Risk factors for therapeutic failure to meglumine antimoniate and miltefosine in adults and children with cutaneous leishmaniasis in Colombia: A cohort study

Castro, María Mercedes Taboada; Cossio, Alexandra; Velasco, Carlos A.; Osório, Lyda

doi:10.1371/journal.pntd.0005515

Cited by 47 publications

(56 citation statements)

References 42 publications

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“…In addition, the authors were able to demonstrate the infectivity of the isolated parasites. Parasite persistence has been also demonstrated in clinical cured patients ( Schubach et al, 1998 ; Coutinho et al, 2002 ; Mendonça et al, 2004 ; Oliveira-Camera et al, 2006 ; Morgado et al, 2010 ; Castro et al, 2017 ; Martínez-Valencia et al, 2017 ). Leishmania persists in skin and mucosal tissues in a high proportion of patients who achieved therapeutic cure of CL ( Martínez-Valencia et al, 2017 ).…”

Section: Parasite Persistencementioning

confidence: 94%

“…Although all age groups can be affected by cutaneous leishmaniasis, the most affected ones can vary from each region, from infants less than 9 years old to teenagers (aging 10–19 years) or adults (up to 45 years-old) ( Aksoy et al, 2016 ; Brazil, 2017 ; Khezzani and Bouchemal, 2017 ). Therapeutic failure is frequently reported among children affected by cutaneous leishmaniasis ( Rubiano et al, 2012 ; Castro et al, 2017 ), which could probably be associated with an immature immune system and consequently a failure in controlling the parasite load.…”

Section: The Host Point Of Viewmentioning

confidence: 99%

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The Binomial Parasite-Host Immunity in the Healing Process and in Reactivation of Human Tegumentary Leishmaniasis

2018

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Leishmaniasis is a vector-borne infectious disease caused by different species of protozoa from the Leishmania genus. Classically, the disease can be classified into two main clinical forms: Visceral (VL) and Tegumentary (TL) leishmaniasis. TL is a skin/mucosal granulomatous disease that manifests mainly as cutaneous localized or disseminated ulcers, papules diffusely distributed, mucosal lesions or atypical lesions. Once the etiology of the infection is confirmed, treatment can take place, and different drugs can be administered. It has already been shown that, even when the scar is clinically evident, inflammation is still present in the native tissue, and the decrease of the inflammatory process occurs slowly during the 1st years after clinical healing. The maintenance of residual parasites in the scar tissue is also well documented. Therefore, it is no longer a surprise that, under some circumstances, therapeutic failure and/or lesion reactivation occurs. All over the years, an impressive amount of data on relapses, treatment resistance and lesion reactivation after healing has been collected, and several factors have been pointed out as having a role in the process. Different factors such as Leishmania species, parasite variability, Leishmania RNA virus 1, parasite load, parasite persistence, age, nutritional status, gender, co-morbidities, co-infection, pregnancy, immunosuppression, lesion duration, number and localization of lesions, drug metabolism, irregular treatment and individual host cellular immune response were described and discussed in the present review. Unfortunately, despite this amount of information, a conclusive understanding remains under construction. In addition, multifactorial influence cannot be discarded. In this context, knowing why leishmaniasis has been difficult to treat and control can help the development of new approaches, such as drugs and immunotherapy in order to improve healing maintenance. In this sense, we would like to highlight some of the findings that may influence the course of Leishmania infection and the therapeutic response, with an emphasis on TL.

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Section: Parasite Persistencementioning

confidence: 94%

Section: The Host Point Of Viewmentioning

confidence: 99%

The Binomial Parasite-Host Immunity in the Healing Process and in Reactivation of Human Tegumentary Leishmaniasis

2018

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“…However, documented treatment failure rates between 20% and 74% [1-5], in some cases attributed to parasite drug resistance [6], together with the toxicity and extended length of treatment regimens, threaten the usefulness of these drugs. Investigations on laboratory derived drug resistant Leishmania strains have revealed mechanisms of experimental resistance to antimonials based on parasite detoxification, sequestration, efflux, and altered activation of pentavalent antimonials (Sb V ) to the bioactive trivalent form (Sb III ) [7-12].…”

Section: Introductionmentioning

confidence: 99%

Profiling gene expression of antimony response genes in Leishmania (Viannia) panamensis and infected macrophages and its relationship with drug susceptibility

et al. 2017

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The mechanisms of Leishmania resistance to antimonials have been primarily determined in experimentally derived Leishmania strains. However, their participation in the susceptibility phenotype in field isolates has not been conclusively established. Being an intracellular parasite, the activity of antileishmanials is dependent on internalization of drugs into host cells and effective delivery to the intracellular compartments inhabited by the parasite. In this study we quantified and comparatively analyzed the gene expression of nine molecules involved in mechanisms of xenobiotic detoxification and Leishmania resistance to antimonial drugs in resistant and susceptible laboratory derived and clinical L.(Viannia) panamensis strains (n=19). In addition, we explored the impact of Leishmania susceptibility to antimonials on the expression of macrophage gene products having putative functions in transport, accumulation and metabolism of antimonials. As previously shown for other Leishmania species, a trend of increased abcc3 and lower aqp-1 expression was observed in the laboratory derived Sb-resistant L.(V.) panamensis line. However, this was not found in clinical strains, in which the expression of abca2 was significantly higher in resistant strains as both, promastigotes and intracellular amastigotes. The effect of drug susceptibility on host cell gene expression was evaluated on primary human macrophages from patients with cutaneous leishmaniasis (n=17) infected ex-vivo with the matched L.(V.) panamensis strains isolated at diagnosis, and in THP-1 cells infected with clinical strains (n=6) and laboratory adapted L.(V.) panamensis lines. Four molecules, abcb1 (p-gp), abcb6, aqp-9 and mt2a were differentially modulated by drug resistant and susceptible parasites, and among these, a consistent and significantly increased expression of the xenobiotic scavenging molecule mt2a was observed in macrophages infected with Sb-susceptible L. (V.) panamensis. Our results substantiate that different mechanisms of drug resistance operate in laboratory adapted and clinical Leishmania strains, and provide evidence that parasite-mediated modulation of host cell gene expression of molecules involved in drug transport and metabolism could contribute to the mechanisms of drug resistance and susceptibility in Leishmania.

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“…The long period of treatment leads to the accumulation of antimony (Sb) in the tissues, producing myalgia, pancreatitis, pancytopenia, hepatic and cardiotoxicity [41]. Other limiting factors are drug resistance and increased therapeutic failure [42]. In India, its use in VL has been contraindicated due to the appearance of resistant L. donovani strains [43].…”

Section: Systemic Therapies 21 Parenteral Treatmentsmentioning

confidence: 99%

Nanomedicines for Cutaneous Leishmaniasis

Sousa-Batista¹,

Rossi-Bergmann²

2018

Leishmaniases as Re-Emerging Diseases

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Leishmaniasis is a vector-borne disease caused by Leishmania parasites, which cause a range of clinical manifestations in man. These are didactically classified into cutaneous leishmaniasis (CL), the most common form of the disease, and visceral leishmaniasis (VL), the life-threatening form. There are so far no vaccines approved for humans. Conventional drugs pose limitations ranging from low efficacy and high cost to systemic toxicity. Low efficacy derives in part from difficult drug access to the parasites, which rides themselves inside macrophage phagosomes. This prompts to high dosage, with consequent increased toxicity. Difficult intracellular drug access can be overcome with nanomedicines such as biocompatible lipid and polymeric nanoparticles that can be phagocytosed by the infected macrophages. Besides cell membranes, appropriate drug nanostructuring may allow tissue barrier penetration and drug administration through higher compliance routes such as skin and intestine, in contrast to the usual intravenous and intramuscular routes. In general, CL and VL are both treated with toxic systemic injections, disregard of disease severity. This chapter will review and discuss studies with nanomedicines that have reached the market such as liposomal amphotericin B for intravenous administration, and innovative preclinical studies aiming at developing effective cutaneous and oral drugs with focus on CL.

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Risk factors for therapeutic failure to meglumine antimoniate and miltefosine in adults and children with cutaneous leishmaniasis in Colombia: A cohort study

Cited by 47 publications

References 42 publications

The Binomial Parasite-Host Immunity in the Healing Process and in Reactivation of Human Tegumentary Leishmaniasis

The Binomial Parasite-Host Immunity in the Healing Process and in Reactivation of Human Tegumentary Leishmaniasis

Profiling gene expression of antimony response genes in Leishmania (Viannia) panamensis and infected macrophages and its relationship with drug susceptibility

Nanomedicines for Cutaneous Leishmaniasis

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