1. No category

Topical treatment of Old World cutaneous
leishmaniasis caused by Leishmania major: A
double-blind control study
Joseph EI-On, PhD,a Sima Halevy, MD,b Marcello H. Grunwald, MD,b and
Louis Weinrauch, MDc Beer Sheva and Jerusalem, Israel
Background: A controlled study of the efficacy of topical paromomycin sulfate (PR) and methylbenzethonium chloride (MBCl) in cutaneous leishmaniasis (CL) has not yet been performed.
Objective: The therapeutic effect of an ointment containing 15% PR and either 12% or 5%
MBCl (15/12 or 15/5 P-ointment) on patients suffering from Old World CL was examined
in a randomized, double-blind, cross-over study.
Methods: Thirty-nine patients with Old World CLcaused by Leishmania major were treated
topically, twice daily, for 10 to 20 days with 15/12 or 15/5 P-ointment and 10 to 20 days
with a placebo ointment to achieve a total of 30 days of treatment in all groups.
Results: In the P-ointment-treated groups, 74.2% (29 of 39 patients) of the patients were
cured versus 26.6% (4 of 15 patients) in the placebo-treated group. Little difference was found
between the 15/12 and 15/5 P-ointment groups.
Conclusion: In most of the patients treated with the active ingredients, total elimination of
the parasites was achieved within the first 10 days of treatment.
(J AM ACAD DERMATOL 1992;27:227-31.)
Topical treatment of cutaneous leishmaniasis
(CL) with an ointment composed of 15% paromomycin sulfate (PR) and 12% methylbenzethonium
chloride (MBCI) in soft white paraffin (SWP)
(15/12 P-ointment) has been recently developed.t
Preliminary clinical study with P-ointment indicated high efficacy against Leishmania major,
Leishmania tropica, and Leishmania aethiopica. 2,3
In the present study we tested the therapeutic effect
of P-ointment with two different concentrations of
MBCI, 12% and 5%, on CL caused by L. major.
Treatment was given for 10 to 20 days, in a
randomized double-blind, cross-over study.
From the Department of Microbiology and Immunology, Faculty of
Health Sciences, Ben Gurian University of The Negev"; the Department of Dermatology, Soroka Medical Center, and Ben Gurion
University of the Negevb; and the Department of Dermatology, Hadassah University Hospital and Hebrew University.c
Supported by the UNDP/World Bank/World Health Organization
special program for research and training in tropical diseases.
Reprint requests: Joseph EI·On, PhD, Department of Microbiology and
Immunology, Faculty of Health Sciences, Ben Gurion University of
the Negev, P.O. Box 653, Beer Sheva 84105, Israel.
16/1/36531
MATERIAL AND METHODS
Patients
Forty-six patients with CL between the ages of 6
months and 52 years were included. Three patients were
dropped because of bilirubinemia before beginning treatment (one patient) or severe pain within 3 to 7 days of
treatment with 15/12 P-ointment (two patients). The remaining 43 patients were divided into two groups that
were treated with either 15/12 P-ointment (32 patients)
or 15/5 P-ointment (11 patients).
Treatment
Three preparations were used: Ointment A, 15%
PR + 12% MBCl in SWP (15/12 P-ointment); ointment
B, placebo ointment, containing SWP only; and ointment
C, 15% PR + 5% MBClin SWP (15/5 P-ointment). Patients were randomly assigned to start a 1O-day treatment
with the ointments according to the following regimen:
(1) AAB; (2) BAB; (3) CCB; (4) BCB. Treatment consisted of two applications per day of the ointment. In this
way, at the end of the study, all patients had received either 10 or 20 consecutive days of treatment with the active ingredient. This study was carried out according to a
double-blind, cross-over design to conceal the identity of
the placebo from both the physician and the patient.
227
Journal of the
American Academy of
Dermatology
228 El-On et al.
Table I. Effect of topical treatment with either 15/12 or 15/5 P-ointment on cutaneous leishmaniasis*
Description of patients
Age(yr)
Effect of treatment
15/12 P-ointment
Parasitologic and
clinical cure
Total
Delayed cure and
parasitologic
cure
Total
Failure
Total
15/5 P-ointment
Parasitologic and
clinical cure
Total
Delayed cure and
parasitologic
cure
Total
Failure
Total
Mean ± SD
Sex
No.
%
M
F
F
17
6
23
4t
1
56.6
20.0
76.6
1303
3.3
23.85 ±
26.55 ±
24.55 ±
25.50 ±
46.00 ±
M
F
5
2
0
16.6
6.6
29.60 ± 11.82
19.50 ± 0.70
0
19.50 ± 0.70
3
3
33.3 19.60 ± 0.57
3303
4.16 ± 3.10
66.6 11.91 ± 8.73
20.00
11.l:\:
0
M
M
F
2:
6"
M
F
1
0
M
F
1
0
2
2:
""6.6
11.1
22.2
22.2
I Range
13.82 0.5-49
22.12 OJ-50
15.91 0.3-50
8.73
19-38
0.00
20.00
0
16.00 ± 8.48
16.00 ± 8,48
19-38
19-20
19-20
19-20
0.5-60
0.5-20
10-22
10-22
Weeks from appearance of
lesion to onset of treatment
Mean ± SD
±
±
±
±
I Range
No. of lesions
per patient
Mean ± SD
IRange
4-48 6.52 ± 5.47
8-43 5.00 ± 6.03
4-48 6.13 ± 5.52
2-26 7.50 ± 5.80
8.00 ± 0.00
1-20
1-15
1-20
2-15
7.80 ± 5.02
8.50 ± 0.70
0
8.50 ± 0.70
2-15
8-9
11.00 ± 5.19
15.66 ± 2.30
13.33 ± 4.41
20.00
0
8-17 2.66 ± 1.52
13-17 1.33 ± 0.57
8-17 2.00 ± 1.26
2.00
0
1-4
1-2
1-4
20.00
0
21.50 ± 12.02
21.50 ± 12.02
2.00
0
13-30 2.00 ± 1.41
13-30 2.00 ± 1.41
13.41
23.33
16.00
11.00
8.00
10.05
16.25
12.32
10.39
± 0.00
10.4 ± 9.09
10.5 ± 3.53
0
10.5 ± 3.53
8-13
8-13
8-9
1-3
1-3
*The lesions were treated twice daily for 10 to 20 days.
tTwo patients were delayed cure.
*Delayed cure.
Clinical and parasitologic examinations
All patients had routine clinical laboratory tests (complete blood cell count, erythrocyte sedimentation rate,
automated chemistry panel, urinalysis) performed before
and after termination of treatment. A smear and culture
sample were taken from the lesion before the start of
treatment and at each subsequent visit. Follow-up examination included one or more of the following: (1) at least
two culture samples after the last treatment, and (2) at
least one clinical examination. The results obtained were
defined as follows: (1) Parasitologic and clinical cure: no
parasites were detected in the treated lesion at the end of
the treatment, followed by complete healing of the lesion.
(2) Delayed cure: Parasites were still present in the
treated lesion at the end ofthe treatment, but disappeared
within the next 10 days, followed by complete healing of
the lesion. (3) Parasitologic cure: no parasites were
detected in the treated lesion at the end of the treatment,
but clinical improvement was not obtained within the first
30 days after termination of treatment. (4) Failure: Nei-
ther parasitologic nor clinical cure was achieved within
the first 30 days after termination of treatment.
RESULTS
Topical treatment with 15/12 P-ointment
The therapeutic effect of 15/12 P-ointment on
patients with CL is summarized in Table 1. Two of
the 32 patients showed no parasites after 10 days of
treatment with the placebo ointment (ointment B).
The cure rate for those patients treated with the active ingredient was 76.6% (23 of 30 patients) as
compared with 18.1 % (2 of 11) in the placebo group
(Table II). A delayed clearing of 10 days was demonstrated in 6% (2 of 30). In an additional 10% (3
of 30) of this group, no clinical improvement of the
treated lesions was demonstrated up to 10 weeks after treatment, although no parasites were demonstrated in these treated lesions at the end of the
Volume 27
Number 2, Part 1
August 1992
Topical treatment of cutaneous leishmaniasis 229
Table II. Effect of topical treatment with 15/12 and 15/5 P-ointment on cutaneous leishmaniasis*
Description of patients
Weeks from appearance of
lesion to onset of treatment
Age(yr)
Effect of treatment
Active ingredients
Parasitologic and
clinical cure
Total
Delayed cure and
parasitologic
cure
Total
Failure
Total
Placebo
Parasitologic cure
Total
Failure
Total
Sex
No.
%
M
F
20
0
29
5
1
51.2
23.0
74.2
12.8
2.5
M
F
M
F
M
F
M
F
Mean ± SD
23.20 ± 12.84 0.5-49
19.02 ± 20.82 OJ-50
21.94 ± 15.42 OJ-50
24.40 ± 7.95
19-38
46.00
Mean ± SD
, Range
13.05 ± 9.41
20.77 ± 13.46
15.44 ± 11.12
12.80 ± 9.98
8.00
4-48
8-43
4-48
2-26
11.33
0.70
6.24
5.34
19-38
19-20
10-22
10-22
12.00 ± 9.03
10.50 ± 3.53
21.00 ± 8.5
16.00 ± 9.62
2-26
8-13
13-30
8-30
26.00 ± 11.28
19.00
24.25 ± 9.89
25.68 ± 13.10
26.00 ± 9.89
25.72 ± 12.64
19-39
9.66 ± 2.88
20.00
12.25 ± 5.67
17.00 ± 13.34
10.50 ± 3.53
15.81 ± 12.27
8-20
6 15.3 28.00 ±
2 5.1 19.50 ±
2 5.1 17.00 ±
"4 10.2 17.75 ±
3 20
1 6.6
4 26.6
9 60
2 13.3
IT 73.3
I Range
19-39
4-41
19-33
4-41
No. of lesions
per patient
Mean ± SD
I Range
5.95 ± 5.24
3.77 ± 5.11
5.27 ± 5.21
6.40 ± 5.59
8.00
1-20
1-15
1-20
2-15
± 5.04
± 0.70
± 2.51
± 3.86
2-15
8-9
1-3
1-9
6.66
8.50
3.33
5.25
2.00 ± 1.73
6.00
8-20 3.00 ± 2.44
8-48 6.11 ± 4.96
8-13 12.50 ± 3.53
8-48 7.27 ± 5.25
1-4
1-6
1-18
10-15
1-18
*The lesions were treated twice daily for 10 to 20 days.
treatment. No effect was observed in 6.6% of the
treated patients (2 of 30).
In the cured group, parasites were totally eliminated from the lesions by the end of the treatment
and the lesions were clinically healed within an additional 1 to 4 weeks (Figs. 1 and 2).
Topical treatment with 15/5 P-ointment
In the group treated with 15/5 P-ointment (Table I), 2 of 11 patients were cured of the parasites
after 10 days of treatment with the placebo ointment
(ointment B). The remaining nine patients were
treated with 15/5 P-ointment (ointment C). Of
these, 66.6% (six of nine) were cured at the end of
the treatment course. Another one ( 11.1%) showed
a delayed cure 10 days after termination of 20 days
of treatment with ointment C, and 22.2% (two of
nine) remained infected after the initial 20 days of
treatment (Table 0.
Placebo treatment
The placebo group received a 10-day course of
ointment B, after which treatment with the active
ingredients was initiated. In this group, 26.6% (4 of
15 patients) were cured at the end of the 10 days. A
comparison between the placebo group and the other
groups treated with the active ingredients (15/
12 + 15/5 P-ointments) is given in Table II. The
results show a much lower cure rate (26.6%) in the
placebo group, as compared with the active ingredient-treated groups (74.2%). In the last groups
an additional 15.3% were either cured parasitologically or had delayed cure, and 10.2% failed to
respond.
Ten versus 20 days of treatment with
P-ointment
No significant difference in the cure rate was observed between the groups treated for either 10 or 20
days. A lO-day treatment with 15/12 P-ointment
(ointment A) cured 86.2% ofthe patients (25 of29).
Extension of the treatment for an additional 10 days
increased the cure rate by 6.9% (2 of 29). In the
group treated with 15/5 P-ointment (ointment C),
66.6% (four of six) were cured after 10 days of
treatment. The remaining two patients were examined only at the end of 20 days of treatment. In the
failure groups treated with either ointment A or C,
Journal of the
American Academy of
Dermatology
230 EI-On et al.
Fig. 1. Patient with cutaneous leishmaniasis lesion, before and after topical treatment with
15/12 P-ointment (ointment A). The lesion was treated twice daily. A, Before treatment. B,
After 10 days of treatment with ointment A. C, After 20 days of treatment. D, After 20 days
of treatment with ointment A and an additional 10 days of treatment with placebo ointment
(ointment B).
prolongation of the treatment for an additional 10
days did not change the results.
Clinical and laboratory examinations
Routine laboratory examinations indicated no
adverse side effects. Various degrees of inflammation, a burning sensation, and local pain, depending
on the lesion size and the host response, were associated with this treatment. Two patients were
dropped from this study because of severe pain associated with erythema and edema· that developed
within 3 to 7 days of treatment with 15/12 P-ointment. An additional patient who had an exudating
lesion of 5 cm in diameter developed similar side effects within 2 days of treatment with the same ointment. This patient was treated for 8 days only. At the
end of treatment all parasites had been eliminated
and the lesion healed within 3 weeks.
DISCUSSION
A randomized, double-blind, controlled study was
performed to determine the efficacy of two concentrations of P-ointment. Almost 74% of the 39
patients treated with either 15/12 or 15/5 P-ointment were cleared of parasites after 10 days of
treatment as compared with only a 26.6% cure rate
obtained in the control group treated with placebo.
An additional 15% treated with the active ingredients either showed delayed cure or were cured parasitologically without any clinical improvement.
These results are similar to our previous study of
15/12 P-ointment that showed a cure rate of 72% to
87%. 2 We have also found that 15/5 P-ointment was
almost as effective as 15/12 P-ointment against eL,
with cure rates of66.6% and 76.6%, respectively. No
increase in efficacy was observed by prolongation of
the treatment from 10 to 20 days. Also the number
Volume 27
Number 2, Part I
August 1992
Topical treatment of cutaneous leishmaniasis 231
Fig. 2. Treated (A, B, C) and untreated control (D, E, F) cutaneous leishmaniasis lesions
of same patient. Lesion was treated twice daily. A and D, Before treatment. B, and E, After
10 days of treatment with placebo ointment. C and F, Ninety-five days after termination of
treatment with placebo ointment (10 days) plus 15/12 P-ointment (10 days) plus placebo
ointment (10 days).
of lesions, their size, or duration did not correlate
with the response rate. In addition, no antibiotic
treatment was required and elimination of the parasites after P-ointment treatment was followed by
total eradication of the superimposed bacterial infection. Generally, apart from local inflammation
and pain, no side effects were associated with the
P-ointment treatment. However, 2 of 43 patients
were dropped from this study because of severe pain
and edema that developed within 3 to 7 days of
treatment with 15/12 P-ointment. The third patient
in whom similar side effects developed completed a
total of 8 days of treatment and was cured. Further
studies with P-ointment containing lower concentrations of MBCl are required to establish the optimal concentration. However, a field study of ointments containing either 12% PR alone4 or 12% PR
and 1%MBCI (Weinrauch and EI-On, unpublished
data) indicated no significant difference between the
active ingredient-treated groups and the placebo-
treated groups. In the present study the cure rate
with the active ingredient was found to be almost
three times higher than the cure rate in the placebotreated group. In addition, a short period of treatment with either 15/12 or 15/5 P-ointment was
found to be sufficient to clear the lesion of Leishmania parasites.
Paromomycin sulfate was supplied by Farmitalia Carlo
Erba, Italy, and Warner-Lambert, Italy.
REFERENCES
1. EI-On J, Jacobs GP, Weinrauch L. Topical chemotherapy
of cutaneous leishmaniasis. Parasitol Today 1988;4:76-81.
2. El-On J, Livshin R, Even Paz Z, et al. Topical treatment
of cutaneous leishmaniasis. J Invest Dermatol 1986;87:
284-8.
3. Strick RA, Borok M, Gasiorowski He. Recurrent cutaneous leishmaniasis. J AM ACAD DERMATOL 1983;9:437-43.
4. El-Safi SH, Murphy AG, Bryceson ADM, et al. A doubleblind clinical trial of the treatment of cutaneous leishmaniasis with paromomycin ointment. Trans R Soc Trop Med
Hyg 1990;84:690-1.