First- and second-line drugs can be differentiated in the treatment of leishmaniosis. First-line drugs include pentavalent antimonials (SbV), while second-line drugs mark substances like allopurinol, pentamidine, ketoconazol, amphotericin B and amminosidine. The latter are often used in unresponsiveness or resistance of first-line drugs. Leishmaniosis in domestic dogs and humans has been treated for many years often with the same drugs or related compounds.

Treatment in dogs

In dogs anti-leishmanial treatment with current drugs often achieves temporary clinical improvement, but frequently the following aims are not guaranteed:

• elimination of the parasite carriership,

• cessation of infectivity to sand fly vectors feeding on the canine host,

• prevention of clinical relapse.

Up to 74% of relapse rates have been reported (Slappendel and Teske, 1997).

Anti-leishmanial therapy can be practiced as monotherapy or in combination, can be given in different routes of administration (s.c., i.v., i.p., orally etc.) and protocols show a great variety of dosage, frequency and treatment length.

Furthermore genetic composition of the individual dog, determining the nature of immune response, as well as the susceptibility to drugs and the natural virulence of the infecting parasite may play an important role in therapy response and dog recovery. Parameters that should be considered before starting anti-leishmanial treatment are hemogram, renal and hepatic functions, electrophoretic protein pattern, antileishmania antibody titers, and bone marrow and lymph node parasite load.

Besides numerous protocols of treatment with different dosages, daily application intervals and duration, a general therapy consensus is the treatment with parenteral meglumine antimoniate over 20-30 days plus a repetition (e.g. of another 20 days) in case of persistent clinical signs, combined with oral allopurinol treatment, which should be continued for 9-12 months or even life time.

To minimize the danger of generating resistance in Leishmania strains, it would be desirable to treat dogs and humans by different drugs, a postulation hardly practicable with the drugs available at the moment. Generally parasitological cure would be the ultimate goal.

Dogs which have been in endemic areas are recommended to be serologically tested four weeks after return. In case of negative results in an IFAT, they should be retested 2-3 times. If a striking clinic combined with negative serology exists, they should be retested due to the possibility of false-negative results.

Monitoring of canine therapy

According to Noli (1999) the best therapy surveillance can be performed via control of total plasma protein and serum protein electrophoresis. The data should be compared with data collected before the beginning of treatment. In contrast, serological titers have proven not to be representative and proportional to the degree of disease. Therapy surveillance can further be performed with culturing of bone marrow biopsies, determination of specific IgG1 and IgG2 or PCR, e.g. of bone marrow aspirates and - to a lower sensitivity - of blood samples.

Cure should be confirmed by negative cytological examination, easing off of all clinical symptoms, normalisation of all blood parameters and double negative PCR results, six months apart (Ferrer, 1997). When the patient is not under maintenance treatment, follow-up proteinograms should be performed with an increase of gamma globulins as first sign of relapse.

Ferrer (1997) stops treatment when clinical signs have disappeared, blood analysis is within normal ranges, the proteinogram is normal, and two PCR examinations of the bone marrow separated by 6 months are negative.

Prognosis

Parasitological cure is often an exception in the course of treatment and relapses are frequently seen. Additionally dogs with a reduced renal function at the start of treatment possess the worst prognosis in general. Allopurinol has shown to keep dogs in the state of clinical remission when given intermittently over years. A high proportion of dogs remain parasitologically positive after therapy and clinical cure, and therefore remain infectious to sand flies.

Drugs

• Pentavalent antimonials (Sbv)

  Meglumine antimoniate (Glucantime^®) is the drug of choice for the treatment of visceral leishmaniosis in dogs. Alternatively sodium stibogluconate (Pentostam^®) is used. These compounds selectively inhibit leishmanial enzymes required for gycolytic and fatty acid oxidation.

  Side effects of antimonials in dogs include gastrointestinal disturbances, painful swelling at the site of injection, anorexia, disturbances in locomotion and weariness. The disadvantages of meglumine antimoniate are: a risk of decrease in sensitivity, a painful and expensive treatment, and the fact that the treatment gives a false impression of effectiveness, resulting in short treatment periods by owners with subsequent relapses and the risk of resistance development.

  Diverse treatment protocols exist either as monotherapy or in combination with allopurinol. The duration of meglumine antimoniate therapy varies between 20-30 days plus a possible repetition for further 20 days in case of persisting clinical signs.

  For meglumine antimoniate after many years in veterinary use three developing trends were observed: 1. a lengthening of the treatment period (possibly due to resistance); 2. drug administration in shorter intervals (once or twice daily); 3. an association with allopurinol.

• Allopurinol

  Allopurinol is an oral purine analogue. Metabolization of allopurinol by Leishmania parasites results in an interruption of the pathogen’s protein synthesis, as they are not able to synthesize purines. A side effect in dogs can be the formation of xanthine uroliths. The advantages of allopurinol are: a relative non-toxicity, efficiency in improving the clinical status, low costs, and the possibility of oral administration.

  Again the drug can be used as mono- or combination therapy with pentavalent antimonials. In combination therapies allopurinol is generally applied over months or even life long.

• Amphotericin B

  It is a very potent and effective drug against Leishmania spp., but is mainly used in case of meglumine antimoniate resistance, among others due to its toxic potential. It is very important for the treatment of SbV resistant human visceral leishmaniosis (VL) and therefore should not be used in veterinary practice in order to avoid selection of parasites resistant to the compound. Additionally in dogs it is uneffective to eliminate the parasites.

• Aminosidine

  It is another human VL drug, which can be used in combination therapy, but also possesses nephrotoxic and ototoxic potential.

• Miltefosine

  It is a very potent, quite recently tested drug in human VL and has also been tested positively in canine leishmaniosis (CanL).

• Miscellaneous

  Further drugs as pentamidine, ketoconazole, metronidazole and fuconazole also possess activity against Leishmania parasites, but are not used in the first line.

Vaccination

Epidemiological considerations judge the vaccination of dogs as the domestic reservoir of L. infantum to be the most effective method of controlling zoonotic visceral leishmaniosis. To date there is only one licensed vaccine against CanL in dogs in Brazil (Leishmune^®). The vaccine contains Fucose-Mannose-ligand (FML) antigen of L. donovani and has proven transmission blocking capabilities. Antibodies raised in the vaccinated host prevented the development of the parasite in the sand fly, thus interrupting the developmental cycle. In the IRD Montpellier research center in France another vaccine candidate, composed solely of antigen proteins excreted by the parasite, has been tested quite promising.

Diverse other approaches also with recombinant proteins or DNA fragments have been performed more or less successful, but no other vaccine is licensed so far.

Treatment in humans

In man different drugs, dosages and treatment regimens are used. Pentavalent antimonials (SbV) have been the foundation of treatment for allforms of leishmaniosis in every endemic region for seven decades. But resistance development demanded higher dosages or even a change to other compounds in some areas.

Pentamidine was an alternative in resistant areas, but also showed decreased efficacy, besides the fact of serious side effects.
Liposomal amphotericin B remains aneffective drug in SbV resistant areas. However, in HIV co-infected patients high doses of lipososmal amphotericin B are ineffective in obtaining a radical cure.

Miltefosine has proven good efficacy in human VLin India and has also been tested in cases of human CL. But there are still clinical manifestations and infectious scenarios to be tested.

Other compounds have been or still are more or less successfully used as ketoconazole, itroconazole, allopurinol, and aminosidine. Finally, photodynamic therapy has also shown good results in the treatment of human cutaneous leishmaniosis.