The Effectiveness of Rifampicin, Ofloxacin, and Clarithromycin

Combination Therapy in Multibacillary Leprosy Patients

Huany Wongdjaja, Irwan Junawanto, H. A. M Adam, Farida Tabri1, Muhlis

Dermatology and Venereology Department, Faculty of Medicine Hasanuddin University, Indonesia

Dr. Wahidin Sudirohusodo Central Public Hospital, Makassar, South Sulawesi, 90245, Indonesia

Keywords: Rifampicin, Ofloxacin, Clarithromycin, Multibacillary leprosy.

Abstract: The aim of this research is to evaluate the effectiveness of rifampicin, ofloxacin, and clarithromycin (ROC)

combination therapy in the treatment of multibacillary leprosy by comparing it with the multi drug therapy

(MDT) for multibacillary leprosy (MB) recommended by WHO. This double-blinded RCT was done in 26

previously-untreated MB leprosy patients who were given 600 mg rifampicin, 400 mg ofloxacin, and 500 mg

clarithromycin combination therapy for 12 weeks (n=13) and MDT regimen (n=13). Clinical improvement,

acid fast bacilli examination, and histopathological examination were assessed before and after the 12-week

treatment period. This study showed that the group treated with ROC combination therapy showed superior

bacteriological and histopathological improvement compared to the MDT group. The ROC regimen is a

potential alternative regimen for MB leprosy patients, especially those who experienced relapse or are

uncompliant.

1 INTRODUCTION

Leprosy is a chronic granulomatous bacterial

inflammatory disease that develops slowly and is

caused by Mycobacterium leprae which may result in

significant comorbidities and disfigurement. The

current approved regimen is the combination of

Rifampicin, Clofazimine, and Dapsone, also known

as the multidrug therapy (MDT). However, the lack

of adherence, long duration of treatment,

pigmentation induced by clofazimine, and episodes of

dapsone hypersensitivity have been reported and are

important issues that need to be addressed. (Prasad,

2010) (Kumar, 2015)

The combination of rifamipicin, ofloxacin, and

minocycline (ROM) been considered as an alternative

treatment for leprosy patients. However, WHO only

recommends this regimen in paucibacillary (PB)

patients with single lesion and studies have shown

lower efficacy compared with MDT treatment.( Setia,

2011) (Manickam, 20141) Although a study

suggested that ROM might be as effective as MDT in

MB patients, the long treatment duration (24 months).

Together, these findings prompt the search of a more

effective alternative treatment and shorter therapy

duration to improve clinical outcome and patient

compliance. (Kumar, 2015)

Clarithromycin has been shown to exhibit potent

bactericidal activity as shown by >99% M.leprae

reduction as well as satisfactory clinical

improvement.(Ji, 1993) However, data on the use of

clarithromycin is very limited. A study showed that

short term combination therapy of rifampicin and

clarithromycin for 3 months successfully decreased

IgM titers in subclinical leprosy. (Tanasal, 2005) A

trial by Hubaya et al showed a significant

bacteriologic improvement in 337 patients following

600 mg rifampicin once a month and 250 mg

clarithromycin given twice daily for 3

months.(Hubayal, 2017) They showed a significant

improvement in both clinical and bacteriologic

examinations. Thus, it is necessary to investigate the

efficacy of a combination of rifampicin 600 mg and

ofloxacin 400 mg (weekly) plus clarithromycin 500

mg / day for 12 weeks in MB leprosy patients by

assessing clinical improvement, bacteriological and

histopathologic profiles before and after treatment

and compare it to the MDT standard regiment.

Wongdjaja, H., Junawanto, I., Adam, H., Tabri, F. and Muhlis, .

The Effectiveness of Rifampicin, Oﬂoxacin, and Clarithromycin Combination Therapy in Multibacillary Leprosy Patients.

DOI: 10.5220/0008154102090213

In Proceedings of the 23rd Regional Conference of Dermatology (RCD 2018), pages 209-213

ISBN: 978-989-758-494-7

209

2 METHODS

2.1 Study Design

This study was a double-blind randomized clinical

trial where 26 previously untreated MB leprosy

patients were divided into two groups. The first group

received WHO multidrug therapy (MDT) and the

second group was treated with 600 mg rifampicin,

400 mg ofloxacin (both given three times a week) and

500 mg clarithromycin (taken every day). Clinical

improvement, acid fast bacilli examination, and

histopathological examination using hematoxylin

eosin (HE) and Fite Faraco staining were carried out

before and after the 12-week treatment and the results

were compared between the two treatment groups.

2.2 Subjects

Eligible subjects were 18-60-years-old previously

untreated MB patients who came for treatment to

Wahidin Sudirohusodo hospital with a minimum

bacteriological index of +2 and were willing to give

their consent. Subjects who were pregnant,

experiencing leprosy reactions, had history of

hypersensitivity to one or more of the above agents,

or having abnormal liver function tests were excluded

from this study. Consecutive sampling method was

used where all eligible patients coming to the

Dermatovenereology department were included and

randomly assigned into each group.

2.3 Assessment

The primary objective was to evaluate the

effectiveness of rifampicin, ofloxacin, and

clarithromycin combination therapy in treating MB

leprosy and comparing it to the standard WHO MDT

regimen. This was achieved by evaluating the clinical

condition, microscopic bacteriologic examination,

and histopathological examination using HE staining

before and after the 12-weeks treatment period.

The clinical condition was graded as improved,

not improved, and worsened and was assessed

through the improvement in erythema, infiltrates,

size, and morphology. Bacteriological examination

was calculated semi-quantitatively based on Ridley

classification and was compared between both groups

before and after treatment.

Histopathological examination using HE staining

was graded as excellent (LL becomes BT or TT, BL

becomes TT), good (LL becomes BB, BL becomes

BT, BB, and TT), moderate (LL becomes BL, BL

becomes BB and BB becomes BT) dan no

improvement (no type changes).

2.4 Statistical Analysis

Statistical analysis was done using Mann-

Whitney U and Wilcoxon Signed Ranks Test with p-

value <0.05 considered as being statistically

significant

3 RESULTS

Table 1 - Characteristics of MB leprosy patients who received MDT – WHO and ROC combination therapy.

Variable MDT- WHO

group (n)

% ROC group (n) %

Sex Male

Female

76,9

23,1

69,2

30,8

Total 13 100,0 13 100,0

Age 34.5 ± 11.56 years

Leprosy type BB

Total

38,5

46,1

15,4

100,0

46,1

30,8

23,1

100,0

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Table 2- Comparison of clinical improvement of MB leprosy patients before and after MDT treatment WHO and ROC

combination.

Treatment Clinical improvement n %

MDT WHO Improved

No improvement

Worsened

61,5

38,5

TOTAL 13 100,0

ROC Improved

No improvement

Worsened

100,0

TOTAL 13 100,0

Statistic test*,p P=0,10

*Mann Whitney U Test

Table 3 - Comparison of bacteriological index (BI) and morphological index (MI) of MB leprosy patients before and after

treatment in each WHO MDT treatment group and ROC Combination.

Treatment

P-value*

MI P-value

Before After Before After

MDT WHO Range

Mean

3-5

3,69

0,63

2-4

2,85

0,55

P= 0,002

2-8

4,62

2,50

0-4

1,85

1,77

P= 0,001

ROC Range

Mean

3-5

3,84

0,80

0-4

1,23

1,48

P= 0,001

2-9

4,08

2,75

0-2

0,46

0,88

P= 0,001

P-value** 0,68 0,006 0,51 0,005

*Wilcoxon Signed Ranks test ** Mann whitney U test

Table 4 - Comparison of histopathologic improvement with HE stain in patients MB leprosy before and after WHO MDT and

ROC Combination Therapy.

Treatment

Group

Type Improvement P-value*

Before After Good Moderate None

WHO MDT BB,BL,LL TT,BB,BL 0 (0%) 5 (38.5%) 8 (61.5%) P= 0,65

ROC BB,BL,LL TT,BB,BL 7 (53.8%) 3 (23.1%) 3 (23.1%) P= 0,004

P-value** P=0,48 P=0,12 P=0,009

*Wilcoxon Signed Ranks Test ** Mann Whitney U Test

Table 1 shows the demographic data of the study

population where 76.9% and 69.2% in the WHO

MDT regimen and ROC combination group were

male. Approximately 70% of subjects in both groups

were between 18 and 37 years old. In the MDT group,

most patients were in the BL type (46.1%) followed

by BB type (38.5%); while in the ROC combination

therapy group, BB was the most common type seen

(46.1%) followed by BL type (30.8%). In both

groups, LL was the least type (15.4% and 23.1% in

the MDT and ROC groups, respectively).

Clinical improvement was seen in 61.5% of the

WHO-MDT group, with 38.5% showed no

improvement and no subject suffered worsening

condition. On the other hand, all subjects (100%) in

the ROC combination therapy experienced clinical

improvement. The clinical improvement in both

groups, however, did not significantly differ (p = 0,

10) (Table 2).

Bacteriological examination, shown by bacterial

and morphological index (BI and MI), showed

significant decrease in both WHO-MDT and ROC

combination groups before and after treatment (Table

2). However, the BI and MI after treatment in the

ROC combination group showed superior result

compared to the WHO MDT group (1.23 compared

to 2.85 and 0.46 compared to 1.85, respectively) and

was statistically significant (p≤0.01). Table 3 shows

the change in leprosy type before and after treatment

based on HE staining. The result suggested that there

The Effectiveness of Rifampicin, Oﬂoxacin, and Clarithromycin Combination Therapy in Multibacillary Leprosy Patients

211

was a significant improvement in bacteriologic

examination in the ROC group after treatment

(p=0.004). In addition, there were 7 subjects with

‘good’ improvement in the ROC group compared to

none the WHO-MDT group. The improvement seen

in ROC group was also significantly higher compared

to the WHO-MDT group (p=0.009)

The side effects reported in the ROC group was

one reversal reaction while two patients and one

patient in the MDT group experienced erythema

nodusum leprosum (ENL) and reversal reaction,

respectively.

4 DISCUSSION

Despite the success of MDT regimen in treating MB

leprosy patients, issues such as long treatment

duration, the weak bactericidal effect exhibited by

dapsone and clofazimine, and incidence of relapse

cases, are emerging and thus required a new

therapeutic approach, with at least the same efficacy

as MDT.(Prasad, 2010) The objective of this study

was to examine clarithromycin as an alternative

treatment for MB leprosy patients.

Our study population consisted of 2 groups each

treated with MDT and ROC, respectively. From table

1 we can see that the type of leprosy in both groups

was similar between both groups. Similar result was

also exhibited in table 3 and 4, where the BI, MI, and

leprosy type based on histopathological examination

in both groups before treatment were not significantly

different, showing that the randomization process was

successful.

Both the ROC and MDT groups showed clinical

improvement after completing the 12 week-period.

However, the after-treatment result between both

groups did not differ, suggesting that the clinical

improvement of ROC was not superior to MDT.

However, the ROC group showed significantly better

bacteriologic and histopathological improvement.

Examination under the microscope using Ridley

criteria showed significantly lower BI and MI values

in the ROC group (1.23 vs 2.85 and 0.46 vs 1.85,

respectively). In addition, histopathologic

examination using HE staining also showed that after

3 months, a significant change in leprosy type was

observed in the ROC group (p=0.004) but not in the

MDT group. This was an important finding as

bacterial index is closely associated with immune

response of an individual and determine the clinical

manifestation and infectivity of the disease ( Adiga,

2016), suggesting that clinical improvement alone is

not sufficient to conclude leprosy treatment.

Other studies using clarithromycin are mostly

case reports ( Hubayal,2017) (Gunawan, 2011) which

showed a satisfactory clinical result. However, both

studies did not examine changes in the bacteriologic

nor histopathological examinations. Another study

evaluating the IgM titer changes in subclinical

leprosy patients showed a significant titer reduction

following 3 months treatment of rifampicin and

clarithromycin.(Tanasal, 2005) Our study is thus the

first randomized double blinded clinical trial

assessing the effectiveness of ROC regimen and

comparing it with the standard MDT regimen.

Subjects experiencing adverse events in the ROC

group was also fewer (one person experiencing

reversal reaction) compared to two ENL cases and

one reversal case in the MDT group. However, the

sample size was not sufficient to make a statistical

analysis. Prospective studies with larger number of

participants are needed to evaluate the safety profile

of this drug.

This study showed that ROC resulted in better

bacteriological and histopathological improvement

compared to the MDT after 3 months of treatment

with no s. As a pilot study assessing the effectivity of

ROC regimen, future study with larger number of

participants and longer follow-up period is needed to

find the optimal protocol for Multibacillary leprosy.

5 CONCLUSIONS

Treatment using ROC therapy showed better

bacteriological and histopathological improvement in

MB patients. The ROC combination therapy also

showed good safety profile with only one person

experiencing a mild reversal reaction. This study

showed that ROC therapy may serve as a potential

alternative treatment for MB leprosy patients.

ACKNOWLEDGEMENTS

This research was supported by Department of

Dermatology & Venereology Faculty of Medicine,

Hasanuddin university.

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