Cross-resistance to nitro drugs and implications for treatment of human African trypanosomiasis

Autor: Alan H. Fairlamb, Sandra L. Oza, Antoaneta Y. Sokolova, Stephen Patterson, Kevin D. Read, Susan Wyllie
Rok vydání: 2010
Předmět:
Zdroj: Antimicrobial agents and chemotherapy. 54(7)
ISSN: 1098-6596
Popis: The protozoan parasites Trypanosoma brucei gambiense and T. b. rhodesiense are the causative agents of human African trypanosomiasis (HAT), commonly known as sleeping sickness. This epidemic disease was largely under control in the 1960s but has reemerged as a major threat due to limited financial resources for the maintenance of control programs as well as population displacement due to political conflict and famine (23). Currently, the World Health Organization estimates that about 400,000 people are infected with HAT, resulting in an annual death toll of around 50,000 (42), although this may be an overestimate (36). In the absence of an effective vaccine, treatment is dependent solely upon a small repertoire of drugs which suffer from a number of problems, including severe toxic side effects (12) and acquired drug resistance (2). In particular, treatment of the second stage of the disease, where parasites invade the central nervous system, has proven to be especially problematic. Two drugs are available: the arsenical melarsoprol and the ornithine decarboxylase inhibitor eflornithine (difluoromethylornithine [DFMO]). Melarsoprol is extremely toxic, with death in 3 to 6% of cases and treatment failures as high as 30% in certain areas. Although better tolerated than melarsoprol, eflornithine is not effective against T. b. rhodesiense infections, which account for 10% of all cases of sleeping sickness. The treatment regimen for T. b. gambiense is prolonged, requiring a total of 56 slow infusions over a 14-day period. As a result, melarsoprol often remains the treatment of choice in regions where health care provision is limited. One important development in the treatment of T. b. gambiense infections is the introduction of nifurtimox-eflornithine combination therapy (NECT) (32). Nifurtimox, a drug used in the treatment of Chagas' disease, has previously been given on compassionate grounds for treatment of melarsoprol-refractory HAT. However, its efficacy as a monotherapy is low, and prolonged treatment is limited by severe toxicity (4, 5). Patients given NECT, consisting of oral nifurtimox over 10 days with DFMO infusions for 7 days, were found to fair just as well as those given the DFMO monotherapy, with cure rates of around 97%. The reduced frequency and duration of DFMO infusions in NECT is seen as highly advantageous in terms of cost, logistics, and human resources in areas of poverty, leading to its inclusion on the Model Lists of Essential Medicines of the World Health Organization. The success of NECT has come at a time of renewed interest in nitroheterocyclic compounds for the treatment of infectious disease. In particular, PA-824 is being assessed for the treatment of tuberculosis (3, 15, 29), while nitazoxanide is currently in phase II clinical trials for the treatment of hepatitis C (15). The increased awareness of the antimicrobial potential of these compounds has also led to the renaissance of fexinidazole (Hoe 239) (41) as a potential chemotherapeutic for late-stage HAT. In 1983, Jennings and Urquhart reported that this compound, given in combination with suramin, effectively cured chronic T. brucei infections in mice (20). Some 26 years later, fexinidazole entered phase II clinical trials as a monotherapy for use against both early- and late-stage African sleeping sickness (8; report available from http://www.dndi.org/). It is well established that naturally occurring strains of Trypanosoma cruzi can be inherently resistant to nifurtimox (28), but it is not known whether a similar situation might occur in the African trypanosome. However, clinical isolates of T. b. gambiense from Sudan and West and Central Africa show a 10-fold range of sensitivities to nifurtimox (25, 26). It was also recently demonstrated that laboratory-generated nifurtimox-resistant T. cruzi cell lines become resistant to another nitro drug, benznidazole (39). To determine whether this may also be the case for T. brucei, we have undertaken similar studies. Here, we examine the in vivo and in vitro resistance potentials of nifurtimox and fexinidazole and its metabolites in bloodstream trypanosomes. The potential for cross-resistance to other nitro compounds is also addressed.
Databáze: OpenAIRE
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