**6. Clinical characteristics of the disease in humans**

Cutaneous leishmaniasis is the milder form of leishmaniasis and usually leads to formation of skin lesions or nodules around the exposed bite sites such as face, neck, or limbs [8, 24]. Lesions can heal spontaneously in few months, or in some extreme cases, it can take few years to resolve [8]. Although CL is self-curing and nonlife-threatening, accumulation of CL often leads to disfigured formations on skin. Lesion number can vary between 1 and 20, and upon healing, distinct scars are left on the skin. Various treatment methods are used in order to speed up the healing process for CL.

Depending on the disease forms observed clinically such as uncomplicated form, chronic recurrent form, and diffuse form, there are four causative pathogens in the Old World and five causative pathogens in the New World [18]. *L. major*, *L. tropica*, *L. infantum*, and *L. aethiopica* are the pathogens of Old World, whereas *L. L. mexicana*, *L. L. amazonensis*, *L. V. braziliensis*, *L. V. guyanensis*, and *L. V. panamensis* are the pathogens of New World in the case of CL [18].

VL also known as kala-azar is the fatal form of leishmaniasis with a mortality rate of 75–95%. Macrophages affected by the parasite spread the infection throughout the body, and patients develop pancytopenia and immunosuppression [6, 43, 44]. VL is often discussed together with HIV as they both affect immune system heavily making patients susceptible to other infections. Incubation period is between 2 weeks and 2 years. Liver- and spleen-related problems are common in patients with VL.

Parasite spreading around the initial bite site using the lymphatic way and infecting the nose or mouth mucosa leads to ML (**Figure 1**) [45]. Immune system reacting to parasite at the tip of the nose effects airway walls causing lumen obstruction which is related to necrosis of the cartilage in the nose. Unlike CL, ML is not a self-healing disease and can cause permanent skin problems. Destruction of the tip

of the nose is a severe condition that may affect patients in their social life. Breathing problems are common result of ML in patients due to the blocked airways [46].

Another form of the disease, post kala-azar dermal leishmaniasis is a complication of VL in which patients cured of VL develops nodular, macular, or maculopapular rash on skin as a result of immune suppression following VL. It is mainly observed in Sudan and India where majority of the VL cases progress into post kala-azar dermal leishmaniasis [47].

#### **7. Treatment and resistance in humans**

There are various treatment methods depending on the host immune system effectiveness and the type of *Leishmania* effecting the host as well as the way parasite is transmitted. Host factors such as genetics or immune response or factors related to treatment such as dosage, duration, and completion of the therapy and finally factors related to the parasite, such as intrinsic sensitivity of the species and lack of resistance to the medication are important determinants regarding to treatment of the disease. Long incubation period of *Leishmania* parasite makes it a challenge in detection and early treatment methods. If applicable early treatment should be applied in order to further prevent the spreading of the parasite. Having no effective human vaccines puts the disease at a critical point.

Pentavalent antimonials, sodium stibogluconate and N-methylglucamine, liposomal amphotericin B, miltefosine, and paramycin are some of the widely used drugs in routine treatment [6, 48]. Compared to liposomal amphotericin B which is a less toxic form, conventional amphotericin B has complicated application procedure and harmful side effects making liposomal amphotericin B a better choice in treatment of both CL and VL which is also an antifungal agent. Still in some underdeveloped or developing countries that cannot afford liposomal amphotericin B treatment, pentavalent antimonials are used. Despite their toxic effects on the liver and kidneys, pentavalent antimonials are still highly effective [49]. On the other hand, emerging resistance limits the therapy frequently. Miltefosine is another drug with known effect of inducing parasite resistance if not used properly.

Global antibiotic resistance problem has emerged in the treatment of leishmaniasis too, and a number of papers reporting treatment failures are increasing [50]. Anthroponotic transmission is the main cause of drug resistance in *Leishmania* species. Humans being the anthroponotic host, various effects can lead to drug resistance for parasite once treatment starts. Ignoring the recommended consuming amount and frequency of the drug, reduced concentration of the drug effecting the parasite, inhibition of drug activation, inactivation of active drug, and alterations in host gene amplifications are some important example mechanisms for parasites gaining drug resistance. Although, the mechanisms of drug resistance in *Leishmania* species are not well elucidated in detail, but the involvement of P-glycoprotein (Pgp)-like ABC transporters and ldmdr1 gene has been detected in hard-to-treat parasites [51–54]. In addition, high amount of thiol levels was found to play a role in developing resistance as they prevent reduction of pentavalent antimonials to trivalent antimonials [55].

#### **8. Latest developments in the diagnosis, prevention, and treatment**

Permanent solution for the leishmaniasis in terms of successful human vaccination is still a major challenge. However, there are different vaccinations currently

**81**

*An Overview of Leishmaniasis: Historic to Future Perspectives*

being tested in mouse model. One of them uses "killed but metabolically active" parasites to induce host immune system reaction. Mice infected by "killed but metabolically active" *L. infantum chagasi* showed no signs of organomegaly or parasite presence 6 months after infection compared to mice infected with live parasite. Finally "killed but metabolically active" *L. infantum chagasi* has also shown to induce parasite-specific protective host immune response that is similar to response

Using salivary peptides of the sandfly holds potential to be used as a vaccine component; however, complex immune response makes it a challenge. Novel drug combinations have been tested in some endemic regions in order to lower the treatment cost and toxicity and preventing resistance gain by the parasite. Nitroquinolines were found to show leishmanicidal activity. Antimicrobial peptides including dermaseptin, andropin, and cecropin have been found effective against CL. Edelfosine is an oral drug with greatly increased activity compared to miltefosine. There are also compounds isolated from plants which are tested and observed to have antileishmanial activity. For example, a polyphenolic flavanoid, quercetin, has shown antileishmanial activity in treatment of VL [57]. Four plant species named *Agave americana*, *Azadirachta indica*, *Eclipta alba*, and *Piper longum* showed

Macrophage targeted drug delivery system is another novel approach to directly effect *Leishmania* parasites that live in the macrophages as their infection mechanism. As getting into macrophages is a challenge, liposomes, microspheres, nanoparticles, and carbon nanotubes are some of the various drug carriers that are studied to target macrophages [62]. In addition, use of specific receptors expressed

Leishmaniasis still remains as a big public health challenge in some parts of the world. Despite developments in scientific knowledge and medical technology, there is still a need for quick and cheap detection of *Leishmania* infections especially in endemic areas. Studies focusing on molecular microbiological methods can help to

In terms of treatment of leishmaniasis, emerging resistance is a big threat for infectious disease specialists like in other microbial diseases. There are two arms of fight. One is the development of a successful vaccine, and the other is the progress of finding new compounds to cure the infection. If applicable early treatment should be applied in order to further prevent the spreading of the parasite. Having no effective human vaccines puts the disease at this critical point. That is why studies focusing on the development of vaccine will be pathfinder in the future decade. On the other hand, studies evaluating the antileishmanial activity of various natural products or chemically modified compounds are needed to find new opportunities in successful treatment of *Leishmania*

The author wants to express his special thanks to Namık Refik Kerküklü for his

*DOI: http://dx.doi.org/10.5772/intechopen.81643*

induced by live *Leishmania* [56]*.*

important antileishmanial activity too [58–61].

**9. Conclusion and future perspectives**

develop new diagnostic methods.

infections for the future.

**Acknowledgements**

kind help during the preperation of this chapter.

by macrophages to actively deliver a drug is also used [63].

#### *An Overview of Leishmaniasis: Historic to Future Perspectives DOI: http://dx.doi.org/10.5772/intechopen.81643*

*Vectors and Vector-Borne Zoonotic Diseases*

kala-azar dermal leishmaniasis [47].

**7. Treatment and resistance in humans**

antimonials to trivalent antimonials [55].

of the nose is a severe condition that may affect patients in their social life. Breathing problems are common result of ML in patients due to the blocked airways [46]. Another form of the disease, post kala-azar dermal leishmaniasis is a complication of VL in which patients cured of VL develops nodular, macular, or maculopapular rash on skin as a result of immune suppression following VL. It is mainly observed in Sudan and India where majority of the VL cases progress into post

There are various treatment methods depending on the host immune system effectiveness and the type of *Leishmania* effecting the host as well as the way parasite is transmitted. Host factors such as genetics or immune response or factors related to treatment such as dosage, duration, and completion of the therapy and finally factors related to the parasite, such as intrinsic sensitivity of the species and lack of resistance to the medication are important determinants regarding to treatment of the disease. Long incubation period of *Leishmania* parasite makes it a challenge in detection and early treatment methods. If applicable early treatment should be applied in order to further prevent the spreading of the parasite. Having no effective human vaccines puts the disease at a critical point. Pentavalent antimonials, sodium stibogluconate and N-methylglucamine, liposomal amphotericin B, miltefosine, and paramycin are some of the widely used drugs in routine treatment [6, 48]. Compared to liposomal amphotericin B which is a less toxic form, conventional amphotericin B has complicated application procedure and harmful side effects making liposomal amphotericin B a better choice in treatment of both CL and VL which is also an antifungal agent. Still in some underdeveloped or developing countries that cannot afford liposomal amphotericin B treatment, pentavalent antimonials are used. Despite their toxic effects on the liver and kidneys, pentavalent antimonials are still highly effective [49]. On the other hand, emerging resistance limits the therapy frequently. Miltefosine is another drug

with known effect of inducing parasite resistance if not used properly.

**8. Latest developments in the diagnosis, prevention, and treatment**

Permanent solution for the leishmaniasis in terms of successful human vaccination is still a major challenge. However, there are different vaccinations currently

Global antibiotic resistance problem has emerged in the treatment of leishmaniasis too, and a number of papers reporting treatment failures are increasing [50]. Anthroponotic transmission is the main cause of drug resistance in *Leishmania* species. Humans being the anthroponotic host, various effects can lead to drug resistance for parasite once treatment starts. Ignoring the recommended consuming amount and frequency of the drug, reduced concentration of the drug effecting the parasite, inhibition of drug activation, inactivation of active drug, and alterations in host gene amplifications are some important example mechanisms for parasites gaining drug resistance. Although, the mechanisms of drug resistance in *Leishmania* species are not well elucidated in detail, but the involvement of P-glycoprotein (Pgp)-like ABC transporters and ldmdr1 gene has been detected in hard-to-treat parasites [51–54]. In addition, high amount of thiol levels was found to play a role in developing resistance as they prevent reduction of pentavalent

**80**

being tested in mouse model. One of them uses "killed but metabolically active" parasites to induce host immune system reaction. Mice infected by "killed but metabolically active" *L. infantum chagasi* showed no signs of organomegaly or parasite presence 6 months after infection compared to mice infected with live parasite. Finally "killed but metabolically active" *L. infantum chagasi* has also shown to induce parasite-specific protective host immune response that is similar to response induced by live *Leishmania* [56]*.*

Using salivary peptides of the sandfly holds potential to be used as a vaccine component; however, complex immune response makes it a challenge. Novel drug combinations have been tested in some endemic regions in order to lower the treatment cost and toxicity and preventing resistance gain by the parasite. Nitroquinolines were found to show leishmanicidal activity. Antimicrobial peptides including dermaseptin, andropin, and cecropin have been found effective against CL. Edelfosine is an oral drug with greatly increased activity compared to miltefosine. There are also compounds isolated from plants which are tested and observed to have antileishmanial activity. For example, a polyphenolic flavanoid, quercetin, has shown antileishmanial activity in treatment of VL [57]. Four plant species named *Agave americana*, *Azadirachta indica*, *Eclipta alba*, and *Piper longum* showed important antileishmanial activity too [58–61].

Macrophage targeted drug delivery system is another novel approach to directly effect *Leishmania* parasites that live in the macrophages as their infection mechanism. As getting into macrophages is a challenge, liposomes, microspheres, nanoparticles, and carbon nanotubes are some of the various drug carriers that are studied to target macrophages [62]. In addition, use of specific receptors expressed by macrophages to actively deliver a drug is also used [63].

### **9. Conclusion and future perspectives**

Leishmaniasis still remains as a big public health challenge in some parts of the world. Despite developments in scientific knowledge and medical technology, there is still a need for quick and cheap detection of *Leishmania* infections especially in endemic areas. Studies focusing on molecular microbiological methods can help to develop new diagnostic methods.

In terms of treatment of leishmaniasis, emerging resistance is a big threat for infectious disease specialists like in other microbial diseases. There are two arms of fight. One is the development of a successful vaccine, and the other is the progress of finding new compounds to cure the infection. If applicable early treatment should be applied in order to further prevent the spreading of the parasite. Having no effective human vaccines puts the disease at this critical point. That is why studies focusing on the development of vaccine will be pathfinder in the future decade. On the other hand, studies evaluating the antileishmanial activity of various natural products or chemically modified compounds are needed to find new opportunities in successful treatment of *Leishmania* infections for the future.

#### **Acknowledgements**

The author wants to express his special thanks to Namık Refik Kerküklü for his kind help during the preperation of this chapter.

*Vectors and Vector-Borne Zoonotic Diseases*
