Intravenous Liposomal Amphotericin B for Complicated Pediatric Cutaneous Leishmaniasis: A Case Series

Abstract

Background: First-line treatments for cutaneous leishmaniasis (CL), including topical agents, are often limited in cases of complicated disease involving multiple, facial, or treatment-resistant lesions. Data on intravenous liposomal amphotericin B (L-AmB) are scarce, especially in children. We report our experience using L-AmB to treat pediatric CL, focusing on treatment rationale, safety, and clinical effectiveness. Methods: A retrospective case series. Diagnosis was confirmed by PCR. Data on demographics, clinical presentation, treatment rationale, adverse events, lab findings, and outcomes, during treatment and follow-up, were collected. Results: Twenty-seven children were included, most (96%) with Leishmania major. The mean number of lesions per child was 5.71 ± 6.19. All had facial involvement; 41% nasal and 15% eyelid. Most lesions were ulcerated (78%). Prior treatment failure was common (78%), with the use of topical antimicrobials, liposomal amphotericin gel, and paromomycin-containing ointments (59%, 38%, 19%, respectively). Twenty-four children (89%) completed treatment successfully. Adverse events occurred in 41% of cases but were mostly mild and reversible: flushing, rash, shortness of breath, and vomiting (11%, each). One case of transient renal impairment and one case with neutropenia were recorded. Early improvement was noted by day 10, with 50% (n = 12) of cases exhibiting crust falling/reduced ulceration and a 50% lesion size reduction. By day 30–90, 92% achieved substantial healing without the need for further therapy. Nevertheless, scarring was noted in 79% of cases. Conclusions: L-AmB treatment appears to be safe and effective for pediatric CL, particularly in cases with facial lesions or prior treatment failure. Clinical improvement was notable, although scarring was common.

1. Introduction

Cutaneous leishmaniasis (CL) is a neglected tropical disease (NTD) caused by protozoan parasites of the genus Leishmania, transmitted by the bite of infected female phlebotomine sandflies [1,2]. In Southern Israel, CL is endemic and poses a significant burden on public health [3,4]. This is particularly important in children, who may experience more severe disease due to their developing immune systems and social implications of disfiguring skin lesions [5,6]. The predominant species in this region is Leishmania major, known for its tendency to cause multiple or large lesions, often in exposed or cosmetically sensitive anatomical locations, such as the face, nose, ears, and eyelids. In addition to L. major, L. tropica is also present in Israel. Species-specific virulence factors such as lipophosphoglycan (LPG) and GP63 protease contribute to immune evasion and lesion severity. The clinical relevance lies in the risk of prolonged ulceration, scarring, and psychosocial impact, especially in children [7].

First-line treatments for CL typically include topical therapies, cryotherapy, intralesional antimonial and systemic antimonial therapy, with treatment choice guided by lesion size, number, location, and patient age [7,8,9,10]. Among topical options, paromomycin-based ointments and liposomal amphotericin B formulations have shown some efficacy [5,11,12]. However, these conventional treatments are often limited by availability, adverse effects, prolonged treatment duration, and suboptimal efficacy in certain clinical settings [13]. In particular, these treatments have been associated with higher failure rates in young children, patients with multiple lesions, those with lesions in anatomically challenging or cosmetically sensitive areas, and individuals who did not respond to initial therapy, representing a subgroup with complex and unmet therapeutic needs [13,14].

Intravenous liposomal amphotericin B (L-AmB, AmBisome^®) is primarily approved for visceral leishmaniasis, but in recent years, its off-label use has been reported in the treatment of complicated cutaneous forms of the disease [15,16,17]. The liposomal formulation allows for targeted delivery with a favorable safety profile, especially in pediatric populations, and has shown promising results in individual case reports and small series of CL treatment [12,14,17,18].

While no consensus guidelines currently endorse L-AmB as a standard treatment for cutaneous leishmaniasis, accumulating evidence suggests its potential utilization in selected clinical scenarios. Clinicians are increasingly turning to L-AmB as a second- or third-line therapy, particularly in patients with facial or periocular lesions, risk of disfiguring scars, intolerance to first-line treatments, or significant social and emotional distress due to esthetic damage [7,8,18,19,20,21]. Several studies have highlighted L-AmB advantages, including rapid lesion resolution, high cure rates, and a favorable safety profile, making it an appealing alternative for patients with contraindications to traditional therapies or those who experienced treatment failure [19,20]. Despite its growing clinical use, comprehensive data on the efficacy and safety of L-AmB in pediatric CL remain sparse. Most existing reports are restricted to individual cases or small case series. Evidently, there is a need for larger studies to better define its role in CL treatment.

This case series aims to present our experience in treating children with CL using L-AmB. All patients were treated at our tertiary care center in Southern Israel, which serves as a national referral center for leishmaniasis treatment. Our main objectives included reporting on the rationale for treatment selection, including prior treatment given and disease characteristics. Second, we evaluated L-AmB therapeutic properties, including adverse effects, laboratory findings, and overall safety. Lastly, we assessed the treatment’s effectiveness in altering the disease course in children suffering from complicated CL.

2. Methods

2.1. Study Design

This is a retrospective case series study evaluating all pediatric patients diagnosed with CL, who were treated with L-AmB at the Soroka University Medical Center (SUMC) between the years 2017 and 2024. This study was approved by the SUMC institutional review board (Approval Number: 0257-24-SOR, 26 February 2025). Due to its retrospective nature, a waiver of informed consent was granted.

2.2. Setting and Study Population

The SUMC is the largest tertiary medical center in Southern Israel, providing both primary and referral healthcare services to a population of approximately 200,000 children under the age of 18. Since it is located in an endemic area for Leishmania major, the hospital serves as a national referral center for leishmaniasis management [3,4,22]. The population of the region includes two distinct ethnic groups: the Jewish population, generally comparable to a Western population, and the Bedouin Arab population, which reflects characteristics of a low-to-middle-income country (LMIC). Both groups have equal access to the national healthcare system. Medical insurance for children in Israel is universal and fully subsidized [3].

2.3. Cutaneous Leishmaniasis Diagnosis

Diagnosis of CL was established by a pediatric infectious disease specialist, based on a combination of clinical evaluation, lesion morphology, history of geographic exposure, and microbiological confirmation using polymerase chain reaction (PCR) assays specific for Leishmania species [1,23,24]. In all cases, species identification was performed via PCR analysis of lesion-derived samples.

Samples were obtained from suspected skin lesions using swab applicators placed into tubes containing transport medium (FLOQSwabs; Copan, Murrieta, CA, USA). Nucleic acid extraction (500 μL sample into 50 μL of elution solution) was conducted using the NucliSENS^® easyMAG^® system (bioMérieux, Marcy l’Etoile, France), with the Starlet extraction automation system (Seegene, Seoul, Republic of Korea) implemented at both HaEmek and Soroka Medical Centers.

The extracted DNA was then amplified using a multiplex PCR protocol, which combined specific forward and reverse primers with five different probes targeting Leishmania spp., L. major, L. tropica, L. braziliensis, and L. infantum/donovani [25]. Additionally, a high-resolution melting (HRM) assay was employed to detect the presence of infection and determine the specific Leishmania species involved.

2.4. Indications for L-AmB Treatment

The decision to initiate the treatment of cutaneous leishmaniasis with L-AmB was individualized based on physician judgment and multidisciplinary team discussions. These teams included a pediatric infectious disease specialist and a dermatologist. L-AmB protocol was considered as second- or third-line treatment in cases with specific clinical challenges. These challenges comprised treatment failure with conventional therapies (e.g., topical paromomycin, cryotherapy, intralesional or systemic antimonials), very young age, multiple or large lesions, involvement of sensitive or cosmetically important sites (e.g., face, eyelids, ears, or nose), and/or significant psychosocial burden due to lesion visibility.

2.5. L-AmB Administration Protocol

Liposomal amphotericin B (L-AmB) was administered intravenously, either in an inpatient or outpatient setting, with appropriate clinical monitoring. The treatment regimen consisted of five doses of 3 mg/kg/day for five consecutive days, followed by a sixth dose administered on the tenth day from the start of treatment. Thus, overall, six doses were given over the duration of ten days. This regimen is based on prior clinical experience and published data demonstrating efficacy in treating visceral leishmaniasis, which may share pathologic mechanisms with CL, although specific evidence in pediatric CL remains limited [14,17].

Additional antimicrobial therapy was prescribed at the discretion of the treating physician in cases with suspected or evident secondary bacterial infection. Laboratory monitoring included complete blood count, renal function, and liver enzymes, performed prior to the initiation of therapy and periodically throughout the treatment course.

Premedication and intravenous hydration were administered according to local institutional protocols to reduce the risk of infusion-related adverse reactions.

2.6. Data Collection

Data were extracted from the electronic medical records system at the SUMC. Collected variables included demographic data (age, sex, ethnicity), clinical presentation (number, size, and location of lesions), microbiological diagnosis confirmation by PCR, and prior treatment regimens, as recorded by the treating physicians in both the community settings and the pediatric infectious disease clinic at the SUMC.

Additional data included the rationale for selecting L-AmB, details on the dosage and duration of therapy, the occurrence of adverse events (AEs), and laboratory monitoring parameters, including complete blood count, liver enzymes, and renal function tests.

Treatment response was assessed through clinical evaluations at two points: at day 10 (the final day of the treatment protocol) and at 30 to 90 days following treatment initiation. Substantial healing was evaluated based on standardized physical examination criteria, which included the following: scab detachment or reduction in ulceration, scar formation, decrease in lesion diameter, reduction in induration, changes in pigmentation, and evidence of complete healing. Additionally, recurrences were documented. It is important to note that a repeated PCR test was not performed on the lesion after treatment to confirm parasite eradication. Instead, clinical evaluation based on lesion characteristics was used to assess the treatment response.

2.7. Outcome Measures

The primary outcomes were clinical response and the safety profile of liposomal amphotericin B (L-AmB). Clinical response was defined as complete epithelialization of all lesions without recurrence within three months of treatment. Treatment failure was defined by the treating physician and determined when the clinical response was insufficient, leading to the initiation of an alternative treatment regimen. Safety was evaluated based on changes in liver enzymes, renal function tests, and infusion-related reactions, as well as any adverse events documented during treatment or follow-up visits.

Adverse events specifically monitored during L-AmB administration (doses 1–6) included flushing/erythema (1), rash (2), shortness of breath (3), abdominal pain (4), vomiting (5), and other reactions (6), as reported by the patient or caregiver and overseen or documented by the medical team.

Secondary outcomes included the time to clinical response and the need for additional medical interventions, such as supplementary antimicrobial therapy or alternative anti-leishmanial treatments.

3. Results

3.1. Characteristics of Patients

Overall, 27 children with complicated CL were treated with L-AmB during the study period (

Table 1. Characteristics of children with complicated cutaneous leishmaniasis (CL) treated with L-AmB.

Characteristics		Overall (n = 27)
Age (years)	Mean ± SD	6.15 ± 4.47
Ethnicity	Jewish (N, %)	17 (63%)
	Bedouin (N, %)	10 (37%)
Gender	Male (N, %)	13 (48%)
	Female (N, %)	14 (52%)
Medical background	Atopic dermatitis or asthma (N, %)	8 (30%)
	Family history CL (N, %)	7 (26%)
Leishmania spp. (PCR)	Leishmania major (N, %)	26 (96%)
	Leishmania tropica (N, %)	1 (4%)
	Total number of lesions; mean ± SD	5.71 ± 6.19
Facial lesions	Children with facial involvement	27 (100%)
	Number of facial lesions; mean ± SD	2.83 ± 3.10
Specific facial location	Eyelid	4 (15%)
	Nose	11(41%)
	Other	13 (48%)
Lesion appearance	Crusted /ulcer/moist (N, %)	26 (96%)
	Lesion discharge (N, %)	21 (78%)
	Largest lesion size (Cm); mean ± SD	1.0 ± 0.31
	Itchy lesion; (N, %)	4 (15%)
Previous treatment	Any (N, %)	21 (78%)
	Paromomycin ointment (N, %)	4 (19%)
	Liposomal amphotericin B gel (N, %)	10 (48%)
	Sodium stibogluconate intra-lesional (N, %)	3 (14%)
	Local antimicrobials (N, %)	16 (59%)
	Local anti-fungal (N, %)	2 (10%)
	Systemic antimicrobials (N, %)	8 (38%)

). The mean age (±SD) was 6.15 ± 4.47 years. Most patients were of Jewish ethnicity (63%, n = 17), while 37% (n = 10) were Bedouin. The cohort included 14 females (52%) and 13 males (48%). A medical background of atopic dermatitis or asthma was reported in 30% (n = 8) of the patients, and a family history of CL was documented in 26% (n = 7) of the patients.

Leishmania species were diagnosed by PCR, with 96% (n = 26) of cases identified as Leishmania major and 4% (n = 1) as Leishmania tropica. The mean number of lesions per child was 5.71 ± 6.19. All children (100%) had facial involvement, with a mean number of 2.83 ± 3.10 facial lesions per patient. Nasal involvement was recorded in 41% (n = 11) of cases, eyelid involvement in 15% (n = 4), and other facial areas (excluding the eyelid and nose) in 48% (n = 13). The majority of lesions (96%, n = 26) had a crusted, ulcerated, or moist appearance, and lesion discharge was observed in 78% (n = 21). The mean size of the largest lesion per patient was 1.0 ± 0.31 cm. Pruritus was reported in 15% (n = 4).

Previous treatment failures were common. Of the 27 patients, 21 had failed at least one prior therapeutic modality. The remaining six patients were administered systemic treatment due to a high number of lesions, complicated disease presentation, or very young age. Topical treatment failures included paromomycin-containing ointments (19%, n = 4), aminoglycoside ointments (19%, n = 4), and liposomal amphotericin B gel (48%, n = 10). Intralesional sodium stibogluconate injections were recorded in 14% (n = 3) of the cases. Additional previous treatment failures included usage of systemic antimicrobials (38%, n = 8), local antimicrobials (76%, n = 16), and local anti-fungal agents (10%, n = 2).

3.2. Treatment Characteristics and Safety Profile

Treatment was initiated predominantly during the fall and winter seasons (81%, n = 22), with the remaining 19% (n = 5) treated during spring and summer. (

Table 2. Treatment characteristics of children with complicated cutaneous Leishmaniasis treated with L-AmB.

Characteristics		Overall (n = 27)
Seasonality	Fall–Winter (N, %)	22 (81%)
	Spring–Summer (N, %)	5 (19%)
Time from appearance to treatment	Months; Mean ± SD	3.67 ± 2.45
Treatment protocol completion	(N, %)	24 (88%)
Adverse event (to any dose)	Flushing (N, %)	3 (11%)
	Rash (N, %)	3 (11%)
	Shortness of Breath (N, %)	3 (11%)
	Abdominal Pain (N, %)	0 (0%)
	Vomiting (N, %)	3 (11%)
	Swelling (N, %)	2 (7%)
	Other (N, %)	7 (26%)
Preparation of subsequent doses	Temporary Discontinuation (N, %)	4 (15%)
	Permanent Discontinuation (N, %)	2 (7%)
	Steroids (N, %)	4 (15%)
	Antihistamines (N, %)	4 (15%)
Laboratory findings	Leukopenia (N, %)	1 (4%)
	Neutropenia (N, %)	1 (4%)
	Leukocytes—Day 1; Mean ± SD	9.11 ± 3.09
	Leukocytes—Days 2–7; Mean ± SD	10.47 ± 4.32
	Neutrophils—Day 1; Mean ± SD	3.54 ± 1.27
	Neutrophils—Days 2–7; Mean ± SD	4.40 ± 1.84
	Sodium—Day 1; Mean ± SD	138.0 ± 1.93
	Sodium—Day 2–7; Mean ± SD	139.36 ± 1.97
	Potassium—Day 1; Mean ± SD	4.59 ± 0.51
	Potassium—Day 2–7; Mean ± SD	4.26 ± 0.57
	Creatinine—Day 1; Mean ± SD	0.32 ± 0.12
	Creatinine—Day 2–7; Mean ± SD	0.35 ± 0.16
	Urea—Day 1; (N, %)	25.27 ± 14.73
	Urea—Day 2–7; (N, %)	30.36 ± 17.51
	Elevated AST/ALT; (N, %) *	5 (19%)

* Aspartate Aminotransferase; Alanine Aminotransferase (normal range: 10–40 U\L; 7–35 U/L, respectively).

) The mean time from lesion appearance to the initiation of treatment was 3.67 ± 2.45 months. All patients were planned to receive a full course of liposomal amphotericin B (L-AmB), and 88% (n = 24) completed the entire treatment regimen. Three patients (11%) did not complete treatment due to adverse circumstances: two discontinued permanently at the request of their parents, and one received only five doses before being lost to the final dose and follow-up.

Adverse events were reported in a subset of patients: flushing (11%), rash (11%), shortness of breath (11%), vomiting (11%), and swelling (7%). Other non-specific side effects were noted in 26% (n = 7). One patient developed leukopenia and neutropenia, and another showed signs of renal dysfunction. Four patients required temporary discontinuation, and eight received supportive treatment with corticosteroids or antihistamines due to suspected hypersensitivity. Four patients (15%) required temporary discontinuation of treatment. Supportive treatment with corticosteroids and antihistamines was administered to four patients (15%) in each group.

Laboratory monitoring revealed a single case of treatment-associated leukopenia and neutropenia. Mean leukocyte counts increased from 9.11 ± 3.09 on day 1 to 10.47 ± 4.32 on days 2 through 7. The neutrophil count increased from 3.54 ± 1.27 to 4.40 ± 1.84, respectively. Blood sodium levels remained stable, with a respective increase from 138.0 ± 1.93 to 139.36 ± 1.97 mmol/L. Potassium levels decreased mildly from 4.59 ± 0.51 to 4.26 ± 0.57 mmol/L. A single case of renal impairment, indicated by elevated creatinine, was documented. Overall, creatinine levels showed a modest increase from 0.32 ± 0.12 to 0.35 ± 0.16 mg/dL, while urea levels rose from 25.27 ± 14.73 to 30.36 ± 17.51 mg/dL. Elevated liver enzymes (AST/ALT) were noted in 19% (n = 5) of all children treated. All those elevations were mild, with a range of 36 to 100 U/L.

3.3. Clinical Outcomes

Of the 24 patients who completed the L-AmB treatment protocol, an early clinical response by day 10 of treatment was noted in most (

Table 3. Treatment clinical outcomes of patients completing L-AmB treatment protocol.

Characteristics		Overall (n = 24)
Response—Day 10	Crust falling/reduced ulceration (N, %)	12 (50%)
	Appearance of scarring (N, %)	2 (8%)
	Lesion size reduction (N, %)	12 (50%)
	Reduced induration (N, %)	15 (63%)
	Pigmentation changes (N, %)	10 (42%)
	Substantial healing (N, %)	0 (100%)
Response—Day 30–90	Crust falling/reduced ulceration (N, %)	23 (96%)
	Scarring (N, %)	19 (79%)
	Lesion size reduction (N, %)	23 (96%)
	Reduced induration (N, %)	24 (100%)
	Pigmentation changes (N, %)	23 (96%)
	Substantial healing (N, %)	19 (79%)
Therapeutic Success	(N, %)	22 (92%)

). Overall, 50% (n = 12) exhibited crust falling or reduced ulceration, and an equal proportion showed lesion size reduction. Induration decreased in 62.5% of patients, while favorable pigmentation changes were recorded in 42%. Scarring was observed in 8% (n = 2) of cases at the early stage. Patients who showed ulcer size reduction after 10 days had significantly larger cysts compared to those whose cysts were smaller (Supplementary Table S1).

At the second two follow-up visits, occurring between 30 and 90 days (mean ± SD; 38.5 ± 17.84) after treatment initiation, 96% (n = 23) showed continued improvement in terms of crust resolution and lesion size reduction. Induration had resolved in all patients (100%, n = 24), and favorable pigmentation changes were evident in 96% (n = 23). Scarring was present in 79% (n = 19), while substantial healing was noted in 79% (n = 19) as well. Overall, therapeutic success, defined as substantial healing without the need for further systemic treatment, was achieved in 92% (22/24) of the patients who completed the L-AmB treatment protocol. The demographic, clinical, and lesion characteristics did not differ significantly between children with or without ulcer reduction, lesion size reduction, or substantial healing (Supplementary Tables S1–S3).

4. Discussion

In the current study, we examined a large cohort of children with complicated CL who were treated with intravenous L-AmB. We assessed lesion characteristics at presentation, indications for initiating systemic L-AmB therapy, treatment parameters including safety and adverse events, and clinical outcomes following treatment.

Most children in our cohort presented with multiple facial lesions, often located in cosmetically sensitive areas, such as the nose and the eyelids. Nearly all patients had ulcerated, crusted lesions consistent with the classic “Oriental sore” appearance [26]. A significant proportion of the children had failed prior topical or systemic therapies, underscoring the complexity of their disease and the rationale for systemic treatment. Importantly, the majority of patients (88%) completed the full six-dose L-AmB protocol.

Adverse events (AEs) appeared in approximately 30% of patients, including hypersensitivity-like reactions, such as flushing, rash, vomiting, and shortness of breath. One patient developed leukopenia and neutropenia, and another showed signs of renal impairment. Four patients required temporary discontinuation, and eight received supportive treatment with corticosteroids or antihistamines due to suspected hypersensitivity. These findings suggest that while adverse events were common, they were manageable under close clinical monitoring.

Clinical improvement was modest by day 10 of treatment, with only partial resolution of ulceration and induration. However, at the follow-up visits, conducted 30 to 90 days post-treatment, we observed a high rate of clinical response. Specifically, 96% of patients presented substantial lesion improvement, including crust detachment, reduced size and induration, and pigmentation changes. Importantly, substantial healing was reported in 79% of patients, although scarring was present at a similar rate.

Our results support the growing understanding that facial involvement, multiple lesions, and prior treatment failure are important clinical indicators for systemic therapy in CL. While the current data on this topic are sparse, our findings are consistent with a previous smaller study, which primarily included adult patients [27]. Our findings suggest that in the absence of established treatment options and limited clinical data, particularly in children, L-AmB may serve as an effective alternative when topical or intralesional therapies are not feasible. It is important to note that in older children (over 12 years), oral miltefosine may be considered a viable treatment option [28]. In our cohort, two patients who did not respond to L-AmB were successfully treated with miltefosine.

Regarding treatment safety, approximately 10% of patients experienced adverse effects severe enough to interrupt therapy, although only one discontinued treatment permanently. Compared to prior studies reporting higher rates of serious AE [29,30], our findings demonstrate that slow infusion rates, parental education, and close clinical and laboratory monitoring allow for the safe administration of L-AmB in the outpatient settings. Minor hematologic and renal changes were observed but were transient and reversible. These results support the feasibility of using L-AmB under strict, controlled settings, even in young children.

The clinical response to treatment was favorable, overall. Although early improvement was limited, most patients showed significant clinical recovery within one to three months. Importantly, our assessment was based solely on clinical observation, without microbiologic confirmation of parasite eradication. Therefore, we do not claim a microbiological cure, but rather substantial clinical improvement, as defined by the treating physician and the patient caregiver. Scarring, although common, did not preclude the classification of treatment success. The literature remains inconsistent in defining treatment response in CL, with distinctions often blurred between microbiologic healing and cosmetic resolution [13,31,32]. Our study shows that although L-AmB leads to significant clinical improvement, esthetic recovery is often incomplete, especially in cases with deep or extensive lesions.

This study has several strengths. It represents one of the largest cohorts of children treated with L-AmB for complicated CL, an area in which data remain limited. All patients were followed closely through an outpatient clinic, allowing for the thorough documentation of clinical outcomes and adverse events. However, we acknowledge several limitations. This is a retrospective cohort with a limited sample size. Some data may have been incompletely recorded, and outcomes were based on clinical assessment without standardized scoring, a safety grading score, or parasitological cure confirmation.

In conclusion, we found that L-AmB is a generally safe and clinically effective treatment option for complicated CL in children, especially in cases with facial involvement or prior treatment failure. While not devoid of side effects, most AEs were addressed with temporary treatment adjustments; however, some required close monitoring and clinical intervention. Our findings support the use of this treatment protocol in selected pediatric populations, demonstrating significant improvement in lesion characteristics. However, residual scarring may still occur. These results also underscore the importance of close clinical and laboratory follow-up throughout the treatment course.