1457
Safety and Efficacy of Intravenous Sodium Stibogluconate in the Treatment of
Leishmaniasis: Recent U.S. Military Experience
Naomi E. Aronson, Glenn W. Wortmann,
Steven C. Johnson, Joan E. Jackson,
Robert A. Gasser, Jr., Alan J. Magill, Timothy P. Endy,
Philip E. Coyne, Max Grogl, Paul M. Benson,
Jeffrey S. Beard, John D. Tally, Jeffrey M. Gambel,
Richard D. Kreutzer, and Charles N. Oster
From the Walter Reed Army Medical Center and Institute of Research,
Washington, D.C., and CAEID, Surfside Beach, South Carolina
The efficacy and toxicity of sodium stibogluconate (SSG) at a dosage of 20 mg/(kgrd) for either
20 days (for cutaneous disease) or 28 days (for visceral, mucosal, or viscerotropic disease) in the
treatment of leishmaniasis is reported. Ninety-six U.S. Department of Defense health care beneficiaries with parasitologically confirmed leishmaniasis were prospectively followed for 1 year. One
patient was infected with human immunodeficiency virus; otherwise, comorbidity was absent. Clinical cure occurred in 91% of 83 cases of cutaneous disease and 93% of 13 cases of visceral/viscerotropic
disease. Adverse effects were common and necessitated interruption of treatment in 28% of cases,
but they were generally reversible. These included arthralgias and myalgias (58%), pancreatitis
(97%), transaminitis (67%), headache (22%), hematologic suppression (44%), and rash (9%). No
subsequent mucosal leishmaniasis was identified, and there were no deaths attributable to SSG or
leishmaniasis.
Infections with parasites of the genus Leishmania can result
in a variety of clinical syndromes, which are collectively referred to as leishmaniasis. The standard therapy for leishmaniasis remains the pentavalent antimonials, which have been in
use since the 1940s [1, 2]. Sodium stibogluconate, or SSG
(Pentostam; Glaxo-Wellcome Foundation, London), is the antimonial used in the United States and is classified as an investigational new drug (IND); it is available from the Centers for
Disease Control and Prevention (CDC, Atlanta) or Walter Reed
Received 12 February 1998; revised 3 August 1998.
The views and assertions contained herein are those of the authors and do
not reflect the official policy or positions of the U.S. Air Force, the U.S. Army,
the U.S. Food and Drug Administration, the U.S. Department of Defense, the
U.S. Department of Health and Human Services, or the U.S. Federal Government.
Financial support: The U.S. Army Medical Materiel Development Activity
provided the sodium stibogluconate and regulatory support. Dr. Kreutzer received financial support from the Walter Reed Army Institute of Research.
Informed consent was obtained from the patients or their parents/guardians.
Guidelines for human experimentation of the U.S. Department of Health and
Human Services, the U.S. Department of the Army, and the Walter Reed Army
Medical Center were followed in the conduct of this clinical research.
Current affiliations: Dr. Johnson, University of Colorado Health Science
Center, Denver, Colorado; Dr. Magill, Department of Parasitology, Naval Medical Research Institute Detachment, Lima, Peru; Dr. Endy, Armed Forces Research Institute for Medical Sciences, Bangkok, Thailand; Dr. Coyne, Center
for Drug Evaluation and Research, United States Food and Drug Administration, Rockville, Maryland; and Dr. Beard, Dermatology and Skin Surgery,
Bradenton, Florida.
Reprints or correspondence: Dr. Naomi Aronson, Infectious Disease Service,
Walter Reed Army Medical Center, 6900 Georgia Avenue NW, Washington,
D.C. 20307-5001.
Clinical Infectious Diseases 1998;27:1457–64
q 1998 by the Infectious Diseases Society of America. All rights reserved.
1058–4838/98/2706–0021$03.00
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Army Medical Center (WRAMC, Washington, D.C.). Meglum ine antimoniate (Glucantime; Rhone Poulenc, Paris) is used
in French- and Spanish-speaking countries [3]. As the recommended regimen of SSG has evolved, the doses and duration
have been increased, with the current recommendation being
20 mg/(kgrd) for 20 days for cutaneous disease and 28 days
for visceral or mucosal disease [4].
As the referral hospital for all U.S. military service members
suspected of being infected with leishmaniasis, the WRAMC
has treated close to 400 cases since 1969. This article reviews
our experience with 96 cases seen between 1989 and 1996, in
which all patients received SSG at a dosage of 20 mg/(kgrd).
These patients are relatively homogenous (young males without
concurrent medical problems), reside in a country of nonendemicity (usually without prior exposure to Leishmania or opportunity to be reinfected), and have undergone carefully monitored standardized antimonial treatment and follow-up
according to an IND protocol.
Methods
Selection of Patients
During the study period (1989 – 1996), all active-duty (and
most reserve-component) U.S. military personnel with leishmaniasis who required IND pentavalent antimony treatment were
referred to WRAMC. U.S. Department of Defense health care
beneficiaries were eligible for this study if they had parasitologically confirmed leishmanial infection and gave written informed consent. Parasitological confirmation was defined as
isolation of Leishmania promastigotes in culture [5 – 7] or demonstration of definitive tissue amastigotes in a Diff-Quik (Dade
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Aronson et al.
Diagnostics, Aguada, Puerto Rico) stained touch preparation
or histopathologic section. Expandable cultures permitted identification of Leishmania species by cellulose acetate electrophoresis for isoenzyme analysis, with comparison to World Health
Organization reference strains [8, 9]. Patients were excluded
if they had serious concomitant cardiac, renal, or hepatic disease, had a history of hypersensitivity to antimonials, or were
pregnant. Prior pancreatitis was not exclusionary. The protocol
was approved by the WRAMC Human Use Committee and
Triservice Scientific and Ethical Review Committee.
Cutaneous leishmaniasis was defined as chronic skin lesion(s) with parasites visible by the methods noted above. Viscerotropic leishmaniasis was defined as a subacute illness associated with a positive leishmanial culture of a bone marrow
or lymph node specimen. These patients typically have mild
symptoms, fairly normal physical examination findings, and
few laboratory abnormalities [10]. Visceral leishmaniasis was
a constellation of fever, cytopenias, and hepatosplenomegaly
in association with parasites identified by biopsy of bone marrow or gastrointestinal or splenic specimens.
Treatment and Follow-Up
After enrollment in the study, patients were administered
SSG at a dosage of 20 mg per kg (total body weight) per day.
Treatment duration was 20 days for cutaneous leishmaniasis
or 28 days for visceral, mucosal, or viscerotropic leishmaniasis.
From 1989 to 1994, SSG was given for 30 days for visceral
or viscerotropic leishmaniasis. SSG was diluted in 50 mL of
5% dextrose in water and infused intravenously via a peripheral
butterfly needle over 10 – 15 minutes. Nine different lots of
Pentostam were used during this period.
Enrolled patients had a detailed history recorded and physical
examination performed initially and were seen by a physician
daily during therapy. Before-treatment and after-treatment photographs of cutaneous lesions documented response to therapy.
Electrocardiograms were obtained on treatment days 0, 4, 7,
14, and 20 (and 28 for visceral leishmaniasis). At baseline and
twice weekly during therapy, urinalysis was performed and
the complete blood cell count (with differential) and levels
of glucose, blood urea nitrogen, creatinine, electrolytes, total
protein, albumin, calcium, phosphorus, lactate dehydrogenase,
total bilirubin, alkaline phosphatase, aspartate aminotransferase
(AST), and alanine aminotransferase (ALT) were determined.
After recognition of the frequent association between SSG
therapy and pancreatitis [11], serum amylase and lipase levels
were monitored daily for the first week and twice weekly thereafter. Patients were asked to refrain from alcohol use during
therapy to avoid potentiation of possible hepatic or pancreatic
toxicity (defined as an AST, ALT, lipase, or amylase serum
level greater than the upper limit of normal [ULN]). Patients
were reexamined at 2 months after initiation of therapy; those
with visceral or viscerotropic leishmaniasis were seen again at
6 and 12 months. For patients with cutaneous leishmaniasis,
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CID 1998;27 (December)
follow-up by telephone at 6 and 12 months sufficed unless
they described a change in the skin lesion or persistent nasal
symptoms, in which case they were asked to return to WRAMC
for evaluation. Fifty patients (52%) were contacted for longer
follow-up to assess for late mucosal leishmaniasis or SSGrelated adverse events.
Definition of Clinical Cure
Leishmanial cutaneous ulcers were considered clinically
cured if complete reepithelialization was evident by 2 months
following the initiation of SSG treatment. Papulonodular or
verrucous cutaneous lesions were considered cured if they were
flattened, were not indurated (unless a cicatrix or keloid had
formed), and showed no signs of new activity over the same
period. When initial improvement of lesions with therapy was
followed by new ulcerative or infiltrative clinical findings after
completion of SSG treatment, the lesions were considered to
have relapsed. Those lesions that did not completely reepithelialize by 2 months following initiation of treatment were considered nonresponders (partially responding to treatment [12]).
Treatment failure was defined by little response of skin lesions
to treatment (õ25% epithelialization).
Viscerotropic leishmaniasis was considered cured if the majority of symptoms diminished in temporal relationship with
SSG treatment and/or if culture of a bone marrow biopsy specimen at the end of treatment yielded no growth. Visceral leishmaniasis was considered to be clinically cured if symptoms
resolved and if hepatosplenomegaly and hematologic parameters normalized by the 6-month follow-up.
Statistical Methods
Data were abstracted from patient records with use of a
standardized form. These data were doubly entered into a database with the program Epi-Info (version 6; CDC), and descriptive data analyses were performed. In the calculation of efficacy, the denominator included the total number of patients
who started SSG treatment. The numerator included the patients who were considered clinically cured and completed at
least 10 days of treatment with SSG.
For statistical comparison of medians between groups of
patients with cutaneous, visceral, and viscerotropic leishmaniasis, the Kruskal-Wallis test was used. Proportions of treatment
responders to nonresponders were compared with the twotailed Fisher’s exact test, and medians between these two
groups were compared with the Mann-Whitney U test. All P
values were considered significant at a level of P õ .05.
Results
Characteristics of Patients
Ninety-six patients with parasitologically confirmed leishmaniasis were treated with SSG and evaluated in this study.
Their demographic characteristics are shown in table 1.
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Sodium Stibogluconate for Leishmaniasis
1459
Table 1. Demographic characteristics of the 96 patients with leishmaniasis treated between 1989 and
1996.
Type of leishmaniasis
Cutaneous
(n Å 82)
Characteristic
Years of age, median (range)
Sex
Male
Female
Ethnicity
White
Black
Hispanic
Asian
History of travel to
Panama
French Guiana
Saudi Arabia
Belize
Sicily
Spain
Central/South America
Days of potential exposure in
areas of endemicity,
median (range)
Days from onset of
symptoms to treatment,
median (range)
Mucocutaneous
(n Å 1)
24 (18 – 53)
Visceral
(n Å 5)
23
82
0
18 (0.6 – 46)
Viscerotropic
(n Å 8)
32 (20 – 43)
1
0
4
1
8
0
68
7
6
1
(83)
(9)
(7)
(1)
0
0
1 (100)
0
3 (60)
1 (20)
0
1 (20)
8 (100)
0
0
0
53
15
11
9
0
0
12
(65)
(18)
(13)
(11)
0
0
0
1 (100)
0
0
0
0
0
0
0
3 (60)
2 (40)
0
0
0
7 (88)
0
0
1 (12)
0
(14)
88 (30 – 360)
8,030
395 (45 – 600)
118 (30 – 360)
360
35 (16 – 300)
P value
200 (60 – 1,460)
.048*
177 (13 – 723)
.792*
NOTE. Data are no. (%) of patients unless otherwise indicated.
* The case of mucosal disease was not included in the Kruskal-Wallis test.
All patients were in excellent health at baseline, with the
exception of one patient with visceral leishmaniasis who had
AIDS. Three HIV-negative patients with visceral leishmaniasis
were children õ4 years of age; otherwise, the patients were
young men. One patient with cutaneous leishmaniasis reported
a history of unsuccessful meglumine antimoniate therapy; the
remaining patients had no history of antimonial treatment. All
patients had traveled to an area in which Leishmania is known
to be endemic.
Table 2 delineates the diagnostic findings in this series. Parasites were visualized in specimens from at least one lesion/site
in each patient. Leishmanial cultures confirmed the diagnosis
in 73 (76%) of the 96 cases. The remaining cases were diagnosed by expert review of histopathology at the Armed Forces
Institute of Pathology (Washington, D.C.). The cause of our
few cases of visceral leishmaniasis was identified as Leishmania (Leishmania) infantum by the Istituto Superiore Di Sanita (Rome), with use of the Montpellier zymodeme classification [13].
Toxicity with Sodium Stibogluconate Therapy
Details of SSG dosing and adverse effects are shown in table
3. An arbitrary absolute upper limit to the daily SSG dose
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was not implemented. No patients were considered obese or
significantly malnourished.
Daily unstructured physician interviews were conducted during therapy (table 4). The most common symptoms were ar-
Table 2. Diagnostic findings in the study cases of leishmaniasis.
Type of leishmaniasis
Characteristic
Cutaneous*
Visceral
Viscerotropic
Leishmania amastigotes visualized
Leishmania culture positive
Leishmania species isolated
L. (Viannia) panamensis
L. (V.) braziliensis
L. (Leishmania) major
L. (L.) mexicana
L. (V.) guyanensis
L. (L.) tropica
L. donovani sensu lato
51/67 (76)
62/83 (75)
(n Å 48)
18 (38)
10 (21)
6 (12)
5 (11)
5 (11)
3 (6)
1 (2)
5/5 (100)
3/3 (100)
(n Å 3)
0
0
0
0
0
0
3 (100)
0/6 (0)
8/8 (100)
(n Å 7)
0
0
0
0
0
7 (100)
0
NOTE. Data are no. (%) of patients.
* One patient with mucocutaneous leishmaniasis also had cutaneous leishmaniasis. This patient is included in the cutaneous group, unless otherwise
noted.
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CID 1998;27 (December)
Table 3. Characteristics of patients’ (n Å 96) clinical courses with sodium stibogluconate therapy
according to type of leishmaniasis.
Type of leishmaniasis
Cutaneous
(n Å 83)
Characteristics
Dose in mg/d, median (range)
No. of doses, median (range)
No. (%) of patients requiring interruption of treatment
Days off treatment, median (range)
Reason for interruption (n/median duration of
interruption, in days)
Musculoskeletal symptoms
Chemical pancreatitis
Symptomatic pancreatitis
Elevated transaminase levels
Thrombocytopenia
Left against medical advice
Not specified
thralgias and myalgias, which developed in the latter half of
therapy. These complaints varied from mild discomfort to activity-limiting effects and were managed by the limiting of
physical exercise and use of nonsteroidal antiinflammatory
agents. Abdominal pain, nausea, and vomiting were generally
noted in the first week and were usually associated with elevated serum amylase and lipase levels. Most cutaneous reactions were few, generalized, erythematous papules. Several patients had small vesicular, pruritic lesions on the palmar or
interdigital aspects of their hands. Four patients (4%) developed
herpes zoster near the end of treatment or in the early convalescent period [14].
Electrocardiographic changes were noted in 20 patients
(21%), principally T-wave inversion or flattening in comparison with baseline findings. The patient with AIDS and visceral
leishmaniasis, who was receiving SSG at a dosage of 1,640
1,620
20
22
3
Visceral/viscerotropic
(n Å 13)
(1,300 – 2,140)
(3 – 20)
(27)
(1 – 17)
1,700
30
5
10
3/4
10/3
5/4
1/2
(200 – 1,890)
(2 – 30)
(38)
(4 – 28)
...
...
3/10
...
1/12
1/1
...
...
2/5
1/. . .
mg/d, developed a prolonged corrected Q-T interval (Q-Tc) of
.551 on day 28.
Laboratory abnormalities associated with SSG treatment
were also analyzed (table 5). Pancreatic abnormalities tended
to occur very early in therapy and to decline despite continued
SSG treatment. Our practice was to withdraw SSG if serum
amylase levels became ú4 times the ULN or lipase levels
became ú15 times the ULN, regardless of symptoms. We
resumed therapy once these values trended significantly toward
normal levels [11]. Fifteen patients’ serial serum triglyceride
levels were followed but were unremarkable. Elevations in
transaminase levels tended to occur later in the treatment course
than the pancreatic enzyme changes.
SSG caused some hematologic toxicity. In viscerotropic or
cutaneous leishmaniasis, peripheral blood cell counts declined
during treatment. In one case thrombocytopenia (platelets,
Table 4. Specific symptoms reported by the 96 patients after initiation of sodium stibogluconate therapy for leishmaniasis.
Median day of symptom
onset (range)
No. (%) of patients*
Symptom
Arthralgias
Myalgias
Fatigue
Abdominal pain
Nausea/vomiting
Anorexia
Headache
Rash
Herpes zoster
Cutaneous
49
45
32
24
22
20
19
9
3
(60)
(55)
(39)
(29)
(27)
(24)
(23)
(11)
(4)
Visceral
7
6
4
4
4
2
2
0
1
(58)
(50)
(33)
(33)
(33)
(17)
(17)
(8)
Cutaneous
12
11
6
6
7
7
8
9
15
(2 – 19)
(3 – 19)
(1 – 20)
(2 – 19)
(1 – 19)
(2 – 23)
(1 – 16)
(5 – 19)
(11 – 19)
Visceral
20
17
5
7
4
9
7
0
40
(3 – 21)
(3 – 25)
(0 – 14)
(1 – 7)
(1 – 10)
(6 – 11)
(1 – 13)
NOTE. NA Å not available; visceral Å visceral/viscerotropic.
* Cutaneous, n Å 83; visceral/viscerotropic, n Å 13.
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Median duration of symptom,
d (range)
Cutaneous
16
20
12
3
3
10
4
11
(1 – 360)
(1 – 240)
(1 – 30)
(1 – 15)
(1 – 19)
(1 – 16)
(1 – 20)
(2 – 32)
NA
Visceral
20
29
20
8
4
9
26
0
(8 – 25)
(5 – 35)
(10 – 300)
(3 – 11)
(2 – 15)
(8 – 10)
(7 – 45)
NA
CID 1998;27 (December)
Sodium Stibogluconate for Leishmaniasis
1461
Table 5. Laboratory results: elevation in pancreatic and hepatic enzyme levels associated with sodium
stibogluconate therapy for leishmaniasis.
Median (range)
No. (%) of
patients with
elevated value
Laboratory test
Cutaneous leishmaniasis (n Å 83)
Amylase*
Lipase*
AST
ALT
Visceral/viscerotropic (n Å 13)
Amylase*
Lipase*
AST
ALT
43/51
49/51
51/83
52/83
Day of
onset
Day of
peak value
Peak value (U/L)
(84)
(96)
(61)
(63)
3
3
9
8
(0 – 14)
(2 – 19)
(0 – 21)
(0 – 20)
6
5
13
14
(3 – 21)
(3 – 19)
(7 – 21)
(7 – 21)
245
889
118
146
6/7 (86)
7/7 (100)
8/12 (67)
7/12 (58)
3
2
4
3
(1 – 4)
(1 – 4)
(0 – 27)
(0 – 8)
5
6
7
5
(2 – 22)
(2 – 22)
(4 – 27)
(4 – 25)
345
2,042
106
201
Duration (d) of
elevated value
(123 – 1,044)
(117 – 8,867)
(48 – 903)
(81 – 446)
19
20
13
18
(2 – 48)
(1 – 48)
(1 – 48)
(1 – 150)
(117 – 3,024)
(583 – 19,350)
(75 – 558)
(122 – 504)
13
28
18
29
(1 – 38)
(15 – 38)
(3 – 30)
(10 – 30)
NOTE. ALT Å alanine aminotransferase; AST Å aspartate aminotransferase.
* Since amylase and lipase levels were systematically measured starting in 1992, denominators include only patients
for whom data were available. Normal ranges in our laboratory: amylase, 30 – 110 U/L; lipase, 23 – 300 U/L; AST,
17 – 59 U/L; ALT, 21 – 72 U/L.
46,000/mm3) developed, necessitating discontinuation of SSG
therapy. In contrast, with visceral disease, hematologic parameters often improved with therapy.
SSG therapy was interrupted (table 3) primarily for pancreatitis or musculoskeletal symptoms. In most cases, therapy was
reinstituted after a brief (2 – 5-day) hiatus without further incident. Therapy was terminated early for nine patients (9%).
Three of 9 patients dropped out against medical advice: 1 left
to join a combat mission and the other 2 left the hospital 1
day before the last dose because of transportation problems.
Two patients requested termination on day 14 and day 18,
respectively, because of severe musculoskeletal symptoms.
Three patients’ therapy was stopped (on days 2, 3, and 12) for
symptomatic pancreatitis. One required support with parenteral
hyperalimentation for 1 week.
Clinical Outcome
Table 6 summarizes the results of SSG treatment. The IND
protocol required a 1-year follow-up. However, to identify possible late mucosal leishmaniasis and adverse effects of medication, longer-term follow-up was initiated; 85 (88%) of the patients were contacted, with an overall median follow-up of 1.3
years (range, 0 – 9 years). During follow-up, no SSG-treated
patient with New World cutaneous leishmaniasis developed
mucosal leishmaniasis.
Three deaths occurred: 1 patient was killed in combat, 1
committed suicide 4 years after SSG treatment, and 1 died of
AIDS complicated by toxoplasma encephalitis.
Five patients (6%) showed some initial improvement but
then relapsed (table 6). Each was given a second 20-day course
of SSG. Of the five patients treated with a second course of
SSG, four (80%) were then clinically cured. One patient re-
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quired a third course of SSG. This patient had also been previously treated with meglumine antimoniate. The small number
of clinical nonresponders limited the conclusions that can be
drawn about them (table 7). Nonresponders were treated with
SSG from multiple lots. Since resistance in vitro has been
identified after intermittent antimony exposure [15], we analyzed the nonresponders for interrupted treatment courses
(33%) and found no significant difference from the responders
(26%).
Toxicity was increased during the second course of antimony. Arthralgias were noted with earlier onset (day 2 – 3).
Two of five patients stopped the second course early, one because of musculoskeletal symptoms and the other for abdominal symptoms with elevated transaminase levels. Two patients
had conjunctival edema and facial puffiness or swelling.
Overall, 93 (97%) of the 96 patients were clinically cured
with SSG, four required a second treatment course, and one
even needed a third course. Two patients received only 2 – 3
doses of SSG, and the likelihood of significant drug effect was
questionable in assessment of outcome, as they received no
further therapy.
Discussion
We determined the efficacy and toxicity of the SSG dosing
regimen currently recommended for the treatment of leishmaniasis [4]. Since SSG is available in the United States under an
IND protocol, requirements for monitoring its use are stringent.
Most of our patients did not reside in areas of endemicity
during follow-up, a circumstance decreasing the likelihood of
reinfection.
The demographic characteristics of our patients were dictated by exposures to Leishmania from military operations.
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Table 6. Sodium stibogluconate (SSG) therapy for leishmaniasis: outcome measures for the 96 cases
studied according to type of leishmaniasis.
Type of leishmaniasis
Measurement
Follow-up
Median no. of years (range)
ú1 y
Clinical cure
Relapse
Response to 2nd SSG course
Response to 3rd SSG course
Treatment failure
Subsequent mucosal infection
(to date)
Discontinuation of SSG therapy
at õ10 d
Death (unrelated to SSG)
Cutaneous
(n Å 82)
Mucocutaneous
(n Å 1)
Visceral
(n Å 5)
Viscerotropic
(n Å 8)
1.3 (0 – 9)
43 (52)
76/82 (93)*
5/82 (6)
4/5 (80)
1/1 (100)
1 (1)
5 (. . .)
1 (100)
1/1 (100)
0
...
...
0
1 (0.5 – 1)
0
5/5 (100)†
0
...
...
0
2 (1 – 6)
6/7 (86)
8/8 (100)‡
0
...
...
0
NA
NA
0
0
1
2
0
0
0
1
1
0
NOTE. NA Å not available.
* One patient received SSG for only 3 days.
†
One patient died at month 5.
‡
One patient received SSG for only 2 days.
Table 7. Data concerning nonresponders to sodium stibogluconate (SSG) therapy, among patients
with cutaneous leishmaniasis.
Nonresponders
(n Å 6)
Remaining patients with
cutaneous disease
(n Å 76)
P value
24 (18 – 34)
1,620 (1,400 – 1,900)
20
24 (18 – 53)
1,620 (1,300 – 2,140)
20
.165
1.0
.734
Characteristic
Median age, in years (range)
SSG dosage in mg/d, median (range)
Median no. of SSG doses
Days from onset of symptoms to treatment
initiation, median (range)
No. of lesions per patient, median (range)
Area of cutaneous lesion (mm2), median
(range)
Total no. of lesions
Location of lesions*
Neck/head
Arm
Leg
Hand
Foot
Back
Abdomen
Torso
Character of skin lesion*
Ulcer
Papulonodular
Eschar
Verrucous
62 (60 – 150)
4 (1 – 9)
315 (40 – 2,100)
9
118 (30 – 360)
2 (1 – 12)
.370
.157
300 (20 – 3,600)
124
.952
(9)
(4)
(13)
(9)
31
30
20
17
8
8
5
5
(25)
(24)
(16)
(13)
(6)
(6)
(4)
(4)
.028†
.597
.01†
.076
.666
1.0
.12
.317
10 (42)
14 (58)
0
0
66
30
13
2
(53)
(24)
(11)
(1)
.374
.002†
.128
1.0
1
4
10
0
2
1
3
2
(4)
(17)
(43)
* Not noted for all lesions.
†
A P value of õ.05 was considered significant.
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Sodium Stibogluconate for Leishmaniasis
Most cases were of New World cutaneous leishmaniasis associated with jungle training; Old World cutaneous (Leishmania
[L.] major) and Leishmania (L.) tropica viscerotropic illness
was acquired in Saudi Arabia (1990 – 1992). Consistent with
these opportunities for exposure to Leishmania, most patients
were male infantry soldiers, Special Forces, Rangers, or SEAL
team members. The predominance of whites (83%) in the leishmaniasis case population is somewhat higher than in the activeduty U.S. Army (62%) (personnel data from the Defense Manpower data center). The distribution of Leishmania species
identified in culture is consistent with previously published
British and U.S. military experience [16 – 21].
Previous reports of SSG toxicity at a dosage of 20 mg/(kgrd)
have been limited and varied [4, 12]. Reported symptoms have
included anorexia, nausea, and/or abdominal pain in 7% – 28%
[22 – 28] and arthralgias and myalgias in 15% – 83% [22 – 24,
26 – 28, 29]. Depression of various hematologic cell lines has
been found in 2% – 37% of patients [26 – 28, 30]. Echocardiographic changes have been noted with 4% – 50% of SSG treatment courses [23, 25, 26, 29]. Severe and even fatal necrotizing
pancreatitis occurring with antimony therapy has been described [31, 32]. Our experience suggests that patients with
clinical or chemical evidence of pancreatitis tolerate rechallenge without recurrence of symptoms or chronic sequelae.
The efficacy of SSG at a dosage of 20 mg/(kgrd) for 20
days in cases of New World leishmaniasis has varied from
88% to 100%, with most failures occurring in cases of disease
caused by Leishmania (L.) mexicana [22, 23, 29, 30]. A similar
dose used for 14 – 15 days has been shown to have 34% – 64%
efficacy in cases of New World leishmaniasis [24, 25].
This study did not have a control arm of untreated patients,
but the natural history of untreated cutaneous leishmaniasis is
well documented [23, 30, 33, 34]. As self-healing can occur,
our results may represent the best possible outcome. With clinical cure as the endpoint, treatment rates among the types and
species of Leishmania represented indicate high efficacy (88
of 96; 92%) and manageable toxicity for a single course of the
20-mg/(kgrd) regimen of SSG.
There are advantages and disadvantages to note in recommending SSG for cutaneous disease. The natural history of
New World cutaneous leishmaniasis suggested that many lesions (22% – 88%) may heal without intervention in 14 weeks
but that those due to Leishmania (V.) braziliensis were less
likely to do so [3]. The risk of late mucosal disease in cases
due to L. (V.) braziliensis has been reported as 2% – 10% among
untreated cases [35, 36], and there remains some risk despite
completion of a course of antimony for localized cutaneous
disease. Antimonials accelerate healing and may decrease the
likelihood of late mucosal disease.
Use of SSG involves prolonged parenteral treatment, expense ($105/100-mL bottle; N. Ahle, personal communication),
costly intensive monitoring, data collection for (United States)
IND status, restricted access, and significant, albeit usually
reversible, toxicity. More than one-quarter of patients must
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temporarily interrupt SSG treatment because of toxicity, and
6% terminate therapy prematurely. Serious rheumatologic, pancreatic, and cardiac toxicity has been observed with SSG. Given
these drawbacks, a better-tolerated, nonparenteral, approved
therapy is needed for cutaneous leishmaniasis.
In conclusion, we found SSG administered intravenously at
a dosage of 20 mg/(kgrd) to have excellent efficacy in the
treatment of nearly 100 patients with leishmaniasis. New World
cutaneous leishmaniasis was most prevalent in our series, but
visceral and viscerotropic leishmaniasis cases were also treated
with good results.
Acknowledgments
The authors thank Ms. P. Henderson and Ms. C. Smalls for
administration of therapy to the patients; Ms. J. Halberstein and
Ms. L. Cortese for the pharmacy preparation of sodium stibogluconate infusions; Mr. R. Neafie and Dr. P. McEvoy for their expert
review of all histopathology; and Dr. N. Ahle for his support in
the administrative aspects of SSG procurement and use.
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