multibacillary leprosy. 
21.) Powerful bactericidal activities of clarithromycin and minocycline 
against Mycobacterium leprae in lepromatous leprosy. 
22.) Leprosy resistant to multi-drug-therapy (MDT) successfully treated 
with ampicillin-sulbactam combination--(a case report). 
23.) Differential protective effect of bacillus calmette-guerin vaccine 
against multibacillary and paucibacillary leprosy in nagpur, india. 
24.) Protective effect of Bacillus Calmette Guerin (BCG) against leprosy: a 
population-based case-control study in Nagpur, India. 
25.) Patient contact is the major determinant in incident leprosy: 
implications for future control. 
26.) The clinical use of fluoroquinolones for the treatment of mycobacterial diseases. 
27.) A case of relapsed leprosy successfully treated with sparfloxacin. 
28.) Active leprosy treated effectively with ofloxacin. 
29.) Reactional states and neuritis in multibacillary leprosy patients following MDT with/without 
immunotherapy with Mycobacterium w antileprosy vaccine. 
30.) Mycobacterium w vaccine, a useful adjuvant to multidrug therapy in multibacillary leprosy: a 
report on hospital based immunotherapeutic clinical trials with a follow-up of 1-7 years after 
treatment. 
31.) What is WHO MDT? 
32.) Is WHO-recommended multidrug therapy (MDT) the best combination available for treatment 
of multibacillary (MB) and paucibacillary (PB) leprosy in leprosy control today? 
33.) WHY MULTIDRUG THERAPY FOR MULTIBACILLLARY LEPROSY CAN BE 
SHORTENED TO 12 MONTHS 
34.) Supervised Multiple Drug Therapy Program, Venezuela 
35.) Search for newer antileprosy drugs. 
36.) Mycobacterium leprae--millennium resistant! Leprosy control on the threshold of a new era. 
37.) The impact of multidrug therapy on the epidemiological pattern of leprosy in Juiz de Fora, 
Brazil. 
38.) Serologic response to mycobacterial proteins in hansen's patients during multidrug treatment. 
39.) HLA linked with leprosy in southern China: HLA-linked resistance alleles to leprosy. 
40.) A Mycobacterium leprae-specific human T cell epitope cross-reactive 
with an HLA-DR2 peptide. 
41.) Association of HLA antigens with differential responsiveness to 
Mycobacterium w vaccine in multibacillary leprosy patients. 
42.) HLA antigens and neural reversal reactions in Ethiopian borderline 
tuberculoid leprosy patients. 
43.) Evidence for an HLA-DR4-associated immune-response gene for 
Mycobacterium 
tuberculosis. A clue to the pathogenesis of rheumatoid arthritis? 
44.) Diaminodiphenylsulfone resistance of Mycobacterium leprae due to 
mutations in the dihydropteroate synthase gene. 
45.) Resolution of lepromatous leprosy after a short course of 
amoxicillin/clavulanic acid, followed by ofloxacin and clofazimine. 
46.) Studies on risk of leprosy relapses in China: relapses after treatment with multidrug therapy. 
47.) An immunotherapeutic vaccine for multibacillary leprosy. 
48.) Nasal mucosa and skin of smear-positive leprosy patients after 24 months of fixed duration 
MDT: histopathological and microbiological study. 
49.) Induction of lepromin positivity following immuno-chemotherapy with Mycobacterium w 
vaccine and multidrug therapy and its impact on bacteriological clearance in multibacillary leprosy: 
report on a hospital-based clinical trial with the candidate antileprosy vaccine. 
50.) SIMLEP: a simulation model for leprosy transmission and control. 
51.) Detection of viable organisms in leprosy patients treated with multidrug therapy. 
52.) An immunotherapeutic vaccine for multibacillary leprosy. 
53.) Addition of immunotherapy with Mycobacterium w vaccine to multi-drug therapy benefits 
multibacillary leprosy patients. 
54.) Immunotherapy with Mycobacterium w vaccine decreases the incidence and 
severity of type 2 (ENL) reactions. 
55.) A follow-up study of multibacillary Hansen's disease patients treated with multidrug therapy 
(MDT) or MDT + immunotherapy (IMT). 
56.) Immunotherapy of lepromin-negative borderline leprosy patients with low-dose Convit vaccine 
as an adjunct to multidrug therapy; a six-year follow-up study in Calcutta. 
57.) Immunotherapy of far-advanced lepromatous leprosy patients with low-dose convit vaccine 
along with multidrug therapy (Calcutta trial). 
58.) A longitudinal study of immunologic reactivity in leprosy patients treated with immunotherapy. 
59.) BCG vaccination protects against leprosy in Venezuela: a case-control study. 
60.) Immunoprophylactic trial with combined Mycobacterium leprae/BCG vaccine against leprosy: 
preliminary results. 
61.) Why relapse occurs in PB leprosy patients after adequate MDT despite they are Mitsuda 
reactive: lessons form Convit's experiment on bacteria-clearing capacity of lepromin-induced 
granuloma. 
62.) A lost talisman: catastrophic decline in yields of leprosy bacilli 
from armadillos used for vaccine production. 
63.) RESEARCH IN LEPROSY - ( H.D.)/ LEPROSY - RESEARCH AND BEYOND THE 
YEAR 2000 
64.)THE CHALLENGE OF LEPROSY” at :- INDIA APPROVES LEPROSY VACCINE ( 
Ganapati Madur, New Delhi ) 
65.) A vaccine for leprosy 
66.) FREQUENTLY ASKED QUESTIONS about Leprosy / Hansen’s Disease 
67.) Leprosy Elimination 
68.) 'LEPROSY' IN THE BIBLE - WHAT WAS IT? 
69.) TI  - Thalidomide's effectiveness in erythema nodosum leprosum is 
associated with a decrease in CD4+ cells in the peripheral blood. 
70.) Leprosy in Venezuela, 1.998 
============================================================= 
============================================================= 
1.) Leprosy: the Disease 
============================================================= 
Leprosy is a chronic infectious disease caused by 
Mycobacterium leprae, an acid-fast, rod-shaped bacillus. The 
disease mainly affects the skin, the peripheral nerves, mucosa of the upper respiratory tract and also 
the eyes, apart from some other structures. Leprosy has afflicted humanity since time immemorial. It 
once affected every continent and it has left behind a terrifying image in history and human memory - 
of mutilation, rejection and exclusion from society. 
Leprosy has struck fear into human beings for thousands of 
years, and was well recognized in the oldest civilizations of China, Egypt and India. A cumulative 
total 
of the number of individuals who, over the millennia, have suffered its chronic course of incurable 
disfigurement and physical disabilities can never be calculated. 

Since ancient times, leprosy has been regarded by the community as a contagious, mutilating and 
incurable disease. There are many countries in Asia, Africa and Latin America with a significant 
number of leprosy cases. As of 1997 around 2 100 000 000 people live in countries where the 
prevalence of leprosy is more than one case per 10 000 population. It is estimated that there are 
between one and two million people visibly and irreversibly disabled due to past and present 
leprosy 
who require to be cared for by the community in which they live. 

When M.leprae was discovered by G.A. Hansen in 1873, it was the first bacterium to be identified 
as causing disease in man. However, treatment for leprosy only appeared in the late 1940s with the 
introduction of dapsone, and its derivatives. Leprosy bacilli resistant to dapsone gradually appeared 
and became widespread. 

In 1997, there were an estimated 1.2 million cases in the world, most of them concentrated in 
South-East Asia, Africa and the Americas. The number of new cases detected worldwide each year 
is about half a million. 
 
=========================================================== 
2.) The Global Alliance for Elimination of Leprosy 
=========================================================== 
source: THE WHO on leprosy 
The Final Push 

An Alliance to eliminate leprosy. . . 

On November 15 th 1999, representatives of leprosy endemic countries, the World Health 
Organisation (WHO), the Nippon Foundation, Novartis and the International Federation of the 
Anti-Leprosy Associations (ILEP) announced a Global Alliance to eliminate leprosy as a public 
health problem from every country by the year 2005.TheAlliance will work closely with patients, 
communities and all agencies interested in leprosy such as the Danish International Development 
Agency (DANIDA) and the World Bank. 

The Alliance and its partners aim to detect and cure all the remaining leprosy cases in the world – 
currently estimated at 2.5–2.8 million – over this six year period. Efforts will focus on generating 
"demand" for treatment through improved awareness of leprosy in conjunction with better access to 
diagnosis and treatment. 

Is it really possible to do away with a disease that has afflicted humanity since time immemorial? It is 
no simple matter, since leprosy is an insidious, slowly-developing disease which flourishes mainly in 
the 'poverty belt' of the globe. It once affected every continent and it has etched a terrifying image in 
history and human memory, of mutilation, rejection and exclusion from society. Leprosy has always 
and everywhere been regarded as a special disease. 

India, Indonesia and Myanmar account for 70% of all the cases in the world. 

In Africa, the second most affected area, the situation is more difficult for the moment.The AIDS 
epidemic, the resurgence of the major tropical diseases, weaknesses in health infrastructure, social 
unrest and armed conflict make leprosy elimination seem like a luxury, an impracticable one at that. 

The situation remains worrying in Latin America. Brazil is particularly badly affected, accounting for 
over 80% of cases in that continent. 

In Central and Eastern Europe, there are sporadic cases; it is impossible at present to tell how many 
such cases go unreported. 
 
============================================================ 
3.) Leprosy in a child of less than two months of age. 
============================================================= 
Benerjee, K, Meyers W.M., 
Clinical Dermatology,  The CMD Case collection, World Congress Of Dermatology 
Berlin (West), 
May 24-29-1.987,: 149. 

History. Patient was a less than 2 months oid male baby belonging to one of the trained  nurses of 
our Institute. The chud had close, intimate contact with arelative who suffered 
from dimorphous leprosy and who had taken treatment for only 6 months before discontinuing it on 
his own. 
Examination. A round, elevated, red-dish lesion was detected on the face. 
Investigations. KOH mount of scrap-ings showed no fungus. A slit smear for acid fast  bacilli was 
negative. 
Histopathology. Skin biopsy material was sent to 4 different centres. Ah of them confirmed it to be 
Hansen's disease of a tuberculoid nature. 
Treatment. The lesion resolved com-pletely within three months' treatment with D.D.S. 2.5 mg for 5 
days each week. 
Conclusion. To my knowledge leprosy at less than 2 months of age has not yet been 
reported and may be disputed. Two cases of leprosy at 6 months of age were reported  by Bruce 
Baker et al. The precise mode of natural transmission, the incuba-tion period 
and clinical manifestation have not yet been established. Early signs and diagnosis may be missed in 
the mistaken belief that leprosy is non-existent in the very young. 

======================================================== 
4.) 7th WHO Expert Committee on leprosy June 1997 
======================================================== 

MAJOR CONCLUSIONS AND RECOMMENDATIONS 
The major conclusions and recommendations of the Expert Committee are summarized below: 

The Global Strategy for the Elimination of Leprosy, based on the implementation of MDT with 
case-finding, is working extremely well in reducing the prevalence of leprosy and should be 
continued. 
There is an important need to detect and treat the remaining undetected cases, for which special 
approaches, along with the extension of MDT services to all general health facilities, are required. 
The progressive simplification of diagnostic and treatment technologies has continued to facilitate 
reaching more leprosy patients. 
Based on a multicentre trial, it is considered that a single dose of a combination of rifampicin, 
ofloxacin and minocycline is an acceptable and cost-effective alternative regimen for the treatment of 
single-lesion PB leprosy. Furthermore, based on available information, it is possible that the duration 
of the current MDT regimen for MB leprosy could be shortened further to 12 months. 
A fresh strategy for the implementation of disability prevention and rehabilitation is called for to 
ensure a practical, community-oriented approach aimed at reaching the largest number of persons in 
need with-cost effective interventions. 
The monitoring of elimination through essential indicators should continue. Information reported 
should be validated and analysed further through independent monitors in order to identify in good 
time problem situations needing action. 
Anti-leprosy activities should become, and should remain beyond the year 2000, an integral part of 
general health services everywhere, and should also involve the communities to the fullest extent 
possible. Coordination between various agencies, including local and international nongovernmental 
organizations, should be consolidated. 
It is recommended that research in leprosy be continued, especially in improving patient care and in 
addressing post-elimination issues. 
It is important to sustain anti-leprosy activities beyond the year 2000 in order to deal with the 
remaining problems, including new cases and persons with disability. 

======================================================== 
Executive Summary 
======================================================== 

The WHO Expert Committee on Leprosy met in Geneva from 26 May to 3 June 1997 to review the 
global state of leprosy and the technology for dealing with it, to identify the remaining obstacles to 
reaching the goal of elimination, and to make technical and operational recommendations related to 
elimination and beyond. 

Definition of a case of leprosy: 
A case of leprosy is a person having one or more of the following features, and who has yet to 
complete a full course of treatment: 
- hypopigmented or reddish skin lesion(s) with definite loss of sensation; 
- involvement of the peripheral nerves, as demonstrated by definite thickening with loss of sensation; 
- skin smear positive for acid-fast bacilli. 
The case definition includes retrieved defaulters having signs of active disease as well as relapsed 
cases who have previously completed a full course of treatment, but does not include cured persons 
with late reactions or residual disabilities. 

Clinical classification for control programmes 
Since single-lesion leprosy may be cured by a shorter regimen than the standard MDT for PB 
leprosy, the Committee suggested that patients be classified into three groups: 
(a) PB single-lesion leprosy (one skin lesion); 
(b) PB leprosy (2-5 skin lesions); and (c) MB leprosy (more than 5 skin lesions). 

BCG re-vaccination 
The widespread application of BCG is likely to be a contributing factor to the decline in leprosy 
incidence observed in certain populations. However, repeated doses of BCG to prevent leprosy are 
not recommended on the grounds of poor cost-effectiveness, lack of acceptability to recipients, 
operational difficulties, and the fact that BCG is contraindicated in symptomatic HIV individuals. 

Shortening duration of MDT regimen for MB leprosy 
The results from both nude mouse experiments and a clinical trial have demonstrated that the 
rifampicin-resistant mutants in an untreated lepromatous patient are likely to be eliminated by 3 to 6 
months of treatment with the dapsone-clofazimine component in MDT regimen. From the 
operational point of view, the duration of MDT for MB leprosy is still very long, which adversely 
affects the implementation of MDT among all patients in need of treatment. When the Study Group 
(1981) designed the MDT regimens, MB leprosy referred to those patients who had a BI of 2 at any 
site in the initial skin smears. Currently MB leprosy includes all smear-positive patients, as well as 
patients with more than five lesions. Among the newly detected cases, the skin-smear positive 
patients represent only 12.5% of the total number. Based on all the available information, the 
Committee accepted that it is possible to reduce the duration of the current MDT regimen for MB 
leprosy to 12 months without significantly compromising its efficacy. 

Flexible MDT delivery system 
Due to poor coverage of the health services in most of the leprosy-endemic countries, supervision of 
the monthly administered drugs by health workers may not always be possible. In that case, more 
than one month's supply of MDT blister packs may be given to the patient, provided he or she is 
given appropriate information and guidance regarding the dosage, rhythm and necessary duration of 
treatment, and is advised to report any untoward signs/symptoms promptly. 

Regimen for single skin lesion PB leprosy 
Based on the results of a large multicentre randomized double-blind controlled clinical trial the 
Committee considered that a single dose of rifampicin 600 mg plus ofloxacin 400 mg and 
minocycline 100 mg, is an acceptable and cost-effective alternative regimen for the treatment of 
single skin lesion PB leprosy. 

Other regimens for special situations 
The Committee suggested that patients who do not accept clofazimine can be treated with a monthly 
administration of a combination consisting of 600 mg of rifampicin, 400 mg of ofloxacin and 100 mg 
of minocycline (ROM) for 24 months. For adult MB patients who cannot take rifampicin, the 
Committee recommended the daily administration of 50 mg of clofazimine, together with 400 mg of 
ofloxacin and 100 mg of minocycline for 6 months; followed by daily administration of 50 mg of 
clofazimine, together with 100 mg of minocycline or 400 mg of ofloxacin for at least an additional 18 
months. 

Drug resistance 
Rifampicin is by far the most bactericidal drug against M. leprae, and will still be the backbone of the 
MDT regimens in the foreseeable future. Consequently, all efforts should be made to prevent the 
emergence of rifampicin-resistant leprosy. To improve the surveillance of rifampicin-resistance, it 
may be useful to establish the genetic method for rapid detection of rifampicin-resistant strains at 
certain regional reference centres. 

Defaulter: definition and management 
A defaulter is a patient who started MDT but who has not received treatment for 12 consecutive 
months despite all attempts to trace the patient. If a defaulter patient returns to the health centre for 
treatment and shows signs of active disease such as new skin lesions, new nerve involvement or new 
nodules, he/she should be given a new course of MDT. In the absence of these, there is no need to 
restart MDT. 

Drug supply logistics 
The provision of an uninterrupted supply of high quality MDT drugs in blister packs, free of charge, 
to all patients is essential, including those living in difficult-to-access areas. To ensure the availability 
of MDT drugs and their proper distribution, a coordination mechanism between the government, 
WHO and donor agencies at the country level is needed. 

Management of reactions 
The crucial elements in the management of leprosy reactions and, thereby, the prevention of 
disabilities are early diagnosis of reactions together with prompt and adequate treatment. Most 
reactions, and neuritis, can be treated successfully under field conditions by a standard 12-week 
course of prednisolone. If patients do not respond to corticosteroid therapy in the field, they should 
be sent to an appropriate referral centre. 

WHO disability grading for leprosy 
At its last meeting in 1987, the WHO Expert Committee on Leprosy had substantially simplified the 
grading into a three-grade (0, 1, 2) system. This Committee endorsed this grading with the 
amendment that lagophthalmos, iridocyclitis and corneal opacities be considered as Grade 2. For 
safety reasons the Committee does not recommend the testing of touch sensibility of the cornea 
under field conditions. 

Reaching pockets of high prevalence 
In most endemic countries, MDT services are able to reach those patients who can easily contact the 
health care system. However, certain areas in some endemic countries have patients with only limited 
access to health care, or have MDT services that are not operating or not being utilized. In such 
areas, leprosy elimination campaigns (LEC) will be able to clear up undetected cases which have 
accumulated over a period of time in the community. Under LEC, three major activities are grouped 
as a new package: capacity building measures for local health workers to improve MDT services; 
increasing community participation; and diagnosing and curing patients, particularly MB cases. 

Reaching special population groups 
To reach patients living in difficult-to-access areas, or those belonging to underserved population 
groups, special action projects for the elimination of leprosy (SAPEL) constitute an important 
initiative to ensure the fullest MDT coverage. The essential elements of SAPEL are, firstly, to find 
cases living in difficult areas or situations who are in need of treatment and, secondly, to cure them. 
Innovative and practical strategies involving mainly operational solutions will be used in order to 
provide MDT to these patients. Since the project operates in situations where the health 
infrastructure is weak or does not exist, the strategies used should promote self-reliance and 
self-help, and must involve the community so that the activities begun under SAPEL can be 
sustained. 

Leprosy and human rights 
Patients on MDT, and those cured of disease, should not suffer from restrictions in areas such as 
employment, education and travel. Any special legal measures that might increase prejudice against 
leprosy or prevent early cases from presenting themselves for diagnosis and treatment should be 
abolished. In some countries, the human rights problem is particularly serious among female patients, 
firstly, because of their gender, and secondly, because of the stigmatization associated with leprosy. 

Strategy beyond elimination 
After the year 2000, simplifying MDT services and strengthening the process of integration into the 
general health services are the keys to sustaining anti-leprosy activities, especially in low prevalence 
situations. The uneven distribution of leprosy makes it possible to have significant endemicity in some 
parts of a country, particularly for larger countries, even though the national elimination target has 
been attained. It is important to focus elimination activities at the most peripheral levels and to plan to 
reach the elimination goal at sub-national levels. 

Monitoring leprosy elimination 
The validity of the essential indicators, reported by the programmes, should be assessed by 
independent monitors in collaboration with the national programmes, through special activities such 
as leprosy elimination monitoring (LEM) and Geographic information systems (GIS). 

Integration of anti-leprosy activities 
Programmes fully-integrated into the general health services would be more appropriate for 
strengthening leprosy elimination activities than vertical or combined programmes. 

Community action and participation 
The local community and its leaders will play a key role in improving public awareness about the 
disease and about the availability of free and effective treatment. Indeed, in some situations they may 
be the only possibility for delivering MDT drugs, supervising the monthly drug administration and 
retrieving defaulters, thereby ensuring that the patients complete their treatment. In addition, the 
prevention of dehabilitation and the rehabilitation of individual persons affected by leprosy depends 
on the community. 

Research priorities 
Due to the great success of implementing MDT, there has been a tendency in recent years for 
support for leprosy research to decline, and this may hamper the development of new technologies 
which are needed for leprosy elimination and beyond. The Committee recommends that national 
governments, scientific communities, international organizations and NGOs continue their support to 
leprosy research, particularly operational research in major endemic countries. 
 

======================================================= 
5.) The US-Japan Joint Leprosy Research Program Meeting, San Francisco, June 28-30, 1999 
======================================================= 

PATRICK J. BRENNAN 
Department of Microbiology, Colorado State University, Fort Collins, CO 80523-1677, USA 

Accepted for publication 1 August 1999 

The US-Japan Cooperative Medical Sciences Program was founded in the 1960s by the 
then-President of the United States and the Prime Minister of Japan and, since then, has had the 
highest political support from both governments. Leprosy was among the first disease entities named 
as part of the overall program, and the US and Japanese leprosy research panels and their guests 
have met in the alternating countries every year for the past 34 years (in 1995, the separate leprosy 
and tuberculosis panels were amalgamated). These meetings of the joint US-Japan panels in the form 
of scientific conferences have become a highlight of the annual leprosy research agenda. Some of the 
major fundamental research developments in leprosy over the past 30 years have been first reported 
at this conference. These include: the early development of the drug regimens leading to present-day 
MDT and ROM; the early development of the mouse footpad; the recognition of sylvian leprosy in 
the armadillo and the development of this model of leprosy and, later, the Mangabey monkey model; 
the original work on the extension of hybridoma technology to leprosy and the development of banks 
of monoclonal antibodies; the first research on the application of genetic recombinant technology to 
Mycobacterium leprae and the production of 15-20 recombinant protein antigens; the discovery of 
the heat-shock proteins and of PGL-I, and the synthesis of corresponding neoglycoproteins and the 
development of ELISA systems; the major developments in the definition of the genome and 
proteome of M. leprae; all major developments in defining the cellular immune response in leprosy; 
the application of thalidomide to leprosy reactions and elucidation of its action mechanism etc. 

The 34th US-Japan Leprosy Research Conference was held in San Francisco in conjunction with 
the US-Japan Tuberculosis Research Conference, June 28-30, 1999. Some of the highlights are as 
follows. 

A. Rambukkana (Rockefeller University, New York, USA) described the latest chapter in his 
important work on the molecular basis of the interaction between the Schwann cell and M. leprae. 
Previously, he had described how the G domain of the laminin a 2 chain in the basal lamina that 
surrounds the Schwann cell-axon unit serves as an initial neural target for M. leprae. This time, he 
addressed the nature of the M. leprae surface molecules that bind to a 2 laminin. By using human a 2 
laminins as a probe, a major 28 kDa protein in the M. leprae cell wall fraction was identified. 
Immunofluorescence and immunoelectron microscopy on intact M. leprae, using monoclonal 
antibodies against the recombinant protein, demonstrated that the protein is surface-exposed. Also, 
the recombinant protein was shown to bind avidly to a 2 laminins, the recombinant G domain of the 
laminin-a 2 chain, and the native peripheral nerve laminin. Thus, these data suggest that this 28 kDa 
protein functions as a critical surface adhesin that facilitates the entry of M. leprae into Schwann 
cells. 

In subsequent discussion of this work, it was revealed that Dr Cristina Pessolani (Fio-Cruz, Rio de 
Janeiro) had also described a 28 kDa protein as a key bacterial ligand in M. leprae-Schwann cell 
interaction and had shown that this is a member of the histone-like protein family. It thus seems that 
the protein described by Dr Rambukkana is this HLP. 

Dr Takeshi Yamada and colleagues (Nagasaki University, Japan) have also focused on this protein 
from a different perspective. They have been investigating the molecular basis of the slow growth of 
M. leprae and other mycobacteria and identified a 28 kDa protein (which they called MDPI) as the 
most abundant protein in M. bovis BCG. The protein was highly polymerized and localized in the 
nucleoid, 50S ribosomal subunit and cell surface. It interfered with replication, transcription and 
translation in E. coli cell-free systems, and was capable of transforming E. coli to slow growth. 
Sequence analysis also indicated a member of the HLP family. Thus, the 28 kDa HLP is apparently 
a major player in the pathogenesis and physiology of M. leprae. Its immunogenicity and diagnostic 
potential should now be examined. 

Efforts to 'cultivate' M. leprae continue, but this time through genetic augmentation of the organism, a 
sensible plan in light of a genome that is small and very defective in gene density. Drs Scott G. 
Franzblau (GWL Hansen's Disease Center, Baton Rouge, LA, USA) and William R. Jacobs (Albert 
Einstein College of Medicine, New York, USA) have used a combination of freshly harvested, 
viable nude mouse-propagated M. leprae and a modified D29 mycobacteriophage vector to achieve 
phage infection of M. leprae and foreign gene expression. Therefore, the key preliminary work has 
been achieved as a prelude to constructing a shuttle cosmid vector, carrying DNA libraries from 
slow growing cultivable mycobacteria and capable of stable expression of foreign DNA in M. 
leprae, allowing, in future, perhaps, in vitro growth competence. 

Widespread resistance to dapsone in the 1970s was the catalyst for the development of multiple 
drug therapy (MDT) for the treatment of leprosy. However, to date, researchers have not been 
successful in characterizing the molecular basis of dapsone resistance. Two laboratories have now 
conducted crucial preliminary experiments (Dr Y. Kashiwabara, Leprosy Research Center, Tokyo, 
Japan, and Dr Diana Williams, GWL Hansen's Disease Center). An analysis by others of 
sulphonamide resistance in E. coli has shown an association with dihydropteroate synthase (DHPS), 
a key enzyme in the folate biosynthetic pathway, encoded by the folp gene. Dr Williams has shown 
that M. leprae possesses two folp homologs (folP1 and folP2). DDS resistance was not associated 
with mutations in folP2 from two high-level DDS-resistant strains of M. leprae. However, mutations 
were observed within a highly conserved region of folP1 in two of these high-level DDS-resistant M. 
leprae clinical isolates. In addition, this folP1 homolog has been shown to encode a functional DHPS 
which itself is highly sensitive to DDS. These new data thus support early predictions that DDS 
resistance in M. leprae is associated with alterations in folate metabolism and that one possible 
mechanism of resistance is due to mutations in folP1. 

Resistance to fluoroquinolones is becoming widespread, at a time when ofloxacin, one of the 
fluoroquinolones, is being used more and more frequently in the form of ROM (rifampin, ofloxacin, 
and minocycline) in leprosy control programs. Dr Y. Kashiwabara has determined the sequences of 
the QRDR (quinolone resistance determining region) of gyrA (the gene encoding the A subunit of 
gyrase, the site of action of the fluoroquinolones) in 13 clinical isolates of M. leprae, and 
demonstrated that eight of them showed mutations in this region. Importantly, five of the eight also 
showed mutations in the rpoB gene (the gene encoding the B subunit of RNA polymerase, the site of 
action of the rifamycins), suggesting that exposure to one or the other of the two drugs can lead to 
resistance to both, a new worry as we develop alternative drug regimens for leprosy. 

The type of molecular epidemiology that is now being applied to M. tuberculosis isolates and 
tuberculosis in general has not been possible with leprosy, because M. leprae is devoid of the type of 
variable but relatively stable genetic polymorphism associated with the IS6110 insertion sequences in 
the M. tuberculosis chromosome. If other forms of DNA polymorphism could be identified in the M. 
leprae genome, the lessons that could be derived from its application would be profound in terms of 
tracking sources of infection, examining the relationship between non-symptomatic carriage of M. 
leprae and disease, probing the possibility of environmental sources of M. leprae, and differentiating 
between reactivation and new infection. Dr Y. Kashiwabara has now found some evidence of such 
polymorphism, albeit limited. The sequences of the rpoT gene from many M. leprae isolates were 
compared, allowing the classification of isolates into two broad categories. One group had three 
tandem repeats of a six-base-pair (AGATCG) sequence, and the other group had four tandem 
repeats. Isolates from Japan and Korea had the four-tandem repeat profile, whereas isolates from 
South-East Asian and Latin American countries had the three-repeat pattern, indicating that this 
genetic characteristic could be used to trace the origins of infections and the evolution of disease. 

The role of various cytokines and different T-cell subsets in leprosy pathogenesis and immunity to 
leprosy has long been a favorite topic of US-Japan participants. The curious balance between 
acquired resistance and pathogenesis is seen in granulomatous infiltration, a consequence of the 
marshalling of the acquired response to essentially contain bacilli, but with pathological sequelae. In 
the hands of Dr Linda Adams (GWL Hansen's Disease Center), mice genetically incapable of 
producing a functional inducible NO synthase (iNOS) showed markedly enhanced granuloma 
formation, and these types of granulomas were composed primarily of CD4+ cells and 
multinucleated giant cells. Thus, iNOS has an unexpected role in leprosy granulomatosis. Among the 
newer cytokines to be involved in the leprosy immune response are IL-12 and IL-10. According to 
Dr Robert Modlin (University of California, Los Angeles, CA, USA), some key lipoprotein ligands 
of M. leprae bind to the toll-like receptors in macrophages, evoking the dual response of NO 
production and IL-12 evocation, two new major players in counteracting infection. We have long 
been very conscious of the role of IFN-g in the type-1 protective immune response in leprosy. 
Apparently, part of the mechanism of this effect is to up-regulate type-1 cytokine expression and 
down-regulate IL-10, one of the type-2 cytokines (Drs Y. Fukutomi and M. Matsuoka, Leprosy 
Research Center, Tokyo, Japan). The newest players in these events are the chemokines. M. leprae 
induces elevated levels of MCP-I, MIP-1a , and MIP-1b expression, and it is now believed that 
chemokines will prove to be important in regulating granuloma formation and other immune 
responses in leprosy (Dr Linda Adams). 

Preliminary results were also reported by Dr T.P. Gillis (GWL Hansen's Disease Center) on the 
application of DNA vaccines to an animal model of leprosy. A recombinant construct of the antigen 
85A injected intradermally proved to be the most promising with strong IgG1 and Ig2a antibody 
responses and increased IFN-g and IL-2 production. However, protection studies in the mouse 
footpad infection model were disappointing. 

With the amalgamation of the US-Japan Leprosy and Tuberculosis Panels in 1995, a fear of leprosy 
research workers within the US-Japan Cooperative Medical Sciences Program was that leprosy 
research would be engulfed by the tuberculosis research juggernaut. This fear has proved to be 
unfounded. Basic research in leprosy is thriving, notably in Japan, where the Leprosy Research 
Center has been incorporated into the prestigious, well-endowed National Institute of Infectious 
Diseases. The formal combination of both panels is clearly benefiting leprosy research. 

============================================================= 
6.) Another View of the Therapy of Leprosy 
============================================================= 
Antimicrobial Agents and Chemotherapy, December 1998, p. 3334-3336, Vol. 42, No. 12 
LETTER/ Dr. Gelber's 
From 1943 until 1982 the standard treatment for lepromatous leprosy was lifelong dapsone 
monotherapy. Though dapsone is bacteriostatic and lepromatous leprosy has the highest bacterial 
burden of all human diseases, as well as an impairment in protective cellular immunity, dapsone 
monotherapy proved surprisingly effective. Only 10% of patients developed resistance (19), and on 
cessation after 18 years of treatment only an additional 10% clinically relapsed (21). In the 1970s 
Freekson and Rosenfeld (3) in Malta treated leprosy patients, many treated previously with dapsone 
alone for many years, with a regimen of daily rifampin, prothionamide, dapsone, and isoniazid (not 
active against Mycobacterium leprae) for 2 years and found that patients were regularly cured. In 
1982 the World Health Organization (WHO) (22, 23) recommended another 2-year regimen of 
multidrug therapy (MDT) (monthly rifampin, 600 mg, plus clofazimine, 300 mg, and daily dapsone, 
100 mg, plus clofazimine, 50 mg). This regimen has been widely implemented, largely in patients 
previously treated with dapsone for prolonged periods, many of whom no longer harbored 
detectable M. leprae, and successfuly (20). However, the one clinical study in previously untreated 
lepromatous patients followed up for a sufficient time found an unacceptably high relapse rate of 20 
to 40%, depending on the initial bacterial burden (12). 

Having discovered that minocycline was bactericidal for M. leprae in mice (5) and in a clinical trial 
(7) and having conducted several studies of the three antimicrobials utilized by Ji et al. (16) in mice 
and patients, I was naturally interested in their findings and conclusions. Against an alternative view 
of the reliability of WHO MDT and the further desirability of a once-monthly supervised regimen, Ji 
et al. (16) report that in leprosy patients single doses of minocycline plus ofloxacin with and without 
rifampin are bactericidal and side effects are acceptable; thus, further clinical application of 
intermittent therapy (monthly) is indicated. I do not believe their results in fact merit these 
conclusions. 

In their introduction the authors state that further applications of regimens to be used with rifampin 
must prove themselves to be bactericidal. However, the single dose of minocycline plus ofloxacin 
used was entirely inactive in 3 of the 10 studied patients, and 68 and 69% bactericidal in two others, 
considered by the authors moderately bactericidal. However, the prototype bacteriostatic agent 
dapsone was previously found by me (4) and others (1), by using these techniques in mice, to be 72 
to 87% bactericidal, and thus, we would consider, 68 to 69% primarily bacteriostatic. In any case 
whether this regimen was bactericidal in 7 of 10 or 5 of 10 of patients, it certainly was not reliably so 
and also far less active in mice than daily dapsone-clofazimine, a combination which together with 
monthly rifampin appears inadequate to effect a cure in previously untreated lepromatous leprosy 
patients (12). Also, in the current studies, 4 of the 10 patients receiving rifampin, minocycline, and 
ofloxacin had gastrointestinal side effects; however mild, this is consequential and likely would 
preclude large-scale utilization of such therapy. Thus, I would conclude, single doses of ofloxacin 
plus minocycline both in mice and in a clinical trial are not reliably bactericidal, and side effects are 
significant. 

Monthly therapy for bacterial disease would be unique if found effective against leprosy. Contrary to 
the opinion of Ji et al. (16), the literature does not support a case for intermittent therapy for each of 
three agents utilized, either in experimental mouse infections or in leprosy patients, particularly the 
monthly regimen they envisage. 

(i) In an established mouse footpad infection monitored by subpassage of M. leprae in serial 10-fold 
dilutions in mice, Grosset et al. (10) found that daily treatment with rifampin was significantly more 
bactericidal than weekly, fortnightly, or monthly treatment. An analysis of relapse rates in 
lepromatous leprosy patients treated with finite chemotherapy regimens which included several 
different frequencies of rifampin administration found that equivalent amounts of rifampin daily 
resulted in significantly lower relapse rates than more intermittent rifampin therapy (18). 

(ii) My colleagues and I (9) found in mice that once-monthly minocycline was unreliable, and in 
clinical trials we (8) (contrary to the interpretation of Ji et al. [16]) and others (2) found single doses 
to be without activity. Though Ji et al. (16) are correct in saying that we (8) found that in six of eight 
patients single doses of minocycline resulted in a fall of the proportion of viable M. leprae, only in 
one patient was this statistically significant, and two of these six had a higher proportion of viable 
bacilli after an additional week of daily minocycline than was found prior to the beginning of 
treatment. Our data thus hardly support the suggestion that single doses of minocycline afford 
bacterial killing. 

(iii) Though pefloxacin in mice was active when administered three times weekly, it was inactive even 
twice weekly, as well weekly and monthly (17). A single dose of ofloxacin was entirely inactive in 
five of eight treated patients (11). Even the study of Ji et al. (16) itself provides evidence against 
monthly therapy: in mice, together with rifampin, daily dapsone plus clofazimine, which are each far 
less active than either minocycline and ofloxacin, were vastly superior to single doses of minocycline 
plus ofloxacin. Though I (6) have also suggested alternative methodological explanations, the Ji et al. 
(16) claim that their case for the bactericidal activity of a single monthly dose, not found by others, is 
a result of the more sensitive "titration" methods they used. However, several of these other studies 
(10, 11, 17) utilized just those methods, and as has been mentioned, titration results have the pitfall 
of labeling activity which is primarily bacteriostatic "bactericidal." In any event there appears to be a 
compelling case favoring daily, as opposed to intermittent, therapy of leprosy. 

Studies of potential synergism or anatagonism of combined treatment against M. leprae are difficult 
to perform and interpret, and the limited results available provide mixed findings for the agents 
proposed by Ji et al. (16). It is noteworthy, however, that the authors' published literature on mice 
(15) and leprosy patients (14) suggests that ofloxacin anatagonizes the killing provided by 
minocycline plus clarithromycin. 

Finally, Ji et al. (16) appear now to advocate a duration of monthly supervised rifampin, minocycline, 
and ofloxacin of 2 years, the major bactericidal activity being provided by rifampin. Such a regimen 
includes less rifampin than what was used by them previously in a 1-month regimen of daily rifampin 
plus ofloxacin, which resulted in a very high rate of clinical relapse (13). 

An effective regimen for the cure of lepromatous leprosy is still needed. Combinations of daily 
rifampin and newer bactericidal drugs (minocycline, clarithromycin, and fluorquinolones), each having 
been demonstrated to be more active than dapsone and clofazimine, appear to be reasonable 
treatments. 

    REFERENCES 

1.  Colston, M. J., G. R. F. Hilson, and D. K. Banerje. 1978. The `proportional bactercidal test': a 
method for assessing bactercidal activity of drugs against Mycobacterium leprae in mice. Lepr. Rev. 
49:7-15[Medline]. 

2.  Fajardo, T. T., Jr., L. G. Villahermosa, E. G. dela Cruz, R. M. Abalos, S. G. Franzblau, and P. 
Walsh. 1995. Minocycline in lepromatous leprosy. Int. J. Lepr. 63:8-17. 

3.  Freerksen, E., and M. Rosenfeld. 1977. Leprosy eradication project of Malta. Chemotherapy 
(Basel) 23:356-386[Medline]. 

4.  Gelber, R. H. 1986. The killing of Mycobacterium leprae in mice by various dietary 
concentrations of dapsone and rifampin. Lepr. Rev. 57:347-353[Medline]. 

5.  Gelber, R. H. 1987. Activity of minocycline in Mycobacterium leprae-infected mice. J. Infect. 
Dis. 156:236-239[Abstract]. 

6.  Gelber, R. H. 1997. Regimens to treat lepromatous leprosy. Antimicrob. Agents Chemother. 
41:1618-1620[Abstract]. 

7.  Gelber, R. H., K. Fukuda, S. Byrd, L. P. Murray, P. Siu, M. Tsang, and T. H. Rea. 1995. A 
chemical trial of minocycline in lepromatous leprosy. Br. Med. J. 304:91-92. 

8.  Gelber, R. H., L. P. Murray, P. Siu, M. Tsang, and T. H. Rea. 1994. Efficacy of minocycline in 
single dose and at 100 mg twice daily for lepromatous leprosy. Int. J. Lepr. 58:568-573[Abstract]. 

9.  Gelber, R. H., P. Siu, M. Tsang, P. Alley, and L. P. Murray. 1991. Effect of low-level and 
intermittent minocycline therapy on the growth of Mycobacterium leprae in mice. Antimicrob. Agents 
Chemother. 35:992-994[Abstract/Full Text]. 

10.  Grosset, J. H., and C. C. Guelpa-Lauras. 1987. Activity of rifampin in infections of normal mice 
with Mycobacterium leprae. Int. J. Lepr. 55:847-851. 

11.  Grosset, J. H., B. Ji, C. C. Guelpa-Lauras, E. G. Perani, and L. N'Deli. 1990. Clinical trial of 
pefloxacin and ofloxacin in the treatment of lepromatous leprosy. Int. J. Lepr. 58:281-295. 

12.  Jamet, P., B. Ji, and the Marchoux Chemotherapy Study Group. 1995. 
Relapse after long-term follow up of multibacillary patients treated by WHO multidrug regimen. Int. 
J. Lepr. 63:195-201[Medline]. 

13.  Ji, B., Jamet, S. Sow, E. G. Perani, I. Traore, and J. H. Grosset. 1997. High relapse rate 
among lepromatous leprosy patients treated with rifampin plus ofloxacin daily for 4 weeks. 
Antimicrob. Agents Chemother. 41:1953-1956[Abstract]. 

14.  Ji, B., P. Jamet, E. G. Perani, S. Sow, C. Lienhardt, C. Petinon, and J. H. Grosset. 1996. 
Bactericidal activity of single dose of clarithromycin plus minocycline, with or without ofloxacin, 
against Mycobacterium leprae in patients. Antimicrob. Agents Chemother. 
40:2137-2141[Abstract]. 

15.  Ji, B., E. G. Perani, C. Petinon, and J. H. Grosset. 1996. Bactericidal activities of combinations 
of new drugs against Mycobacterium leprae in nude mice. Antimicrob. Agents Chemother. 
40:393-399[Abstract]. 

16.  Ji, B., S. Sow, E. Perani, C. Lienhardt, V. Diderot, and J. Grosset. 1998. Bactericidal activity 
of a single-dose combination of ofloxacin plus minocycline, with or without rifampin, against 
Mycobacterium leprae in mice and in lepromatous patients. Antimicrob. Agents Chemother. 
42:1115-1120[Abstract/Full Text]. 

17.  Pattyn, S. R. 1987. Activity of ofloxacin and pefloxacin against Mycobacterium leprae in mice. 
Antimicrob. Agents Chemother. 31:671-672[Medline]. 

18.  Pattyn, S. R. 1993. Search for effective short-course regimens for the treatment of leprosy. Int. 
J. Lepr. 62:72-81. 

19.  Pearson, J. M. H., R. J. W. Rees, and M. F. R. Waters. 1975. Sulphone resistance in leprosy. 
A review of one hundered proven cases. Lancet ii:69-72. 

20.  Rajendran, V., C. Vellut, and C. Pushpadass. 1993. Profile of relapse cases in field trial of 
combined therapy in multibacillary leprosy. Int. J. Lepr. 61(Suppl.):4A. 

21.  Waters, M. F. R., R. J. W. Rees, A. B. G. Laing, K. F. Khoo, T. W. Meade, W. Parikshah, 
and W. R. S. North. 1986. The rate of relapse in lepromatous leprosy following completion of 
twenty years of supervised sulphone therapy. Lepr. Rev. 57:101-109. 

22.  World Health Organization. 1994. Chemotherapy of leprosy. Technical report series no. 847. 
World Health Organization, Geneva, Switzerland. 

23.  World Health Organization Study Group. 1982. Chemotherapy of leprosy for control 
programmes. Technical report series, no. 675. World Health Organization, Geneva, Switzerland. 
     Robert H. Gelber 
Departments of Medicine and Dermatology/ University of California/ San Francisco, California 
 
Dr. Gelber's letter covered many important aspects of chemotherapy of leprosy, which would be 
impossible to address in a single reply. However, his view on the seriousness of dapsone-resistant 
leprosy and the efficacy and achievement of World Health Organization (WHO)-recommended 
multidrug therapy (MDT) for leprosy are beyond the scope of our articles (5, 6, 8, 9) and have been 
clearly addressed in the report of the latest WHO Expert Committee on Leprosy (14); in addition, 
some of the issues, such as a detectable bactericidal effect of single-dose minocycline (MINO) or 
ofloxacin (OFLO) treatment had been raised in his previous letter to the editor (3) and responded to 
by us (7). Therefore, we will focus only on those of his comments that were not covered by the 
previous correspondence. 

In one of our pilot trials, 20 lepromatous patients were randomly allocated to two groups (10 each) 
and treated with a single dose of either 600 mg of rifampin (RMP) plus 400 mg of OFLO and 100 
mg of MINO or 400 mg of OFLO plus 100 mg of MINO (9). Because the treatment was inactive 
in three patients receiving OFLO-MINO and mild gastrointestinal adverse events were observed in 
two (not four, as wrongly quoted in the letter) patients of this group, Dr. Gelber concludes that a 
single dose of OFLO-MINO is not reliably bactericidal and the side effects are significant. We 
disagree with the conclusion based on the following reasons. (i) By definition (11), any antibacterial 
effect detected by the "proportional bactericidal test" (1) should be bactericidal, and there is no 
reason to consider the 68 to 69% killing of viable organisms as bacteriostatic. (ii) Bactericidal effect 
was observed in a great majority (7 of 10) of patients treated with a single dose of OFLO-MINO, 
and even with RMP, by far the most bactericidal drug against Mycobacterium leprae (5), 
single-dose treatment may not display detectable bactericidal effect in all patients; e.g., no 
bactericidal effect was observed in 1 of 10 patients receiving a single dose of RMP-OFLO-MINO 
(9). Finally, (iii) the adverse events in a clinical trial are not necessarily equivalent to the side effects 
caused by actual treatment, particularly when the events are mild and transitory (without significant 
findings on physical examination). Whether such degree of mild adverse events is significant is a 
matter of judgement. Nevertheless, more and more patients are treated with a single dose of 
RMP-OFLO-MINO in the field with excellent tolerance (12), indicating that Dr. Gelber's prediction 
precluding large-scale utilization of such therapy was wrong. 

Besides OFLO and MINO, Dr. Gelber also challenges the justification for treating leprosy with 
monthly administration of RMP, despite the fact that it is the backbone of the MDT regimens for 
both paucibacillary and multibacillary leprosy since 1981. More than 8 million leprosy patients have 
been cured by the beginning of 1997 with a very low relapse rate (14). Numerous publications, 
including one by Dr. Gelber himself (2), have indicated that RMP displays very powerful and rapid 
bactericidal activity against M. leprae in experimental animals and in patients. Immediately after RMP 
treatment is begun, the great majority of viable M. leprae organisms are killed. No one has been able 
to convincingly demonstrate that after a few doses of RMP-containing regimens, daily administration 
is more bactericidal than monthly treatment. On the contrary, we have observed that, in nude mice 
with established M. leprae infection (5), monthly administration of RMP-containing regimens always 
produced significantly greater bactericidal activities than the same number of doses of daily 
treatment. To prove that daily treatment with RMP was significantly more bactericidal than weekly, 
fortnightly, or monthly treatment, Dr. Gelber quotes one of our earlier results for immunocompetent 
mice with established M. leprae infection (4). However, we have already pointed out that because of 
the rapid spontaneous killing of M. leprae in untreated controls, established infection in 
immunocompetent mice is not a suitable system for comparing the activities of different drug 
regimens, and the results must be interpreted with caution (4). Furthermore, the duration of treatment 
in the quoted experiments was only 8 to 12 weeks, and the differences in bactericidal effects 
between daily and monthly administrations were marginal though statistically significant; based on our 
experience with infection in nude mice (5), it is likely that the differences may not exist after a longer 
duration, e.g., 6 months, of treatment. To support his argument, Dr. Gelber also cites studies on 
relapse rates for lepromatous patients treated with various RMP-containing regimens, which 
concluded that equivalent amounts of daily RMP resulted in significantly lower relapse rates than 
those in patients treated with intermittent RMP (10). Nonetheless, one has to be extremely cautious 
in drawing conclusions from such an analysis, because the pretreatment characteristics of the patients 
in the different groups may not be comparable. Association between relapse rate and frequency of 
RMP administration was not confirmed for patients treated with the same regimens by an Institut 
Marchoux study after a longer follow-up period (13). 

Finally, we would like to point out that, based on the considerations of cost-effectiveness and 
operational feasibility, the main objective of our research activities is to develop a minimal but not 
suboptimal regimen(s) that is effective, simple, and affordable. To eradicate leprosy, such minimal 
regimens are badly needed in many countries of endemicity, particularly in areas where the health 
infrastructure is poor and/or accessibility is difficult. On the other hand, it is understandable that the 
regimen for the treatment of a handful leprosy patients in developed countries may be far more 
sophisticated, as long as it can be justified by the physicians, tolerable by the patients, and affordable 
by the community. 

    REFERENCES 

1.  Colston, M. J., G. R. F. Hilson, and D. K. Banerjee. 1978. The "proportional bactericidal test," 
a method for assessing bactericidal activity of drugs against Mycobacterium leprae in mice. Lepr. 
Rev. 49:7-15[Medline]. 

2.  Gelber, R. H., and L. Levy. 1987. Detection of persisting Mycobacterium leprae by inoculation 
of the neonatally thymectomized rat. Int. J. Lepr. 55:872-878. 

3.  Gelber, R. H. 1997. Regimens to treat lepromatous leprosy. Antimicrob. Agents Chemother. 
41:1618-1619[Medline]. (Letter to the editor.) 

4.  Grosset, J. H., and C. C. Guelpa-Lauras. 1987. Activity of rifampin in infections of normal mice 
with Mycobacterium leprae. Int. J. Lepr. 55:847-851[Medline]. 

5.  Ji, B., E. G. Perani, C. Petinom, and J. H. Grosset. 1996. Bactericidal activities of combinations 
of new drugs against Mycobacterium leprae in nude mice. Antimicrob. Agents Chemother. 
40:393-399[Abstract]. 

6.  Ji, B., P. Jamet, E. G. Perani, S. Sow, C. Lienhardt, C. Petinon, and J. H. Grosset. 1996. 
Bactericidal activity of single dose of clarithromycin plus minocycline, with or without ofloxacin, 
against Mycobacterium leprae in patients. Antimicrob. Agents Chemother. 
40:2137-2141[Abstract]. 

7.  Ji, B., E. G. Perani, C. Petinon, J. H. Grosset, P. Jamet, S. Sow, and C. Lienhardt. 1997. 
Regimens to treat lepromatous leprosy. Antimicrob. Agents Chemother. 41:1619-1620. (Letter to 
the editor.) 

8.  Ji, B., P. Jamet, S. Sow, E. G. Perani, I. Traore, and J. H. Grosset. 1997. High relapse rate 
among lepromatous leprosy patients treated with rifampin plus ofloxacin daily for 4 weeks. 
Antimicrob. Agents Chemother. 41:1953-1956[Abstract]. 

9.  Ji, B., S. Sow, E. Perani, C. Lienhardt, V. Diderot, and J. Grosset. 1998. Bactericidal activity of 
a single dose combination of ofloxacin plus minocycline, with or without rifampin, against 
Mycobacterium leprae in mice and in lepromatous patients. Antimicrob. Agents Chemother. 
42:1115-1120[Abstract/Full Text]. 

10.  Pattyn, S. R. 1993. Search for effective short-course regimens for the treatment of leprosy. Int. 
J. Lepr. 61:76-81. 

11.  Shepard, C. C. 1982. Statistical analysis of results obtained by two methods for testing drug 
activity against Mycobacterium leprae. Int. J. Lepr. 50:96-101. 

12.  Single-Lesion Multicentre Trial Group. 1997. Efficacy of single dose multidrug therapy for the 
treatment of single-lesion paucibacillary leprosy. Indian J. Lepr. 69:121-129[Medline]. 

13.  Sow, S., B. Ji, and Marchoux Chemotherapy Study Group. 1998. Intervals between stopping 
rifampin-containing regimens and occurrence of relapse in multibacillary leprosy, abstr. CH19. In 
Program and abstracts of the 15th International Leprosy Congress, Beijing, China, 7 to 12 
September 1998. 

14.  WHO Expert Committee on Leprosy. 1998. Seventh report. WHO Technical Series, no. 874. 
World Health Organization, Geneva, Switzerland. 
     Baohong Ji 
Jacques H. Grosset 
Faculté de Médecine Pitié-Salpêtrière/ Paris/ France 
 
============================================================= 
7.) Rifampicin/minocycline and ofloxacin (ROM) for single lesions--what is the evidence? 
============================================================= 
Lepr Rev 1997 Dec;68(4):299-300 Related Articles, Books, LinkOut 

Earlier this year the results of a double-blind randomized controlled trial comparing a potential new 
treatment (single dose rifampicin/ofloxacin and minocycline (ROM)) for monolesion paucibacillary 
leprosy with the current 6-month treatment with rifampicin and dapsone (WHO-PB-MDT) were 
published. The executive report of the 7th WHO Expert Committee on Leprosy (Geneva, 26 May-3 
June 1997) noted that the Committee considered the single-dose ROM an acceptable and 
cost-effective regimen for the treatment of single skin lesion PB leprosy. The paper and report have 
been highly influential and already strategic planners in several countries, notably India and Brazil, 
have introduced ROM treatment for single-lesion disease into their national programmes. We are 
reprinting this important paper in this issue of Leprosy Review (p. 299-300) by kind permission of 
the Editor of the Indian Journal of Leprosy since we feel that readers may wish to study the original 
publication for themselves. 

The introduction of single-dose treatment for a subset of leprosy patients is obviously attractive from 
an operational standpoint and will make a significant impact in reducing prevalence in some areas. 
However it is also fraught with dangers, and hence the evidence for its effectiveness should be 
considered in some depth. 

The trial involved nine different centres, each recruiting between 103 and 400 patients over a 
10-month period to give a total of 1483 patients. Follow-up over an 18-month period was good 
with a 93% completion rate. 

There are a number of difficulties in interpreting the data. The first of these relates to the diagnosis of 
leprosy in these patients. It is not clear how lesions were tested for anaesthesia nor which modalities 
of sensation were examined. Much of the initial testing (skin biopsy, histamine testing, lepromin 
testing and even detailed neurological examination) was optional. Hence it is not possible to know 
how many patients in the trial had definite evidence of leprosy. The system used in the Karonga trial, 
of grading patients on a scale of diagnostic certainty for leprosy is a useful way of addressing the 
problem of diagnosis.1 From an operational point of view it would be helpful to know how many 
patients were evaluated and prepared for entry to the trial but then proved to be slit-skin smear 
positive and so ineligible for treatment with ROM. There is no information on how many patients had 
skin biopsies with microscopic evidence of leprosy. 

Children above the age of 5 were eligible for the trial but no details are given of numbers of children 
treated nor the drug doses used. The side-effects observed in the trial patients are briefly discussed. 
No mention is made of monitoring for specific side-effects and no details are given of potential 
side-effects such as tooth discoloration in children given minocycline. 

The major outcome measure was derived from a scoring system based on five different clinical 
observations of the lesions. No details of how this scale was constructed nor what weights were 
given to the five components nor how scoring was standardized between centres are provided. This 
makes interpretation of the results difficult. Of the 1381 patients who completed the trial only 12 
patients failed to improve, and of these 2 deteriorated. The investigators set an improvement of 13 
points in the clinical score as their definition of marked clinical improvement; their other outcome 
measure was complete cure. Patients treated with the conventional WHO-PB-MDT regimen 
showed statistically significantly better results on both these measures when compared with the 
patients treated with the ROM regimen. The significance level for the difference in complete cure 
rates is incorrectly given in Table V as P = 0 04, the correct figure is actually even more significant at 
P = 0 004 as given in the text. It is not possible from the data given to discern which modalities 
improved most. A more detailed analysis of the data such as an analysis of covariance would have 
allowed examination of the effect of age, sex or type of improvement on response to treatment. This 
would be valuable in determining which patients would benefit most from treatment with ROM. 
These details are important because this trial was designed to be a gold standard trial of ROM 
showing its medical effectiveness, not an operational trial showing that it is an easy treatment to 
administer. 

The follow-up period of 18 months for ROM treated patients and 12 months for WHOPB-MDT 
treated patients is too short to detect relapses with a relapse rate for paucibacillary disease of 1% 
per year. It is to be hoped that the patients will continue under active surveillance so that this 
important figure can be determined. 

ROM is undoubtedly an attractive treatment. It is operationally easy to administer and is probably 
suitable for some patients. If it is to be incorporated into treatment schedules then it is important that 
workers follow good practice guidelines. It is vital that all patients should be examined carefully to 
ensure that there really is only a single lesion. Women may be reluctant to be examined fully and if 
so, should not be prescribed ROM. It is also vital that a careful neurological examination is done to 
ensure that no nerve thickening or impairment of motor or sensory function is present. There was no 
statistical difference in the number of reactions or neuritis in each of the treatment groups. This serves 
as a reminder that even patients with monolesions can suffer reactions and so need to be kept under 
follow-up even after single dose treatment when it will be very tempting to have less stringent 
follow-up. 

In conclusion this trial as published leaves many doubts: how many of the patients treated in this trial 
actually had leprosy, which outcome measure improved, did sensation in the lesions improve, what 
side-effects were monitored? The analysis reveals few details but the two measures reported 
showed significant superiority for the existing WHO-PB-MDT regimen. Thus it is inaccurate to claim 
on the basis of the published data, as the authors did in their abstract that ROM is 'almost as 
effective as WHO-PB-MDT'. The implementation of single dose ROM should be undertaken with 
care; it is likely to be of value for some patients, but the attraction of operational expediency could 
easily result in misuse. 

DIANA N. J. LOCKWOOD 

============================================================= 
8.) What are the new antileprosy drugs - ROM - now available for the treatment of leprosy? 
============================================================= 
Recently three more drugs have shown bactericidal activity against M. leprae. These are 

ofloxacin-a fluoroquinolone, 
minocycline-a tetracycline 
clarithromycin-a macrolide 

Several experimental and clinical studies have demonstrated that these drugs either alone or in 
combination with other antileprosy drugs have significant bactericidal activity. 

WHO started supplying quantities of special ROM blister packs in late 1997 to India, Bangladesh, 
Nepal and Brazil for the treatment of single lesion PB leprosy. 

============================================================ 
9.)What are the types of leprosy that can be treated by ROM ? 
============================================================ 
The 7th WHO Expert Committee on Leprosy recommended the use of a combination of rifampicin 
600 mg, ofloxacin 400 mg and minocycline 100 mg (ROM) for the treatment of two categories of 
leprosy patients: 

patients presenting with single skin lesion paucibacillary leprosy can be treated with only one dose of 
ROM 
multibacillary leprosy patients who do not accept clofazimine can be treated with monthly 
administration of 24 doses of ROM. 

============================================================= 
10.)What is the reason for introducing single dose treatment for paucibacillary leprosy presenting 
with a single skin lesion? 
============================================================= 
Most of the paucibacillary leprosy cases presenting with only one skin lesion have a high tendency to 
heal without any specific antileprosy treatment. However, today it is not possible to identify those 
who will develop progressive disease and all such cases need to be treated. In some programmes 
(especially vertical programmes which have a strong active case finding component) such patients 
constitute a significant proportion of newly detected cases. The six-month MDT regimen puts a 
heavy burden both on patients and the health services as a large proportion of such patients are 
children and the compliance to treatment is usually less than satisfactory. 

============================================================= 
11.) What is the basis for the recommended alternative regimen for the treatment of paucibacillary 
leprosy presenting with a single skin lesion? 
============================================================= 
The discovery of effectiveness of ofloxacin and minocycline in the treatment of leprosy encouraged 
WHO to assess the efficacy of single dose treatment for this group of patients. A large multicentre, 
double-blind study was organized. The results demonstrated that single dose of a combination of 
rifampicin 600 mg, ofloxacin 400 mg and minocycline 100 mg (ROM) is as effective as the standard 
6-month WHO MDT for paucibacillary leprosy. 

============================================================= 
12.)Does WHO recommend that all programmes should treat single lesion paucibacillary leprosy 
cases with one dose of ROM? 
============================================================= 
No, as such patients are detected in large numbers mainly by vertical programmes having a strong 
active case finding component. The introduction of this regimen in programmes detecting very few 
single-lesion leprosy cases will only add to the logistic problems of catering to a third regimen and 
also complicate the information system. Such programmes should continue to treat these cases with 
the standard WHO MDT for paucibacillary leprosy for six months. Therefore, WHO recommends 
that this regimen may be used only by programmes detecting a large number of (1 000 or more) such 
cases annually. 
 
============================================================= 
13.) Efficacy of single dose multidrug therapy for the treatment of single-lesion paucibacillary 
leprosy. Single-lesion Multicentre Trial Group. 
============================================================= 
Source 
Indian J Lepr, 69(2):121-9 1997 Apr-Jun 
Abstract 
A multicentre double-blind controlled clinical trial was carried out to 
compare the efficacy of a combination of rifampicin 600 mg plus ofloxacin 
400 mg plus minocycline 100 mg (ROM) administered as single dose with that 
of the standard six-month WHO/MDT/PB regimen. The subjects included 1483 
cases with one skin lesion who were previously untreated, were 
smear-negative, and had no evidence of peripheral nerve trunk involvement, 
and they were randomly divided into study and control groups. The total 
duration of the study from the day of intake was 18 months, and 1381 
patients completed study. Only 12 patients were categorized as treatment 
failure and no difference was observed between the two regimens. Occurrence 
of mild side-effects and leprosy reactions were minimal (less than 1%) in 
both groups. This study showed that ROM is almost as effective as the 
standard WHO/MDT/PB in the treatment of single lesion PB leprosy. 

============================================================= 
14.) Minocycline in lepromatous leprosy. 
============================================================= 
Author 
Fajardo TT Jr; Villahermosa LG; dela Cruz EC; Abalos RM; Franzblau SG; 
Walsh GP 
Address 
Clinical Research Branch, Leonard Wood Memorial Center, Cebu City, The 
Philippines. 
Source 
Int J Lepr Other Mycobact Dis, 63(1):8-17 1995 Mar 
Abstract 
Twelve patients were treated with three dose levels of minocycline for 30 
days, primarily to detect the dose-related effects on Mycobacterium leprae 
viability, followed by another 5 months of daily minocycline for overall 
efficacy and persistence of clinical and antibacterial effects. 
Subsequently, the patients were given standard WHO/MDT chemotherapy for 
multibacillary leprosy. Clinical improvement was recognizable during the 
first month, occurring much earlier among those on minocycline 200 mg daily 
than those who received minocycline 100 mg daily. A similar change also was 
observed in one patient 11 days after three daily doses of 100 mg of 
minocycline. At the end of 6 months, all patients were clinically improved 
with a slight reduction in the average bacterial index (BI) and logarithmic 
index of bacilli in biopsy (LIB). The effects of minocycline on viability 
by mouse foot pad inoculation and palmitic acid oxidation assays were noted 
beginning at 10 to 14 days of daily dosing and becoming more definite after 
30 days of treatment. Both tests correlated fairly well. Doses of 200 mg 
daily did not appear to be more efficient than minocycline 100 daily. 
Phenolic glycolipid-I (PGL-I) antigen determinations done on some patients 
during the first month remained positive and did not correlate with changes 
in viability results. At the end of 6 months, after 5 months of 100 mg of 
minocycline monotherapy, no viable organisms could be demonstrated by mouse 
foot pad inoculation and palmitic acid oxidation assays; assays for PGL-I 
antigen were all negative.(ABSTRACT TRUNCATED AT 250 WORDS) 

============================================================= 
15.) Efficacy of minocycline in single dose and at 100 mg twice daily for lepromatous leprosy. 
============================================================= 
Int J Lepr Other Mycobact Dis  (United States), Dec 1994, 62(4) p568-73 
AUTHOR(S):  Gelber RH; Murray LP; Siu P; Tsang M; Rea TH 
AUTHOR'S ADDRESS:  San Francisco Regional Hansen's Disease Program, CA 94115. 
PUBLICATION TYPE:  CLINICAL TRIAL; JOURNAL ARTICLE 
ABSTRACT:  A clinical trial of minocycline in a total of 10 patients with 
previously untreated lepromatous leprosy was conducted in order to evaluate 
the efficacy of a single, initial, 200-mg dose and 100 mg twice daily of 
minocycline for a total duration of up to 3 months. Patients improved 
remarkably quickly. Although single-dose therapy did not result in a 
significant killing of Mycobacterium leprae, viable M. leprae were cleared 
from the dermis regularly by 3 months of twice-daily therapy, a rate 
similar to that achieved by minocycline 100 mg once daily. Because more 
side effects were noted herein than previously with 100 mg daily, we 
recommend that minocycline, when applied, be administered at 100 mg daily 
to leprosy patients. 

============================================================= 
16.) Field trial on efficacy of supervised monthly dose of 600 mg rifampin, 400 mg ofloxacin and 
100 mg minocycline for the treatment of leprosy; first results. 
============================================================= 
Author 
Mane I; Cartel JL; Grosset JH 
Address 
Institut de Leprologie Appliquee, Dakar CD Annexe, Senegal. 
Source 
Int J Lepr Other Mycobact Dis, 65(2):224-9 1997 Jun 
Abstract 
In 1995, a field trial was implemented in Senegal in order to evaluate the 
efficacy of a regimen based on the monthly supervised intake of rifampin 
600 mg, ofloxacin 400 mg and minocycline 100 mg to treat leprosy. During 
the first year of the trial, 220 patients with active leprosy (newly 
detected or relapsing after dapsone monotherapy) were recruited: 102 
paucibacillary (PB) (60 males and 42 females) and 118 multibacillary (MB) 
(71 males and 47 females). All of them accepted the new treatment (none 
requested to be preferably put under standard WHO/MDT), no clinical sign 
which could be considered as a toxic effect of the drug was noted, and none 
of the patients refused to continue treatment because of any clinical 
trouble. The compliance was excellent: the 113 patients (PB and MB) 
detected during the first 6 months of the trial have taken six monthly 
doses in 6 months, as planned. The rate of clearance and the progressive 
decrease of cutaneous lesions was satisfactory. Although it is too soon to 
give comprehensive results, it should be noted that no treatment failure 
was observed in the 56 PB patients who have completed treatment and have 
been followed up for 6 months. The long-term efficacy of the new regimen is 
to be evaluated on the rate of relapse during the years following the 
cessation of treatment. If that relapse rate is acceptable (similar to that 
observed in patients after treatment with current standard WHO/ MDT), the 
new regimen could be a solution to treat, for instance, patients very 
irregular and/or living in remote or inaccessible areas since no selection 
of rifampin-resistant Mycobacterium leprae should be possible (a monthly 
dose of ofloxacin and minocycline being as effective as a dose of dapsone 
and clofazimine taken daily for 1 month). Nevertheless, until longer term 
results of this and other trials become available, there is no 
justification for any change in the treatment strategy, and all leprosy 
patients should be put under standard WHO/MDT. 

============================================================= 
17.) Bactericidal activity of a single-dose combination of ofloxacin plus minocycline, with or without 
rifampin, against Mycobacterium leprae in mice and in lepromatous patients. 
============================================================= 
Author 
Ji B; Sow S; Perani E; Lienhardt C; Diderot V; Grosset J 
Address 
Facult´e de M´edecine Piti´e-Salp^etri`ere, Paris, France. 
[email protected] 
Source 
Antimicrob Agents Chemother, 42(5):1115-20 1998 May 
Abstract 
To develop a fully supervisable, monthly administered regimen for treatment 
of leprosy, the bactericidal effect of a single-dose combination of 
ofloxacin (OFLO) and minocycline (MINO), with or without rifampin (RMP), 
against Mycobacterium leprae was studied in the mouse footpad system and in 
previously untreated lepromatous leprosy patients. Bactericidal activity 
was measured by the proportional bactericidal method. In mouse experiments, 
the activity of a single dose of the combination OFLO-MINO was dosage 
related; the higher dosage of the combination displayed bactericidal 
activity which was significantly inferior to that of a single dose of RMP, 
whereas the lower dosage did not exhibit a bactericidal effect. In the 
clinical trial, 20 patients with previously untreated lepromatous leprosy 
were treated with a single dose consisting of either 600 mg of RMP plus 400 
mg of OFLO and 100 mg of MINO or 400 mg of OFLO plus 100 mg of MINO. The 
OFLO-MINO combination exhibited definite bactericidal activity in 7 of 10 
patients but was less bactericidal than the RMP-OFLO-MINO combination. Both 
combinations were well tolerated. Because of these promising results, a 
test of the efficacy of multiple doses of ROM in a larger clinical trial 
appears justified. 

============================================================= 
18.) Bactericidal activity of single dose of clarithromycin plus minocycline, with or without ofloxacin, 
against Mycobacterium leprae in patients. 
============================================================= 
Author 
Ji B; Jamet P; Perani EG; Sow S; Lienhardt C; Petinon C; Grosset JH 
Address 
Facult´e de M´edecine Piti´e-Salp^etri`ere, Paris, France. 
Source 
Antimicrob Agents Chemother, 40(9):2137-41 1996 Sep 
Abstract 
Fifty patients with newly diagnosed lepromatous leprosy were allocated 
randomly to one of five groups and treated with either a month-long 
standard regimen of multidrug therapy (MDT) for multibacillary leprosy, a 
single dose of 600 mg of rifampin, a month-long regimen with the dapsone 
(DDS) and clofazimine (CLO) components of the standard MDT, or a single 
dose of 2,000 mg of clarithromycin (CLARI) plus 200 mg of minocycline 
(MINO), with or without the addition of 800 mg of ofloxacin (OFLO). At the 
end of 1 month, clinical improvement accompanied by significant decreases 
of morphological indexes in skin smears was observed in about half of the 
patients of each group. A significant bactericidal effect was demonstrated 
in the great majority of patients in all five groups by inoculating the 
footpads of mice with organisms recovered from biopsy samples obtained 
before and after treatment. Rifampin proved to be a bactericidal drug 
against Mycobacterium leprae more potent than any combination of the other 
drugs. A single dose of CLARI-MINO, with or without OFLO, displayed a 
degree of bactericidal activity similar to that of a regimen daily of doses 
of DDS-CLO for 1 month, suggesting that it may be possible to replace the 
DDS and CLO components of the MDT with a monthly dose of CLARI-MINO, with 
or without OFLO. However, gastrointestinal adverse events were quite 
frequent among patients treated with CLARI-MINO, with or without OFLO, and 
may be attributed to the higher dosage of CLARI or MINO or to the 
combination of CLARI-MINO plus OFLO. In future trials, therefore, we 
propose to reduce the dosages of the drugs to 1,000 mg of CLARI, 100 mg of 
MINO, and 400 mg of OFLO. 

========================================================================= 
19.) WHO Expert Committee on Leprosy. 
========================================================================= 
Source: World Health Organ Tech Rep Ser, 874():1-43 1998 
Abstract 
Considerable progress has been made in the fight against leprosy during the 
past 10-15 years, following the introduction of multidrug therapy (MDT) 
regimens and the establishment of the goal of eliminating leprosy as a 
public health problem by the year 2000. Current estimates indicate that 
there are about 1.15 million cases of leprosy in the world, compared with 
10-12 million cases in the mid-1980s. This report presents the conclusions 
of a WHO Expert Committee convened to review the global leprosy situation 
and the technology available for eliminating the disease, to identify the 
remaining obstacles to reaching the goal of eliminating leprosy as a public 
health problem, and to make appropriate recommendations for the future on 
technical and operational matters. The current status of leprosy 
elimination is discussed, and the various antileprosy drugs are reviewed, 
including the most recently available drugs. On the basis of field trials 
and clinical studies, the Committee concludes that a single dose of a 
combination of rifampicin, ofloxacin and minocycline is an acceptable and 
cost-effective alternative regimen for the treatment of single-lesion 
paucibacillary leprosy, and that the duration of the current MDT regimen 
for multibacillary leprosy could possibly be shortened to 12 months. The 
Committee points out the need for improved management of reactions and 
neuritis and prevention of leprosy-related disabilities and impairments, 
and recommends that antileprosy activities should become an integral part 
of general health services and should involve communities to the fullest 
extent possible. 

========================================================================= 
20.) Experimental evaluation of possible new short-term drug regimens for 
treatment of multibacillary leprosy. 
========================================================================= 
Author 
Banerjee DK; McDermott-Lancaster RD; McKenzie S 
Address 
Department of Medical Microbiology, St George's Hospital Medical School, 
London, United Kingdom. [email protected]. 
Source 
Antimicrob Agents Chemother, 41(2):326-30 1997 Feb 
Abstract 
Groups of nude mice, with both hind footpads infected with 10(8) 
Mycobacterium leprae organisms, were treated with 4-week courses of 
different drug combinations. The effect treatment on each group was 
evaluated by subinoculating footpad homogenates from the treated mice into 
groups of normal and nude mice for subsequent regrowth, assessed 1 year 
later. A combination of rifampin (RMP) with clarithromycin (CLARI), 
minocycline (MINO), and ofloxacin (OFLO) resulted in the complete killing 
of M. leprae after 3 weeks of treatment. A combination of sparfloxacin 
(SPAR) and RMP also resulted in a similar bactericidal effect after 3 weeks 
of treatment. Other drug combinations showed variable effects. Very little 
or no effect was observed with any regimen if the treatment was given for 
less than 2 weeks. World Health Organization (WHO) multidrug therapy (MDT) 
given for 8 weeks was as effective as the two combinations described above. 
The results suggest that multidrug combinations consisting of RMP-OFLO (or 
SPAR)-CLARI (and/or MINO) are as effective as the WHO MDT for the treatment 
of experimental leprosy. Moreover, they imply that these combinations, 
which were found to be active in a 4-week experimental treatment protocol, 
could be administered as treatment to patients for a period of time shorter 
than the present 2-year regimen without a loss of effectiveness. 

========================================================================= 
21.) Powerful bactericidal activities of clarithromycin and minocycline 
against Mycobacterium leprae in lepromatous leprosy. 
========================================================================= 
ARTICLE SOURCE:  J Infect Dis  (United States), Jul 1993, 168(1) p188-90 
AUTHOR(S):  Ji B; Jamet P; Perani EG; Bobin P; Grosset JH 
AUTHOR'S ADDRESS:  Faculte de Medecine Pitie-Salpetriere, Paris, France. 
PUBLICATION TYPE:  CLINICAL TRIAL; JOURNAL ARTICLE; RANDOMIZED 
CONTROLLED 
TRIAL 
ABSTRACT:  Thirty-six patients with newly diagnosed lepromatous leprosy 
were allocated randomly to three groups and treated for 56 days with 
minocycline (100 mg daily), clarithromycin (500 mg daily), or 
clarithromycin (500 mg) plus minocycline (100 mg daily). All groups had 
rapid and remarkable clinical improvement and significant decline of the 
bacterial and morphologic indices in skin smears during treatment. More 
than 99% and 99.9% of the viable Mycobacterium leprae had been killed by 28 
and 56 days of treatment, respectively, as measured by inoculation of 
organisms recovered from skin samples, taken before and during treatment, 
into the footpads of immunocompetent and nude mice. Clinical improvement 
and bactericidal activity did not differ significantly among the three 
groups. Adverse reactions were rare and mild, and no laboratory abnormality 
was detected during the trial. Both clarithromycin and minocycline 
displayed powerful bactericidal activities against M. leprae in leprosy 
patients and may be considered important components of new multidrug 
regimens for the treatment of multibacillary leprosy. 

============================================================ 
22.) Leprosy resistant to multi-drug-therapy (MDT) successfully treated 
with ampicillin-sulbactam combination--(a case report). 
============================================================ 
  Mehta VR 
  L.T.M.M. College, Bombay. 
  Indian J Med Sci  (INDIA)  Nov 1996  50 (11) p305-7  ISSN: 0019-5359 
  Language: ENGLISH 
Document Type:   JOURNAL ARTICLE 
  Journal Announcement: 9707 
  Subfile: INDEX MEDICUS 
  A 50 year male developed a discoid lesion of leprosy on the face. 
Inspite of Dapsone 100 mg/day and Rifampicin 600 mgm per day the disease 
spread to both sides of the face and forehead.  It became worse with 
Prednisolone and Clofazimine.  It cleared completely when Sultamicillin was 
added to the latter.  This seems to be the first patient of leprosy to be 
treated with this combination and reported. 

========================================================================= 
23.) Differential protective effect of bacillus calmette-guerin vaccine 
against multibacillary and paucibacillary leprosy in nagpur, india. 
========================================================================= 
Public Health 1999 Nov;113(6):311-3 

Kulkarni HR, Zodpey SP 
Department of Preventive and Social Medicine and Clinical Epidemiology 
Unit, Government Medical College, Nagpur, India. 

For this paper we conducted a secondary data analysis to test the 
hypothesis that a linear trend exists in the protective effect of bacillus 
Calmette-Guerin (BCG) vaccine against types of leprosy. We used data from 
two previous case-control studies to perform an unmatched test for linear 
trend. We observed that both the studies revealed a significant linear 
trend (P<0.00001). One study that estimated an insignificant protective 
effect of BCG against paucibacillary leprosy showed a significant departure 
from linearity. We conclude that, the protective effect of BCG vaccination 
is differential across severity of leprosy as it brings about a shift in 
the immune response to a higher level of cell mediated immunity. We 
recommend that future studies dealing with the protective effect of BCG 
against leprosy should also conduct an analysis for trend. 

========================================================================= 
24.) Protective effect of Bacillus Calmette Guerin (BCG) against leprosy: a 
population-based case-control study in Nagpur, India. 
========================================================================= 
Lepr Rev 1999 Sep;70(3):287-94 

Zodpey SP, Bansod BS, Shrikhande SN, Maldhure BR, Kulkarni SW 
Clinical Epidemiology Unit, Govt Medical College, Nagpur, MS, India. 

A population-based pair-matched case-control study was carried out in an 
urban community, Nagpur, India, to estimate the effectiveness of BCG 
vaccination in the prevention of leprosy. The study included 212 cases of 
leprosy (diagnosed by WHO criteria), below the age of 35 years, detected 
during a leprosy survey conducted by the Government of Maharashtra over a 
population of 20,03,325. Each case was pair-matched with one neighbourhood 
control for age, sex and socioeconomic status. A significant protective 
association between BCG and leprosy was observed (OR = 0.40, 95% CI = 
0.23-0.68). The overall vaccine effectiveness (VE) was estimated to be 60% 
(95% CI = 32-77). The BCG effectiveness against multi-bacillary and 
paucibacillary leprosy was 72% (95% CI = 35-88) and 45% (95% CI = 3-73), 
respectively. Vaccine was more effective during the first decade of life, 
among females and in lower socioeconomic strata. The overall prevented 
fraction was 39% (95% CI = 16-58). In conclusion, this first ever 
population-based case control study performed in Central India, identified 
a beneficial role of BCG vaccination in prevention of leprosy in study 
population. 

========================================================================= 
25.) Patient contact is the major determinant in incident leprosy: 
implications for future control. 
========================================================================= 
Int J Lepr Other Mycobact Dis 1999 Jun;67(2):119-28 

van Beers SM, Hatta M, Klatser PR 
Department of Biomedical Research, Royal Tropical Institute, Amsterdam, The 
Netherlands. 

Notwithstanding the elimination efforts, leprosy control programs face the 
problem of many leprosy patients remaining undetected. Leprosy control 
focuses on early diagnosis through screening of household contacts, 
although this high-risk group generates only a small proportion of all 
incident cases. For the remaining incident cases, leprosy control programs 
have to rely on self-reporting of patients. We explored the extent to which 
other contact groups contribute to incident leprosy. We examined 
retrospectively incident leprosy over 25 years in a high-endemic village of 
2283 inhabitants in Sulawesi, Indonesia, by systematically reviewing data 
obtained from the local program and actively gathering data through 
interviews and a house-to-house survey. We investigated the contact status 
in the past of every incident case. In addition to household contact, we 
distinguished neighbor and social contacts. Of the 101 incident cases over 
a 25-year period, 79 (78%) could be associated to contact with another 
leprosy patient. Twenty-eight (28%) of these 101 cases were identified as 
household contacts, 36 (36%) as neighbors, and the remaining 15 (15%) as 
social contacts. Three patients had not had a traceable previous contact 
with another leprosy patient, and no information could be gathered from 19 
patients. The median span of time from the registration of the primary case 
to that of the secondary case was 3 years; 95% of the secondary cases were 
detected within 6 years after the primary case. The estimated risk for 
leprosy was about nine times higher in households of patients and four 
times higher in direct neighboring houses of patients compared to 
households that had had no such contact with patients. The highest risk of 
leprosy was associated with households of multibacillary patients. The risk 
of leprosy for households of paucibacillary patients was similar to the 
risk of leprosy for direct neighboring houses of multibacillary patients, 
indicating that both the type of leprosy of the primary case and the 
distance to the primary case are important contributing factors for the 
risk of leprosy. Contact with a leprosy patient is the major determinant in 
incident leprosy; the type of contact is not limited to household 
relationships but also includes neighbor and social relationships. This 
finding can be translated into a valuable and sustainable tool for leprosy 
control programs and elimination campaigns by focusing case detection and 
health promotion activities not only on household contacts but also on at 
least the neighbors of leprosy cases. 

============================================================ 
26.) The clinical use of fluoroquinolones for the treatment of mycobacterial diseases. 
============================================================ 
Clin Infect Dis 1997 Nov;25(5):1213-21 Related Articles, Books, LinkOut  Alangaden GJ, Lerner 
SA 

Department of Biochemistry and Molecular Biology, Wayne State University School of Medicine, 
Detroit, Michigan, USA. 

Mycobacterial diseases often require prolonged therapy with multidrug regimens. Fluoroquinolones 
have excellent bactericidal activity against many mycobacteria; achieve effective serum, tissue, and 
intracellular levels following oral administration; and produce few adverse effects. These properties 
have led to the increasing use of fluoroquinolones for the treatment of mycobacterial infections. We 
reviewed clinical studies and reports involving the use of fluoroquinolones for mycobacterial 
diseases. Ofloxacin, ciprofloxacin, sparfloxacin, and pefloxacin exhibit clinical efficacy against 
mycobacterial diseases, especially tuberculosis and leprosy. Fluoroquinolones have generally been 
administered in regimens that include other agents. However, when a fluoroquinolone has been found 
to be the sole active agent in a multidrug regimen, the ready emergence of resistance to 
fluoroquinolones has been recognized, just as when they have been used as monotherapy. Therefore, 
to forestall the emergence of resistance to fluoroquinolones during the treatment of mycobacterial 
diseases, these drugs should always be used in combination with at least one other active agent, and 
they should be used only when effective alternative drugs are not available. 

============================================================ 
27.) A case of relapsed leprosy successfully treated with sparfloxacin. 
============================================================ 
Arch Dermatol 1996 Nov;132(11):1397-8 Related Articles, Books, LinkOut 

Sugita Y, Suga C, Ishii N, Nakajima H 

Publication Types: 
Letter 
============================================================ 

============================================================ 
28.) Active leprosy treated effectively with ofloxacin. 
============================================================ 
Intern Med 1996 Sep;35(9):749-51 Related Articles, Books, LinkOut 

Mochizuki Y, Oishi M, Nishiyama C, Iida T 

Department of Neurology, Nihon University School of Medicine, Tokyo. 

The patient is a 25-year-old Filipino who showed polymorphous eruptions over the whole body, 
right ulnar nerve paresis, polyneuropathy and hypalgesia in the area of eruptions. Because the biopsy 
specimen showed foam cells, histiocytes, epithelioid cells, many Mycobacterium leprae and no giant 
cells, the diagnosis of borderline-lepromatous (BL) type was made. The symptoms were improved 
by the administration of 300 mg/day ofloxacin. Because the monotherapy using ofloxacin has been 
reported to be effective in all 5 previously reported cases of BL type leprosy, it may be 
recommended for a larger number of leprosy cases. 
 

============================================================ 
29.) Reactional states and neuritis in multibacillary leprosy patients following MDT with/without 
immunotherapy with Mycobacterium w antileprosy vaccine. 
============================================================ 
Lepr Rev 2000 Jun;71(2):193-205 Related Articles, Books, LinkOut 

Sharma P, Kar HK, Misra RS, Mukherjee A, Kaur H, Mukherjee R, Rani R 

National Institute of Immunology, New Delhi, India. 

A vaccine based on autoclaved Mycobacterium w was administered, in addition to standard 
multidrug therapy (MDT), to 157 untreated, bacteriologically positive, lepromin negative 
multibacillary leprosy patients, supported by a well matched control group of 147 patients with 
similar type of disease, who received a placebo injection in addition to MDT. The MDT was given 
for a minimum period of 2 years and continued until skin smear negativity, while the vaccine/placebo 
was given at 3-monthly intervals up to a maximum of eight doses. The incidence of type 2 reaction 
and neuritis during treatment and follow-up showed no statistically significant difference in the 
vaccine and placebo groups. The incidence of type 1 reaction (mild in most cases), however, was 
higher in the vaccine group (P = 0.041, relative risk ratio 1.79), considering LL, BL and BB leprosy 
types together, and considerably higher (P = 0.009) in LL type, probably because of confounding 
due to higher number of patients with previous history of reaction in this group. The occurrence of 
reactions and neuritis in terms of single or multiple episodes was similar in the vaccine and placebo 
groups. The association of neuritis and reactions, as well as their timing of occurrence (during MDT 
or follow-up), was also similar in the two groups, with more than 90% of occurrences taking place 
during MDT. The incidence of reversal reaction was significantly higher among the males in the 
vaccine group (34.5% versus 8.3%, P = 0.019). Patients with high initial BI (4.1-6.0) showed higher 
incidence of reactions (70.3%) as compared to those with medium (2.1-4.0) and low (0.3-2.0) BI 
where the reactions were observed with a frequency of 56.1% and 38.8%, respectively. However, 
unlike reactions, neuritis incidence did not seem to be affected by initial BI to the same extent in the 
vaccine group, with frequencies of 35.3%, 36.3% and 25.9% in the three mentioned BI ranges. 
Overall, the vaccine did not precipitate reactional states and neuritis over and above that observed 
with MDT alone. 

============================================================ 
30.) Mycobacterium w vaccine, a useful adjuvant to multidrug therapy in multibacillary leprosy: a 
report on hospital based immunotherapeutic clinical trials with a follow-up of 1-7 years after 
treatment. 
============================================================ 
Lepr Rev 2000 Jun;71(2):179-92 Related Articles, Books, LinkOut 

Sharma P, Misra RS, Kar HK, Mukherjee A, Poricha D, Kaur H, Mukherjee R, Rani R 

National Institute of Immunology, New Delhi, India. 

A vaccine based on autoclaved Mycobacterium w was administered, in addition to standard 
multidrug therapy (MDT), to 156 bacteriologically positive, lepromin negative multibacillary leprosy 
patients compared to a well matched control group of 145 patients with a similar type of disease 
who received a placebo injection in addition to MDT. The MDT was given for a minimum period of 
2 years and continued until skin smear negativity, while the vaccine was given at 3-month intervals up 
to a maximum of eight doses. The fall in clinical scores and bacteriological indices was significantly 
more rapid in vaccinated patients, from 6 months onward until years 2 or 3 of therapy. However, no 
difference was observed in the fall in bacteriological index in the two groups from year 4 onwards. 
The number of LL and BL patients released from therapy (RFT) following attainment of skin smear 
negativity, after 24-29 months of treatment was 84/133 (63.1%) in vaccinated and 30/120 (25.0%) 
in the placebo group; the difference was highly statistically significant (P < 0.0001). In all, 90.2% 
patients (146/162) converted from lepromin negativity to positivity in the vaccine group, as against 
37.9% (56/148) in the placebo group. The average duration of lepromin positivity maintained 
following eight doses of vaccine administered over 2 years was 3.016 years in the vaccine and 0.920 
years in the placebo group. Histological upgrading after 2 years of treatment in the LL type was 
observed in 34/84 (40.5%) cases in the vaccine and 5/85 (5.9%) cases in the placebo group, the 
difference being statistically significant (P < 0.001). The incidence of type 1 reactions was 
significantly higher (30.5%) in the vaccine group than (19.7%) in the placebo group (P = 0.0413); 
the difference was mainly observed in LL type (P = 0.009). The incidence of type 2 reactions was 
similar (31.8 and 34.6%) in vaccine and placebo groups. The vaccine did not precipitate neuritis or 
impairments over and above that encountered with MDT alone. After 5 years of follow-up following 
RFT, no incidence of bacteriological or clinical relapses was observed in both groups. 

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