Evidence that the High Incidence of Treatment Failures in Indian Kala-Azar Is Due to the Emergence of Antimony-Resistant Strains of Leishmania donovani

Kala-azar, or visceral leishmaniasis, has become a growing problem in India. Over the past 11 years, there have been an estimated 430,000 cases of kala-azar diagnosed, but the actual number of cases is believed to be five times larger. Eastern India is estimated to carry about half of the world’s annual cases of visceral leishmania. If this disease is left untreated, the fatality rate is nearly 100%, but in the past few years the treatment has been losing its effectiveness. A daily 20mg dose of sodium antimony gluconate (SAG) for 20 to 30 days was effective in curing kala-azar in the 1980’s, but a study performed between 1994 to 1997 showed patients treated had an unresponsive rate of 34%-64%. This large percentage of unresponsive cases led Lira et al. (1999) to consider the emergence of drug-resistant parasites.

SAG had been studied in the past for anti-leishmanial drug action, but a comparison of the SAG sensitivity of Indian isolates from responsive and unresponsive patients had not been studied. In order to test the SAG sensitivity in patients, Lira et al. (1999) isolated L. donovani strains from 24 patients that lived in Bihar, India, and that had all been diagnosed with kala-azar. Each of the patients had been treated with two courses of SAG daily, which consists of 333 mg of SAG/ml and 100 mg total of antimony/mL. Patients response to the treatment was evaluated by splenic aspiration at the end of the 30 day treatment. Nine of the L. donovani strains were isolated from patients that responded well to the SAG treatment and had no relapse. The remaining 15 strains were isolated from patients who were unresponsive to the treatment. Different concentrations of SAG were tested on intracellular amastigotes from each strain that was growing in vitro within mouse macrophages. After incubation and the addition of SAG, it was found L. donovani amastigotes from the unresponsive strains were an average of three to five times more resistant to SAG treatment than amastigotes from the responsive strains (R. Lira et al. 1999).

The results of this study suggest the challenges in treating Indian kala-azar may be becoming more prevalent due to the emergence of antimony-resistant Leishmania donovani strains.  Antimony-unresponsiveness with L. donovani only occurred with amastigotes and not with promastigotes as seen in other Leishmania species (R. Lira et. al. 1999). The stage specificity of this parasites’ SAG resistance shows that the development of a drug that is specific to the amastigote stage of the parasite is necessary to cure people infected with this antimony-unresponsive strand.

This article relates to the study by Samuelson et al. (1991) “A Mouse Model of Leishmania braziliensis braziliensis Infection Produced by Coinjection with Sand Fly Saliva” because Samuelson et al. (1991) found a relationship between intermediate hosts and how they effect the severity of parasite infection. In the study by Lira et al. (1999), the intensity of the parasite infection was being studied and how the stage of the parasite effects intensity.  Due to the lack of studies performed on L. braziliensis, L. donovani was chosen for my future articles because of their similarities.

Citation

R. Lira, S. Sundar, A. Makharia, R. Kenney, A. Gam, E. Saraiva, D. Sacks, 1999, Evidence that the High Incidence of Treatment Failures in Indian Kala-Azar Is Due to the Emergence of Antimony-Resistant Strains of Leishmania donovani, Journal of Infectious Diseases, 180: 564-567

-Kaitlin Smith