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Development of a topical liposomal formulation of Amphotericin B for the treatment of cutaneous leishmaniasis
research-article
Author(s):
Mahmoud Reza Jaafari
a
,
b
,
∗ ,
Mahdi Hatamipour
a ,
Seyedeh Hoda Alavizadeh
a
,
b ,
Azam Abbasi
a ,
Zahra Saberi
a ,
Sima Rafati
c ,
Yasaman Taslimi
c ,
Akram Miramin Mohammadi
d ,
Ali Khamesipour
d
,
∗∗
Publication date (Electronic):
23 September 2019
Publisher:
Elsevier
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Abstract
Background
Currently, there is no topical treatment available for any form of cutaneous leishmaniasis (CL) in most of the endemic areas. The aim of the current study was to develop a topical nano-liposomal Amphotericin B (AmB) for the treatment of CL.
Methodology/principal findings
Liposomes containing 0.1, 0.2 and 0.4% AmB (Lip-AmB) were formulated and characterized for the size, entrapment efficiency, long term stability, and skin penetration properties using Franz diffusion cells. Liposomes diameters were around 100 nm with no change during more than 20 months’ storage either at 4 °C or at room temperature. Franz diffusion cells studies showed that almost 4% of the applied formulations penetrated across the skin and the highest skin retention (73.92%) observed with Lip-AmB 0.4%. The median effective doses (ED 50), the doses of AmB required to kill 50% of L. major amastigotes were 0.151, 0.151, and 0.0856 (μg/mL) in Lip-AmB 0.1, 0.2, 0.4%, respectively. Lip-AmB 0.4% caused 80% reduction in fluorescence intensity of GFP+ L. tropica infected macrophages at 5 μg/mL of AmB concentration. Topical Lip-AmB was applied twice a day for 4 weeks to the skin of BALB/c mice to treat lesions caused by L. major. Results showed the superiority of Lip-AmB 0.4% compared to Lip-AmB 0.2 and 0.1%. The parasite was completely cleared from the skin site of infection and spleens at week 8 and 12 post-infection in mice treated with Lip-AmB 0.4%. The results suggest that topical Lip-AmB 0.4% may be a useful tool in the treatment of CL and merits further investigation.
Graphical abstract
Highlights
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Novel topical AmB liposome for treatment of cutaneous leishmaniasis was formulated.
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The formulation inhibits L. major promastigotes and amastigotes growth in vitro.
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The formulation inhibits L. tropica amastigotes growth in vitro.
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The formulation is able to treat lesions caused by L. major in BALB/c mice.
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Lip-AmB 0.4 was stable at room temperature for more than 20 months.
Related collections
Most cited references58
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Amphotericin B formulations: a comparative review of efficacy and toxicity.
Richard Hamill (2013)
Because of the increasing prevalence and changing microbiological spectrum of invasive fungal infections, some form of amphotericin B still provides the most reliable and broad spectrum therapeutic alternative. However, the use of amphotericin B deoxycholate is accompanied by dose-limited toxicities, most importantly, infusion-related reactions and nephrotoxicity. In an attempt to improve the therapeutic index of amphotericin B, three lipid-associated formulations were developed, including amphotericin B lipid complex (ABLC), liposomal amphotericin B (L-AmB), and amphotericin B colloidal dispersion (ABCD). The lipid composition of all three of these preparations differs considerably and contributes to substantially different pharmacokinetic parameters. ABLC is the largest of the lipid preparations. Because of its size, it is taken up rapidly by macrophages and becomes sequestered in tissues of the mononuclear phagocyte system such as the liver and spleen. Consequently, compared with the conventional formulation, it has lower circulating amphotericin B serum concentrations, reflected in a marked increase in volume of distribution and clearance. Lung levels are considerably higher than those achieved with other lipid-associated preparations. The recommended therapeutic dose of ABLC is 5 mg/kg/day. Because of its small size and negative charge, L-AmB avoids substantial recognition and uptake by the mononuclear phagocyte system. Therefore, a single dose of L-AmB results in a much higher peak plasma level (Cmax) than conventional amphotericin B deoxycholate and a much larger area under the concentration-time curve. Tissue concentrations in patients receiving L-AmB tend to be highest in the liver and spleen and much lower in kidneys and lung. Recommended therapeutic dosages are 3-6 mg/kg/day. After intravenous infusion, ABCD complexes remain largely intact and are rapidly removed from the circulation by cells of the macrophage phagocyte system. On a milligram-to-milligram basis, the Cmax achieved is lower than that attained by conventional amphotericin B, although the larger doses of ABCD that are administered produce an absolute level that is similar to amphotericin B. ABCD exhibits dose-limiting, infusion-related toxicities; consequently, the administered dosages should not exceed 3-4 mg/kg/day. The few comparative clinical trials that have been completed with the lipid-associated formulations have not demonstrated important clinical differences among these agents and amphotericin B for efficacy, although there are significant safety benefits of the lipid products. Furthermore, only one published trial has ever compared one lipid product against another for any indication. The results of these trials are particularly difficult to interpret because of major heterogeneities in study design, disease definitions, drug dosages, differences in clinical and microbiological endpoints as well as specific outcomes examined. Nevertheless, it is possible to derive some general conclusions given the available data. The most commonly studied syndrome has been empiric therapy for febrile neutropenic patients, where the lipid-associated preparations did not appear to provide a survival benefit over conventional amphotericin B deoxycholate, but did offer a significant advantage for the prevention of various breakthrough invasive fungal infections. For treatment of documented invasive fungal infections that usually involved hematological malignancy patients, no individual randomized trial has demonstrated a mortality benefit due to therapy with one of the lipid formulations. Results from meta-analyses have been contradictory, with one demonstrating a mortality benefit from all-cause mortality and one that did not demonstrate a mortality benefit. In the only published study to examine HIV-infected patients with disseminated histoplasmosis, clinical success and mortality were significantly better with L-AmB compared with amphotericin B deoxycholate; there were no differences in microbiological outcomes between treatment groups. The lipid-associated preparations were not significantly better than amphotericin B deoxycholate for treatment of AIDS-associated acute cryptococcal meningitis for either clinical or microbiological outcomes that were studied. In all of the trials that specifically examined renal toxicity, the lipid-associated formulations were significantly less nephrotoxic than amphotericin B deoxycholate. Infusion-related reactions occurred less frequently with L-AmB when compared with amphotericin B deoxycholate; however, ABCD had equivalent or more frequent infusion-related reactions than conventional amphotericin B, and this resulted in the cessation of at least one clinical trial. At the present time, this particular lipid formulation is no longer commercially available. For the treatment of most invasive fungal infections, an amphotericin B lipid formulation provides a safer alternative than conventional amphotericin B, with at least equivalent efficacy. As the cost of therapy with these agents continues to decline, these drugs will likely maintain their important role in the antifungal drug armamentarium because of their efficacy and improved safety profile.
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Targeting to macrophages: role of physicochemical properties of particulate carriers--liposomes and microspheres--on the phagocytosis by macrophages.
F Ahsan (2002)
Heterogeneous functions of macrophages in human immune systems have renewed interest in targeting of drugs to these cells. Various carrier systems have emerged to deliver drugs to macrophages, albeit the efficacy, reliability and selectivity of these carriers are still in question. To date, the most extensively studied carriers are liposomes and microspheres. Various physicochemical properties of these carriers can alter their efficacy and specificity to a great extent. These properties include hydrophilicity, surface charge, composition, concentration, and presence of various ligands. In this review, a comprehensive evaluation of the literature has been carried out in order to show the role of these parameters in the design of carriers for targeting of drugs to macrophages.
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Diagnosis and Treatment of Leishmaniasis: Clinical Practice Guidelines by the Infectious Diseases Society of America (IDSA) and the American Society of Tropical Medicine and Hygiene (ASTMH)*
Naomi Aronson, Barbara Herwaldt, Michael Libman … (2017)
Executive Summary Guidelines for the clinical management of persons with leishmaniasis were prepared by a Panel of the Infectious Diseases Society of America (IDSA) and the American Society of Tropical Medicine and Hygiene (ASTMH). The guidelines are intended for internists, pediatricians, family practitioners, and dermatologists, as well as infectious disease specialists, practicing in the United States and Canada (for simplicity, referred to here as North America). The Panel followed a guideline development process that has been adopted by IDSA, which includes a systematic method of grading both the quality of evidence (very low, low, moderate, or high) and the strength of the recommendation (weak or strong) [1] (Figure 1 Figure 1: Approach and implications to rating the quality of evidence and strength of recommendations using the GRADE methodology (unrestricted use of the figure granted by the U.S. GRADE Network) [1] ). In these guidelines, we describe our approaches to the diagnosis and management of cases of cutaneous, mucosal, and visceral leishmaniasis, the three main clinical syndromes caused by infection with Leishmania parasites. Less common or rare syndromes that may require specialized expertise are beyond the scope of these guidelines. Whenever possible, our recommendations are based on randomized clinical trials. However, because of the diversity encompassed by leishmaniasis, which includes a spectrum of diseases caused by >20 Leishmania species found in many areas of the world, many of the recommendations are based on observational studies, anecdotal data, or expert opinion. Although there may be disagreement with some of our recommendations and suggestions, the approaches we describe have been both useful and feasible in North America. Cutaneous leishmaniasis (CL) is the most common leishmanial syndrome worldwide and the one most likely to be encountered in patients in North America. The skin lesions of CL are usually painless and chronic, often occurring at sites of infected sand fly bites. Slow spontaneous healing as cell-mediated immunity develops is the usual natural history, accelerated by antileishmanial therapy. A minority of cutaneous infections caused by Leishmania (Viannia) braziliensis (L. [V.] braziliensis) and related species in the Viannia subgenus, including L. (V.) panamensis and L. (V.) guyanensis, are associated with concomitant or late mucosal leishmaniasis (ML), which can cause destructive lesions of the naso-oropharyngeal/laryngeal mucosa. No universally applicable treatment has been identified for CL; the choice of agent, dose, and duration of therapy should be individualized. Parasite and host factors must be considered, as well as clinical characteristics (Table 1). Visceral leishmaniasis (VL), which reflects dissemination of Leishmania parasites throughout the reticuloendothelial system, is potentially life threatening without treatment. VL is an opportunistic infection in persons with HIV/AIDS or other causes of cell-mediated immunosuppression. The primary goals of therapy for VL and CL/ML are to prevent mortality and morbidity, respectively. The only Food and Drug Administration (FDA)-approved medications for the treatment of leishmaniasis are intravenous liposomal amphotericin B (L-AmB) for VL and oral miltefosine for CL, ML, and VL caused by particular species. For prevention of leishmaniasis in travelers, no vaccines or chemoprophylaxis currently are available; personal protective measures to minimize exposure to sand fly bites are recommended. Our recommendations for the diagnosis and clinical management of leishmaniasis are listed below. Background information about leishmaniasis, a description of our methods, and the evidence summaries that support our recommendations can be found online in the full text, tables, figures, and appendix of the guidelines. Recommendations for the Diagnosis of Leishmaniasis (Cutaneous, Mucosal, and Visceral) I. In a person with a compatible skin lesion(s) and exposure history, what specimen(s) should be collected for diagnostic testing for CL? Recommendations 1. Tissue specimens should be collected from a lesion(s) when a clinical suspicion for CL exists. Full-thickness skin biopsy specimens allow for simultaneous testing for other diagnoses, such as by histopathology and cultures [Strong, moderate]. 2. Obtain a sample from a cleansed lesion, from which cellular debris and eschar/exudates have been removed [Strong, very low]. II. In a person with manifestations suggestive of New World mucosal leishmaniasis (ML), what types of specimens should be obtained for diagnostic testing? Recommendations 3. The initial and most prominent mucosal manifestations typically are nasal (e.g., chronic unexplained congestion/secretions). Oral/palatal, pharyngeal, and laryngeal involvement may develop as ML progresses or, in some persons, may be the first or the only noted abnormalities. The clinical signs, which may evolve over time, may include erythema, edema, hyperemia, infiltration, nodules, erosion, ulceration, and tissue destruction (e.g., perforation of the nasal septum) [FACT, no grade]. 4. Mucosal areas that have macroscopic abnormalities are recommended for specimen collection; biopsy specimens, obtained by an otolaryngologist, are useful for confirming the diagnosis by molecular and traditional methods and for excluding other etiologies [Strong, low]. III. During the initial and subsequent evaluations of persons with CL acquired in Central or South America who may have or be at risk for mucosal leishmaniasis (ML), what should be done to assess the possibility of mucosal disease? Recommendations 5. All persons at risk for ML—on the basis of the etiologic agent of the Leishmania infection, if known, and the region in the New World in which infection was acquired—should be questioned about and examined for mucosal symptoms and signs, respectively, even during the initial evaluation [Strong, low]. 6. During all evaluations (i.e., initial and subsequent), persons at risk for ML should be questioned explicitly about the development, evolution, and other characteristics of mucosal symptoms; and they should have a thorough examination of the naso-oropharyngeal mucosa even if they do not have any mucosal symptoms [Strong, low]. 7. Persons at risk for ML should be educated and provided personalized documentation about the importance of seeking medical attention for possible ML if they ever develop persistent, atypical (unusual for the person) naso-oropharyngeal/laryngeal manifestations that do not have a clear etiology [Strong, low]. 8. Persons at risk for ML who have persistent mucosal symptom(s) or compatible abnormalities of the naso-oropharyngeal mucosa should be referred to a specialist for an otorhinolaryngologic examination, which typically should include fiberoptic endoscopy [Strong, low]. 9. Clinicians might refer some at-risk persons without documented mucosal symptoms or signs to an otolaryngologist, especially if it was not possible to conduct a thorough review of systems and mucosal examination or if the assessments may not have been adequate or reliable [Weak, very low]. IV. In a person with a compatible clinical course and epidemiologic context, what types of samples should be collected to evaluate for the diagnosis of VL? Recommendations 10. We recommend the collection of tissue aspirates or biopsy specimens for smears, histopathology, parasite culture, and molecular testing [Strong, low]. 11. Bone marrow aspiration is the preferred first source of a diagnostic sample. Liver, enlarged lymph nodes, and whole blood (buffy coat) are other potential sources of tissue specimens [Strong, low]. 12. Serum should be collected for detection of antileishmanial antibodies (see VIII) [Strong, moderate]. 13. In immunocompromised persons, blood should be collected for buffy coat examination, in vitro culture, and molecular analyses [Strong, very low]. V. What laboratory tests should be used to diagnose leishmaniasis? Recommendations 14. We recommend using multiple diagnostic approaches to maximize the likelihood of a positive Leishmania result, using methods such as visualization of the characteristic amastigote in smears or tissue (histopathology); parasite isolation by in vitro culture; molecular detection of parasite DNA; and, for VL, serologic testing (see VI–VIII and Table 2). Simultaneous testing for other diagnoses (e.g., by histopathology and culture) should be considered [Strong, low]. 15. We recommend attempting parasite isolation with the assistance of reference laboratories. We recommend that clinicians contact their leishmaniasis reference laboratory before collecting specimens (Table 2). If Leishmania parasites are isolated in culture, reference laboratories can identify the species by DNA-based assays or isoenzyme analysis [Strong, low]. 16. Molecular amplification assays typically should be performed because they are the most sensitive Leishmania tests currently available (see VII) [Strong, moderate]. 17. Leishmania skin testing is not recommended or available in the United States or Canada; there are no standardized, approved, or commercially available skin-test products in North America [Strong, very low]. VI. In a person with leishmaniasis, why could it be helpful to identify the infecting Leishmania species? Recommendation 18. We suggest that identification of the infecting parasite to the species level be attempted in cases of suspected CL. Species identification may help inform clinical management decisions for individual persons (e.g., whether and how to treat) [Weak, moderate]. VII. What is the role of DNA-based assays in the diagnosis of leishmaniasis? Recommendation 19. DNA-based assays should be performed, especially if other diagnostic testing is unrevealing. They are emerging as the most sensitive assays for the diagnosis of leishmaniasis [Strong, moderate]. VIII. What is the role of serologic testing in the diagnosis of leishmaniasis? Recommendations 20. Serologic testing is recommended for persons with suspected VL in whom definitive diagnostic tests for the parasite (microscopic identification, culture, and molecular tests for parasite DNA) cannot be conducted or have negative results. The sensitivity and specificity of serologic tests depend on the assay and antigens used, as well as host factors. Serologic tests cannot be used to assess the response to treatment. Antileishmanial antibodies can be detected years after clinically successful therapy in some persons [Strong, moderate]. 21. We suggest that tests for antileishmanial antibodies not be performed as the sole diagnostic assay. Antibodies may be undetectable or present at low levels in persons with VL who are immunocompromised because of concurrent HIV/AIDS or other reasons. The potential for false-negative test results limits the utility of serologic assays in this setting [Weak, low]. 22. Serologic testing is not recommended as part of the diagnostic evaluation for CL. The currently available serologic assays are neither sensitive nor specific for the diagnosis of CL [Strong, moderate]. Recommendations for the Treatment of Leishmaniasis Cutaneous Leishmaniasis IX. In a person with a consistent travel history and compatible skin lesion(s), is it necessary to obtain parasitologic confirmation of the diagnosis of leishmaniasis before starting treatment? Recommendation 23. After a careful diagnostic evaluation in which neither leishmaniasis nor another diagnosis is confirmed, empiric treatment may be indicated on the basis of an individualized risk-benefit assessment [Weak, very low]. Remark: This should be discussed with the patient and reevaluated periodically, taking into account the clinical evolution. X. Is treatment of clinically manifest cutaneous infection (CL) always indicated? Recommendations 24. We recommend that immunocompetent persons with skin lesions that are caused by infection with Leishmania species that are not associated with increased risk for ML, that are defined as clinically simple lesions (Table 1), and that are healing spontaneously may be observed without treatment if the patient concurs with this management [Strong, moderate]. 25. For persons with CL when the Leishmania species is not known but the infection was not acquired in an increased ML-risk region (Table 1, Figure 2 Figure 2: Maps of the Geographic Distribution of Cutaneous Leishmaniasis (CL). Notes: Adapted and modified from Chapter 277, Leishmania species. Principles and Practice of Infectious Diseases [31] 1In Guatemala, the reported cases of CL have been acquired in the northern departments (particularly, El Petén and Alta Verapaz but also Izabal, El Quiché, Baja Verapaz, and Jalapa). 2The etiologic agents of CL in Israel primarily include L. major and L. tropica but also L. infantum-chagasi. 3The species L. (Leishmania) martiniquensis, which was formally named in 2014, has been identified as the etiologic agent of cutaneous and visceral leishmaniasis in the French West Indies (Martinique Island) and Thailand, where it previously was referred to as “L. siamenensis” (not considered a taxonomically valid name). 4In Sri Lanka, L. donovani has been identified as the etiologic agent of cutaneous and visceral leishmaniasis. 5Not all Leishmania species that cause CL are included in this map (eg, L. amazonensis in South America). ), treatment of clinically simple or healing skin lesions is not required in an immunocompetent patient who concurs with this management [Strong, low; E.C. dissents, recommending that all persons with NWCL receive treatment]. Remark: See XXIV and XXV regarding the management of CL in immunocompromised persons. 26. We suggest that systemic treatment be offered for persons even with healing/recently healed CL lesions caused by increased ML-risk species or when the species is unknown but the infection was acquired in an increased ML-risk region. Risks and benefits of such treatment should be discussed with the patient [Weak, low]. Remark: In some cases, watchful waiting, with vigilance for signs and symptoms of ML, may be a reasonable approach. 27. We recommend that any decision to observe a patient with CL without treatment should be reevaluated periodically, and the decision not to treat should be reconsidered if healing does not progress as anticipated [Strong, very low]. 28. In all cases of CL, wound care, individualized documentation of lesion evolution, and patient education regarding the manifestations and detection of local therapeutic failure/relapse and ML should be routine components of management (see III and XV) [Strong, low]. XI. In a person with CL, what could be the consequences of no treatment or suboptimal therapy, and how should persons who received no or suboptimal therapy be monitored? Recommendations 29. Potential consequences of inadequate treatment include poor cosmetic outcome due to scarring or superinfection, the persistence of a chronic wound(s), and, with some Leishmania species, destructive and disfiguring ML. In immunocompromised persons, cutaneous, mucosal, and visceral dissemination may occur [FACT, no grade]. 30. Persons with CL should be actively monitored by clinical appearance, including by performing a careful nasal and oropharyngeal examination periodically up to 1 year, or at least 2 years if at increased risk for ML. They should be educated about the signs and symptoms of relapse and ML and instructed to seek medical attention anytime these appear [Strong, low]. 31. Symptoms such as chronic nasal stuffiness, epistaxis, or hoarseness or findings such as septal perforation that occur anytime in a person with a prior or current diagnosis of CL or a scar consistent with prior CL should prompt evaluation for ML, including fiberoptic examination of the affected area if relevant (see II and III) [Strong, moderate]. XII. In a person with CL, what factors should prompt consideration of use of a systemic (oral or parenteral) agent for initial therapy? Recommendations 32. Systemic treatment is recommended for persons with complex CL as defined in Table 1 [Strong, moderate]. 33. Initial systemic therapy (see XIII) may be used in persons with CL in whom it is not practical to use local therapy or (possibly) if more rapid healing of large, cosmetically or functionally concerning lesions is preferred [Weak, very low]. 34. Less common cutaneous syndromes, such as leishmaniasis recidivans (caused by L. tropica and occasionally other species), diffuse cutaneous leishmaniasis (caused by L. mexicana, L. amazonensis, and L. aethiopica), and disseminated cutaneous leishmaniasis (caused by L. [V.] braziliensis), usually require systemic therapy [Strong, low]. XIII. What systemic treatment options are available in North America for CL, and what factors should be considered when selecting a medication for an individual patient? Recommendations 35. The parenteral options for systemic therapy currently available in North America include conventional amphotericin B deoxycholate, lipid formulations of amphotericin B, pentavalent antimonial (SbV) compounds, and pentamidine (listed in alphabetical order). Oral options include miltefosine and the “azole” antifungal compounds, including ketoconazole (if potential benefits outweigh risks for hepatotoxicity and QT prolongation) and fluconazole [FACT, no grade]. 36. To maximize effectiveness and to minimize toxicity, the choice of agent, dose, and duration of therapy should be individualized [Strong, moderate]. Remarks: No ideal or universally applicable therapy for CL has been identified. Some therapies/regimens appear highly effective only against certain Leishmania species/strains in certain areas of the world. Both the parasite species and host factors (e.g., comorbid conditions and immunologic status) should be considered. 37. Factors that should be considered when selecting CL treatment for an individual patient include the risk for ML; the Leishmania strain/species and published response rates for antileishmanial agents in the pertinent geographic region; the potential for adverse events; age extremes; childbearing competence and pregnancy; obesity; hepatic, pancreatic, renal, and cardiac comorbid conditions; preference for and convenience of various routes of administration; the rapidity with which one wishes to control the infection; the impact of lesions on daily activities and patient self-confidence; the patient/provider comfort level with logistics (e.g., Investigational New Drug protocols); and other practical issues (e.g., drug availability, various types of cost, insurance reimbursement) (see XII and XXVI; Tables 3 and 4) [Strong, low]. XIV. In which clinical settings can local therapy be used effectively in a person with CL? Recommendations 38. Local therapy is preferred for treatment of OWCL lesions defined as clinically simple (Table 1) and may be useful for localized NWCL caused by Leishmania species not associated with increased risk for ML [Strong, moderate]. Remark: Local therapy includes heat and cryotherapy, topical ointments/creams with paromomycin and other ingredients, intralesional injections of pentavalent antimonial drugs (±cryotherapy), and photodynamic or laser treatment. 39. Eschar(s) overlying ulcers should be debrided before administration of local therapy and any secondary infection managed to maximize treatment effect [Strong, very low]. XV. What are the recommended timeframes and findings to assess response to treatment in a person with CL? Recommendations 40. Response to treatment is assessed by clinical criteria; repeat parasitologic testing is not recommended if the skin lesion appears to be healing [Strong, low]. Remark: The healing process may continue after the treatment course is completed especially for large ulcerative lesions. 41. Persons with CL should have their skin lesions monitored for 6–12 months after treatment for clinical evidence of therapeutic failure, which is initially seen at the border of a healed lesion [Strong, low]. Remark: The first sign of healing is usually flattening of the skin lesion. By 4–6 weeks after treatment, the lesion size should have decreased by >50%, ulcerative lesions should be reepithelializing, and no new lesions should be appearing. Ulcerative lesions are generally fully reepithelialized and clinically healed by approximately 3 months after treatment. XVI. What are the recommended approaches for additional management in a person with CL that does not respond to therapy? Recommendations 42. Additional therapy is recommended (but not necessarily always with a different agent or approach) when there is development of new skin lesions or worsening of existing lesions. Additional therapy is also recommended if there is incomplete healing by 3 months after completion of the treatment course [Strong, low]. 43. We recommend that therapeutic failure be assessed by physical appearance. Relatively little improvement or worsening while on therapy suggests an inadequate response and an alternate treatment approach should be planned [Strong, low]. Remark: A paradoxical increase in the local inflammatory response may be seen in the first 2–3 weeks of treatment and can be difficult to differentiate from therapeutic failure. 44. Consultation with a leishmaniasis expert about other treatment options is recommended for management of persons' lesions associated with therapeutic failure [Strong, very low]. Mucosal Leishmaniasis XVII. What are the treatment options for American (New World) mucosal leishmaniasis (ML)? Recommendations 45. All persons with clinically manifest, metastatic, American ML should receive systemic antileishmanial therapy, with the goals of preventing morbidity (e.g., disfigurement) and mortality (e.g., from aspiration pneumonia or respiratory obstruction) [Strong, low]. 46. Before treatment is initiated, a complete examination of the naso-oropharyngeal/laryngeal mucosa should be conducted by a specialist to assess the anatomic extension and clinical severity of the mucosal disease, which have prognostic implications [Strong, moderate]. 47. We recommend inpatient monitoring and prophylactic corticosteroid therapy for persons with laryngeal/pharyngeal disease and increased risk for respiratory obstruction, as indicated by symptoms and otolaryngologic/radiologic examinations, because of the potential for inflammatory reactions after initiation of antileishmanial therapy [Strong, low]. 48. The choice of antileishmanial agent, dose, and duration of therapy for persons with ML should be individualized (Table 3) [Strong, moderate]. Remarks: The traditional options for ML include treatment with a pentavalent antimonial (SbV) compound (20 mg SbV/kg daily, IV or IM, for 28–30 days) or with amphotericin B deoxycholate (0.5–1.0 mg/kg per dose, IV, daily or every other day, for a cumulative total of ∼20–45 mg/kg). More recently, on the basis of comparatively limited data, the armamentarium has expanded to include lipid formulations of amphotericin B (typically, liposomal amphotericin B [L-AmB], with a cumulative total dose ranging widely from ∼20–60 mg/kg), as well as the oral agent miltefosine (∼2.5 mg/kg per day [maximum, 150 mg/day] for 28 days). Visceral Leishmaniasis XVIII. In what circumstances should a person with visceral Leishmania infection be treated? Recommendations 49. We recommend that persons with clinical abnormalities compatible with VL and laboratory evidence of VL be treated (Table 3) [Strong, moderate]. 50. We suggest that clinicians closely monitor persons with asymptomatic visceral infection and generally initiate therapy only if clinical manifestations of VL develop [Weak, very low]. XIX. What is the optimal treatment for VL in a symptomatic immunocompetent person (person without an identified immune defect) in North America? Recommendations 51. For an immunocompetent person with VL, treatment with liposomal amphotericin B (L-AmB) is recommended. The FDA-approved dosage regimen is 3 mg/kg/day IV on days 1–5, 14, and 21 (total dose, 21 mg/kg) (Table 3) [Strong, high]. Remarks: Multiple regimens in which the total L-AmB dose is 18–21 mg/kg have been used effectively in regions other than East Africa. Doses of 40 mg/kg or more may be necessary in persons with VL acquired in East Africa. Other lipid-associated formulations of amphotericin B, such as amphotericin B lipid complex and amphotericin B colloidal dispersion, are not generally recommended: they have not been approved by FDA for treatment of VL; and they have been less well studied in VL treatment trials (i.e., bioequivalence has not been established). 52. For an immunocompetent person with VL caused by L. donovani, acquired in the Indian subcontinent (South Asia), who is ≥12 years of age, weighs ≥30 kg, and is not pregnant or breastfeeding, treatment with the oral agent miltefosine, 2.5 mg/kg per day (maximum, 150 mg, in 3 divided doses) for 28 days, is a possible alternative to L-AmB, particularly in persons weighing <75 kg (see XXVI and Table 3) [Strong, moderate]. XX. What alternative agent(s) can be used for a person with VL who cannot tolerate liposomal amphotericin B or miltefosine or in whom these agents otherwise are contraindicated? Recommendations 53. Pentavalent antimonial therapy (20 mg SbV/kg/day IV or IM for 28 days) is a recommended therapy for immunocompetent persons with VL acquired in areas where the prevalence of antimony-resistant Leishmania species is low (<10%) [Strong, high]. 54. We do not recommend switching to amphotericin B deoxycholate in persons with contraindications to, or substantial toxicity with, L-AmB, with the exception of persons who develop liposome-induced complement activation-related pseudoallergy (CARPA). Amphotericin B lipid complex is a consideration in this situation [Strong, low]. XXI. In persons with VL, what parameters should be used to assess the clinical response to treatment? Recommendations 55. Clinical parameters correlate well with parasitologic responses to VL treatment and should be used to monitor the response [Strong, low]. 56. Parasitologic confirmation of response (such as by repeat bone marrow aspiration for microscopy and culture after treatment) is not recommended in a patient showing a timely clinical response. Antibody levels fall but over many months or longer [Strong, moderate]. XXII. How should a person with VL be treated who does not respond to initial therapy as assessed by these parameters [or who has a relapse]? Recommendations 57. Immunocompetent persons with VL who do not respond to therapy with L-AmB should be treated with an alternative drug or with a higher dose or a longer course of L-AmB [Strong, low]. 58. Immunocompetent persons with VL who do not respond to initial therapy with miltefosine or a pentavalent antimonial compound should be treated with L-AmB or an alternative drug if L-AmB is unavailable [Strong, low]. 59. Immunocompetent persons with VL who respond to initial therapy but subsequently have a relapse should be treated with an alternative drug or with another, potentially longer, course of therapy with the initial drug. If L-AmB was the drug used for initial therapy, use of a higher dose can be considered [Strong, low]. 60. Combination therapies may be considered but have not been well studied after therapeutic failure in persons with VL [Weak, low]. Leishmaniasis in Immunocompromised Hosts XXIII. How should HIV/AIDS-associated visceral leishmaniasis (VL) be treated in persons in North America, and what other management issues should be considered? Recommendations 61. Liposomal amphotericin B (L-AmB) is recommended for the treatment of VL in immunocompromised persons in North America (Table 3) [Strong, low]. Remark: The FDA-approved dosage regimen of L-AmB for such persons, including those with concurrent HIV/AIDS, is 4 mg/kg/day IV, on days 1–5, 10, 17, 24, 31, and 38 (10 doses over a 38-day period), for a total dose of 40 mg/kg. 62. Combination therapy (e.g., L-AmB plus miltefosine) might be considered, especially for persons with refractory cases of VL [Weak, very low]. Remark: The efficacy and optimal duration of miltefosine monotherapy (and combination therapy) for HIV/AIDS-associated VL have not been established. 63. Because of the importance of effective immune reconstitution in HIV-VL-coinfected persons, antiretroviral therapy (ART) should be initiated or optimized as soon as the person is sufficiently stable to tolerate it (e.g., either during or soon after the initial course of therapy for VL) [Strong, low]. 64. Leishmania infection that becomes clinically manifest or worsens after initiation of ART should be treated with antileishmanial (and, if indicated, corticosteroid) therapy; leishmaniasis-associated immune reconstitution inflammatory syndrome (IRIS) reactions after initiation of ART have been reported occasionally [Strong, very low]. 65. We recommend administering secondary prophylaxis (chronic maintenance therapy) to decrease the risk for posttreatment relapse of VL in persons with HIV/AIDS-associated immunosuppression (e.g., CD4 T-lymphocyte cell counts <200 cells/mm3) [Strong, moderate]. 66. Persons with VL-HIV/AIDS coinfection should be monitored indefinitely (until effective immune reconstitution) for evidence of posttreatment relapse; ART and secondary prophylaxis provide only partial protection against relapse. Antileishmanial treatment is indicated for persons who have clinical and parasitologic evidence of recurrence [Strong, low]. XXIV. How should HIV/AIDS-associated CL or ML be treated in persons in North America who do not have evidence of VL, and what other management issues should be considered? Recommendations 67. In HIV/AIDS-associated CL/ML, systemic antileishmanial therapy is recommended, particularly in persons who are moderately to severely immunosuppressed (e.g., have CD4+ T-lymphocyte cell counts <200–350 cells/mm3), who may be at increased risk for suboptimal therapeutic responses, for posttreatment relapses, and for cutaneous, mucosal, or visceral dissemination [Strong, very low]. 68. The systemic regimens used for CL/ML in otherwise comparable immunocompetent persons typically are recommended for the initial treatment of coinfected persons, taking into account the potentials for drug interactions and toxicity (Tables 3 and 4) [Strong, very low]. Remark: Whether coinfected persons who experience multiple posttreatment relapses of CL/ML would benefit from secondary prophylaxis (chronic maintenance therapy) has not yet been established. 69. Antiretroviral therapy (ART) should be initiated or optimized in accordance with standard practice for HIV/AIDS; no evidence-based, CL/ML-specific recommendations regarding ART have been established [Strong, low]. XXV. What is the preferred treatment of visceral/cutaneous leishmaniasis in immunocompromised hosts with solid organ transplant, persons with lymphatic-hematologic malignancies, or persons receiving immunosuppressive therapy for other reasons? Recommendations 70. Liposomal amphotericin B (L-AmB) is recommended as the drug of choice for immunosuppressed persons with VL (Table 3) [Strong, low]. Remarks: The FDA-approved regimen is 4 mg/kg/day IV on days 1–5, 10, 17, 24, 31, and 38 (total dose of 40 mg/kg). Higher doses and longer durations of therapy may be needed depending in part on the level of immunosuppression. 71. Doses of immunosuppressive drugs should be decreased in persons with VL during antileishmanial therapy whenever possible [Strong, very low]. 72. Secondary prophylaxis is not recommended for initial management in persons with VL who have not manifested a relapse [Weak, low]. Remark: Immunosuppressed persons with VL who are not coinfected with HIV typically have higher response rates to initial treatment and lower recurrence rates than HIV-coinfected persons. 73. Routine serologic screening of organ donors from leishmaniasis-endemic areas is not recommended. If an available donor is known to be seropositive, it is advisable to perform clinical and laboratory monitoring of the recipient in the post-transplant period rather than to reject the organ for transplant [Strong, low]. 74. We suggest that clinicians not routinely perform diagnostic testing to assess persons for evidence of asymptomatic visceral infection, including persons who have lived or traveled in leishmaniasis-endemic regions (Figure 3 Figure 3: Maps of the Geographic Distribution of Visceral Leishmaniasis (VL) ) and are considering organ transplantation or initiation of therapy with biologic immunomodulating agents. Immunosuppressed persons known or found to be asymptomatically infected and those with a history of VL warrant close monitoring. Neither preemptive treatment nor primary prophylaxis for VL in asymptomatically infected persons is suggested [Weak, very low]. 75. Immunosuppressed persons with VL who are not coinfected with HIV should be monitored for a minimum of 1 year (ideally lifelong or until effective immune reconstitution) to assess for posttreatment relapse. During clinical follow-up, assess for symptoms and, if present, pursue parasitologic confirmation of relapse [Strong, very low]. 76. Confirmed VL therapeutic failure typically can be managed by retreatment using L-AmB at the same or a higher total dose [Strong, very low]. Remark: Pentavalent antimonials could be used in some persons with VL under close follow-up. 77. We suggest that CL/ML associated with the use of tumor necrosis factor (TNF)-alpha antagonist therapy be managed with systemic therapy and standard drug regimens for the pertinent setting/species (e.g., geographic area where the infection was acquired) [Weak, very low]. Remark: Withdrawal of TNF-α antagonists during antileishmanial therapy may be appropriate: the risks, benefits, and feasibility of this action should be assessed on a case-by-case basis. Special Populations and Leishmaniasis XXVI. How should the treatment of leishmaniasis be modified in persons who are pregnant or lactating; are young children or older adults; or have comorbidities such as renal, hepatic, or cardiac dysfunction? Recommendations 78. In general, clinically manifest cases otf VL and ML should be treated even in these special populations of persons because the benefits of treatment typically outweigh the risks. However, patient-specific factors, including the presence of comorbid conditions, should be considered in the selection of the antileishmanial therapy, dosage regimen, and monitoring approach (Table 4) [Strong, low]. 79. Decisions regarding whether and how to treat cases of CL in persons with special characteristics or comorbid conditions should take into account the potential risks and benefits of various approaches, such as initially observing without antileishmanial therapy, deferring treatment (e.g., until after pregnancy/delivery), and using local (vs systemic) therapy as the sole approach or as a temporizing measure, if otherwise appropriate and feasible [Strong, very low]. Supplementary Material Supplemental Guidelines.
Author and article information
Contributors
Mahmoud Reza Jaafari
Ali Khamesipour
Journal
Journal ID (nlm-ta): Int J Parasitol Drugs Drug Resist
Journal ID (iso-abbrev): Int J Parasitol Drugs Drug Resist
Title:
International Journal for Parasitology: Drugs and Drug Resistance
Publisher:
Elsevier
ISSN
(Electronic):
2211-3207
Publication date PMC-release: 23
September
2019
Publication date Collection:
December
2019
Publication date
(Electronic):
23
September
2019
Volume: 11
Pages: 156-165
Affiliations
[a
]Nanotechnology Research Center, Pharmaceutical Technology Institute, Mashhad University
of Medical Sciences, Mashhad, Iran
[b
]Department of Pharmaceutical Nanotechnology, School of Pharmacy, Mashhad University
of Medical Sciences, Mashhad, Iran
Author notes
[∗
]Corresponding author. Nanotechnology Research Center, Pharmaceutical Technology Institute,
Mashhad University of Medical Sciences, Mashhad, Iran.
jafarimr@
123456mums.ac.ir
Article
Publisher ID: S2211-3207(19)30054-5DOI: 10.1016/j.ijpddr.2019.09.004
PMC ID: 6904837
PubMed ID: 31582344
SO-VID: b69794d1-e77d-4b64-b9ae-ce527cb0774b
Copyright © © 2019 Published by Elsevier Ltd on behalf of Australian Society for Parasitology.
License:
This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/).
History
Date
received
: 20
April
2019
Date
revision received
: 14
September
2019
Date
accepted
: 17
September
2019
Categories
Subject:
Includes articles from the special issue “Novel therapies for cutaneous leishmaniasis”,
pp. 106 - 179
Data availability: