Drug Resistance in Leishmaniasis
01 Jan 2006-Clinical Microbiology Reviews (American Society for Microbiology)-Vol. 19, Iss: 1, pp 111-126
TL;DR: It is essential that there be a strategy to prevent the emergence of resistance to new drugs; combination therapy, monitoring of therapy, and improved diagnostics could play an essential role in this strategy.
Abstract: Leishmaniasis is a complex disease, with visceral and cutaneous manifestations, and is caused by over 15 different species of the protozoan parasite genus Leishmania. There are significant differences in the sensitivity of these species both to the standard drugs, for example, pentavalent antimonials and miltefosine, and those on clinical trial, for example, paromomycin. Over 60% of patients with visceral leishmaniasis in Bihar State, India, do not respond to treatment with pentavalent antimonials. This is now considered to be due to acquired resistance. Although this class of drugs has been used for over 60 years for leishmaniasis treatment, it is only in the past 2 years that the mechanisms of action and resistance have been identified, related to drug metabolism, thiol metabolism, and drug efflux. With the introduction of new therapies, including miltefosine in 2002 and paromomycin in 2005-2006, it is essential that there be a strategy to prevent the emergence of resistance to new drugs; combination therapy, monitoring of therapy, and improved diagnostics could play an essential role in this strategy.
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TL;DR: Based on the previous experience of 20 years of coinfection in Europe, this review focuses on the management of Leishmania-HIV-coinfected patients in low-income countries where leishmaniasis is endemic.
Abstract: Summary: To date, most Leishmania and human immunodeficiency virus (HIV) coinfection cases reported to WHO come from Southern Europe. Up to the year 2001, nearly 2,000 cases of coinfection were identified, of which 90% were from Spain, Italy, France, and Portugal. However, these figures are misleading because they do not account for the large proportion of cases in many African and Asian countries that are missed due to a lack of diagnostic facilities and poor reporting systems. Most cases of coinfection in the Americas are reported in Brazil, where the incidence of leishmaniasis has spread in recent years due to overlap with major areas of HIV transmission. In some areas of Africa, the number of coinfection cases has increased dramatically due to social phenomena such as mass migration and wars. In northwest Ethiopia, up to 30% of all visceral leishmaniasis patients are also infected with HIV. In Asia, coinfections are increasingly being reported in India, which also has the highest global burden of leishmaniasis and a high rate of resistance to antimonial drugs. Based on the previous experience of 20 years of coinfection in Europe, this review focuses on the management of Leishmania-HIV-coinfected patients in low-income countries where leishmaniasis is endemic.
776 citations
TL;DR: An updated view on progress in elucidating the epidemiology and pathogenesis of canine leishmaniosis is presented, and the second part focuses on advances in diagnosis, treatment and prevention.
612 citations
Cites background from "Drug Resistance in Leishmaniasis"
...The zoonotic potential of CanL, lack of a parasitological cure, and the reported occurrence of parasitic resistance to pentavalent antimonials, amphotericin B, aminosidine and miltefosine [ 31 ] indicate that it would be best to avoid or minimize the use of the same drugs for therapy of CanL and human leishmaniosis....
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TL;DR: A consensus of opinions on the diagnosis, treatment, prognosis and prevention of CanL is presented, and a system of four clinical stages, based on clinical signs, clinicopathological abnormalities and serological status is proposed.
526 citations
Cites background from "Drug Resistance in Leishmaniasis"
...and miltefosine is well known in human medicine (Croft et al., 2006), only limited information is available for the dog....
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TL;DR: The meaning of “resistance” related to leishmaniasis and its molecular epidemiology are discussed, particularly for Leishmania donovani that causes visceral leish maniasis, and how resistance can affect drug combination therapies are discussed.
Abstract: Reevaluation of treatment guidelines for Old and New World leishmaniasis is urgently needed on a global basis because treatment failure is an increasing problem. Drug resistance is a fundamental determinant of treatment failure, although other factors also contribute to this phenomenon, including the global HIV/AIDS epidemic with its accompanying impact on the immune system. Pentavalent antimonials have been used successfully worldwide for the treatment of leishmaniasis since the first half of the 20th century, but the last 10 to 20 years have witnessed an increase in clinical resistance, e.g., in North Bihar in India. In this review, we discuss the meaning of “resistance” related to leishmaniasis and discuss its molecular epidemiology, particularly for Leishmania donovani that causes visceral leishmaniasis. We also discuss how resistance can affect drug combination therapies. Molecular mechanisms known to contribute to resistance to antimonials, amphotericin B, and miltefosine are also outlined.
511 citations
TL;DR: Kinetoplastids are a group of flagellated protozoans that include the species Trypanosoma and Leishmania, which are human pathogens with devastating health and economic effects.
Abstract: Kinetoplastids are a group of flagellated protozoans that include the species Trypanosoma and Leishmania, which are human pathogens with devastating health and economic effects. The sequencing of the genomes of some of these species has highlighted their genetic relatedness and underlined differences in the diseases that they cause. As we discuss in this Review, steady progress using a combination of molecular, genetic, immunologic, and clinical approaches has substantially increased understanding of these pathogens and important aspects of the diseases that they cause. Consequently, the paths for developing additional measures to control these "neglected diseases" are becoming increasingly clear, and we believe that the opportunities for developing the drugs, diagnostics, vaccines, and other tools necessary to expand the armamentarium to combat these diseases have never been better.
499 citations
References
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TL;DR: The ability to predict and circumvent drug resistance is likely to improve chemotherapy, and it has become apparent that resistance exists against every effective drug, even the authors' newest agents.
Abstract: Chemotherapeutics are the most effective treatment for metastatic tumours. However, the ability of cancer cells to become simultaneously resistant to different drugs--a trait known as multidrug resistance--remains a significant impediment to successful chemotherapy. Three decades of multidrug-resistance research have identified a myriad of ways in which cancer cells can elude chemotherapy, and it has become apparent that resistance exists against every effective drug, even our newest agents. Therefore, the ability to predict and circumvent drug resistance is likely to improve chemotherapy.
5,105 citations
TL;DR: The mode of action of antifungals and their mechanisms of resistance are discussed, and an attempt is made to discuss the correlation between fungal and bacterial resistance.
Abstract: The increased use of antibacterial and antifungal agents in recent years has resulted in the development of resistance to these drugs. The significant clinical implication of resistance has led to heightened interest in the study of antimicrobial resistance from different angles. Areas addressed include mechanisms underlying this resistance, improved methods to detect resistance when it occurs, alternate options for the treatment of infections caused by resistant organisms, and strategies to prevent and control the emergence and spread of resistance. In this review, the mode of action of antifungals and their mechanisms of resistance are discussed. Additionally, an attempt is made to discuss the correlation between fungal and bacterial resistance. Antifungals can be grouped into three classes based on their site of action: azoles, which inhibit the synthesis of ergosterol (the main fungal sterol); polyenes, which interact with fungal membrane sterols physicochemically; and 5-fluorocytosine, which inhibits macromolecular synthesis. Many different types of mechanisms contribute to the development of resistance to antifungals. These mechanisms include alteration in drug target, alteration in sterol biosynthesis, reduction in the intercellular concentration of target enzyme, and overexpression of the antifungal drug target. Although the comparison between the mechanisms of resistance to antifungals and antibacterials is necessarily limited by several factors defined in the review, a correlation between the two exists. For example, modification of enzymes which serve as targets for antimicrobial action and the involvement of membrane pumps in the extrusion of drugs are well characterized in both the eukaryotic and prokaryotic cells.
1,489 citations
"Drug Resistance in Leishmaniasis" refers background in this paper
...Although resistance mechanisms differ between prokaryotic and eukaryotic organisms, some general principles can be identified (68, 79)....
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TL;DR: The signalling pathways involved in regulating tumour cell response to chemotherapy more completely than ever before are characterized, which will facilitate the future development of rational combined chemotherapy regimens, in which the newer targeted therapies are used in combination with cytotoxic drugs to enhance chemotherapy activity.
Abstract: Resistance to chemotherapy limits the effectiveness of anti-cancer drug treatment. Tumours may be intrinsically drug-resistant or develop resistance to chemotherapy during treatment. Acquired resistance is a particular problem, as tumours not only become resistant to the drugs originally used to treat them, but may also become cross-resistant to other drugs with different mechanisms of action. Resistance to chemotherapy is believed to cause treatment failure in over 90% of patients with metastatic cancer, and resistant micrometastic tumour cells may also reduce the effectiveness of chemotherapy in the adjuvant setting. Clearly, if drug resistance could be overcome, the impact on survival would be highly significant. This review focuses on molecular mechanisms of drug resistance that operate to reduce drug sensitivity in cancer cells. Drug resistance can occur at many levels, including increased drug efflux, drug inactivation, alterations in drug target, processing of drug-induced damage, and evasion of apoptosis. Advances in DNA microarray and proteomic technology, and the ongoing development of new targeted therapies have opened up new opportunities to combat drug resistance. We are now able to characterize the signalling pathways involved in regulating tumour cell response to chemotherapy more completely than ever before. This will facilitate the future development of rational combined chemotherapy regimens, in which the newer targeted therapies are used in combination with cytotoxic drugs to enhance chemotherapy activity. The ability to predict response to chemotherapy and to modulate this response with targeted therapies will permit selection of the best treatment for individual patients.
1,416 citations
"Drug Resistance in Leishmaniasis" refers background in this paper
...Although resistance mechanisms differ between prokaryotic and eukaryotic organisms, some general principles can be identified (68, 79)....
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TL;DR: Recent progress in understanding the biochemical mechanisms and regulation of the caspase activation pathway, the roles of the pathway in physiology and disease, and their potential therapeutic values are focused on.
Abstract: Apoptosis, or programmed cell death, is involved in development, elimination of damaged cells, and maintenance of cell homeostasis. Deregulation of apoptosis may cause diseases, such as cancers, immune diseases, and neurodegenerative disorders. Apoptosis is executed by a subfamily of cysteine proteases known as caspases. In mammalian cells, a major caspase activation pathway is the cytochrome c-initiated pathway. In this pathway, a variety of apoptotic stimuli cause cytochrome c release from mitochondria, which in turn induces a series of biochemical reactions that result in caspase activation and subsequent cell death. In this review, we focus on the recent progress in understanding the biochemical mechanisms and regulation of the pathway, the roles of the pathway in physiology and disease, and their potential therapeutic values.
1,303 citations
"Drug Resistance in Leishmaniasis" refers background in this paper
...However, these effects do not involve the classical caspasemediated pathway (130) and do not meet the more recent stringent definition of apoptosis (85)....
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TL;DR: Increasing risk factors are making leishmaniasis a growing public health concern for many countries around the world, and some are related to a specific eco-epidemiological entity, others affect all forms of leish maniasis.
Abstract: Economic development leads to changing interactions between humans and their physical and biological environment. Worldwide patterns of human settlement in urban areas have led in developing countries to a rapid growth of mega-cities where facilities for housing, drinking-water and sanitation are inadequate, thus creating opportunities for the transmission of communicable diseases such as leishmaniasis. Increasing risk factors are making leishmaniasis a growing public health concern for many countries around the world. Certain risk factors are new, while others previously known are becoming more significant. While some risk factors are related to a specific eco-epidemiological entity, others affect all forms of leishmaniasis. Risk factors are reviewed here entity by entity.
1,016 citations
"Drug Resistance in Leishmaniasis" refers background in this paper
...Increasing numbers of human immunodeficiency virus (HIV) coinfections, human migration, and resettlement, especially important where leishmaniasis is zoonotic, make resurgence a possibility (47)....
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