User:Marykate20/Trypanosome Drug Resistance

Trypanosome Drug Resistance
Drug resistance has been described as a genetically transferred resistance of a microbe to a drug  to which it was previously susceptible. isometamidium chloride (ISM), which has both therapeutic and prophylactic effects, and diminazine aceturate (DA), which has only curative capabilities, are the two main medications used by livestock keepers to treat African Animal Trypanosomiasis. Farmers throughout most of Africa have easy access to the trypanocides due to the privatization of veterinary services, which has led to widespread overuse and under-dosage of the drugs, activities that have been blamed for the formation of trypanocidal drug resistance .Hastings listed the following as some of the crucial elements influencing how quickly medication resistance develops in a population of parasites:(i) the frequency and pattern of medication usage, (ii) the mutation rate from wild type to resistant genotype, and (iii) the parasitaemia within the host, or the number of parasites exposed to the drug following the treatment of the host. The presence of strains that are cross-resistant to Diminazine Aceturate (DA) and isometamidium has been shown in the wild and during experimental infection. Although the cause of trypanosomes' widespread resistance to these trypanocides is unknown, it has been postulated that it may be connected to cross-resistance between the various drugs due to their closely comparable chemical structures. Therefore, trypanosome medication resistance poses a significant threat to livestock productivity.

Epidemiology
For the epidemiological control of African trypanosomiases, geo-referenced data on trypanosome infections in tsetse flies is crucial since it enables researchers to assess the risks of the disease from a wider angle. Similarly, collecting information on tsetse fly drug-resistant trypanosomes will be helpful for pinpointing the regions where these trypanosomes are spread. Each year, trypanosomosis kills 3 million head of cattle, putting 50 million animals in sub-Saharan Africa at risk. In 21 African nations, drug resistance has been documented. Thus, drug resistance in animal trypanosomes displays a pattern distinct from that seen with Plasmodium sp. (the malaria-causing parasite), where a complete cessation of chloroquine use allows for a return to drug sensitivity. The first trypanosome medication resistance case was documented in northern Nigeria in 1967.

Drug Resistance in Human African Trypanosomiasis
A neglected tropical illness called human African trypanosomiasis, also known as "sleeping sickness," is brought on by the parasite Trypanosoma brucei. There are two distinct subspecies that cause the two types of Human African Trypanosomiasis (HAT). The chronic form of T. b. gambiense, which is common in Central and West Africa, often progresses through the first (hemolymphatic) stage to the second (neurological) stage over the course of 18 months, followed by another 18 months till death. T. b. rhodesiense causes an acute disease with a shortened first and second stage in Eastern and Southern Africa that can be fatal within weeks to months of infection. However, there are just a few number of medications available, and they have been around for anywhere from 20 to 80 years. The emergence of treatment resistance would be disastrous for the ongoing care of the condition and would halt the disease's current declining trend in prevalence. Depending on the stage of the infection, six main medications are available for the treatment of HAT: pentamidine, suramin, melarsoprol, eflornithine, nifurtimox/eflornithine combination therapy (NECT), and fexinidazole. The Amino Acid Transporter (AATT)-rich regions of Trypanosoma DNA are disrupted by pentamidine's method of action, which also suppresses mitochondrial function. Pentamidine was the first antiprotozoal diamidine to be commonly used for human african trypanosomiasis (HAT) treatment. Pentamidine resistance has been connected to modifications in the drug's transmembrane transport, namely high-affinity pentamidine transporter 1 (HAP1) and Trypanosoma brucei adenosine transporter 1/purine 2 (TbAT1/P2). Aquaglyceroporin transporters 2/3 (AQP2/3) in trypanosomes have been linked to resistance to the arsenical medication melarsoprol. Nifurtimox/eflornithine combination therapy (NECT), which has low toxicity and a short therapeutic time, has become more popular due to resistance, albeit weekly intravenous infusions have proven difficult in places with limited resources. For stage 1 disease pentamidine is given, usually by intramuscular injection, with once-daily 4 mg kg-1 dosing for 7 days. suramin is usually given by slow intravenous injection every 3–7 days, to a total of five dosings over a 4-week period. For stage 2 disease, melarsoprol is administered intravenously in a 3.6% solution in propylene glycol, typically every day for 10 days (although earlier schedules involved inclusion of interrupted courses lasting a month). Eflornithine as monotherapy, is given over 14 days with four 100 mg kg-1 intravenous infusions per day. When used in the nifurtimox-eflornithine combination therapy (which is occurring with increasing frequency) eflornithine doses are halved (200 mg/kg twice per day for 7 days) with nifurtimox being given orally three times a day for 10 days. The protocols required to sustain these recommended administration parameters are complex and can inevitably be compromised in some instances leading to treatment failure and possibly even promoting selection of resistance.Therefore, the pharmacokinetic characteristics of antitrypanosomal medications are also very important to their activity. In the end, parasites need to be exposed to drugs in order to become active at deadly levels for long enough to have a trypanocidal impact. Pharmacokinetics is even more crucial in stage 2 HAT because medications must get to parasites in the central nervous system CNS and other favored body compartments. Correct diagnosis of whether the disease is in stage 1 or stage 2 is crucial but challenging because different treatments have different capacities to distribute to these compartments.

Drug Resistance in African Animal Trypanosomiasis
The emergence of drug-resistant trypanosome strains is considered a serious problem in trypanosomiasis control particularly for the resource-poor, at-risk populations and farmers in Africa. The presence of indiscriminate drug utilization practices and subsequent complaints over the efficacy of the available trypanocidal drugs supplemented the presence of resistant strains Less research have examined how drug-resistant trypanosomes affect the production of animals. Yet, it is crucial to evaluate the problem's distribution as well as the obstacles that prevent the disease from being effectively controlled and its economic impact. The problem of drug resistance in animal trypanosomosis is highly spreading geographically to many regions where the disease occurs The removal of trypanosomes that are resistant to a low dose of a trypanocide by a greater dose of the same substance appears to be the first stage in the development of resistance. The primary methods of treating the illness are chemotherapy and chemoprophylaxis. DIM derivatives, suramin, quinapyramine, homidium, ISMM, and pyrithidium are the substances frequently used for treating or preventing animal trypanosomosis. .

Diminazene Aceturate
It is the only trypanocidal drug used against Babesia spp. It is one of the most commonly used trypanocide drug. In 1955, diminazene was made available as a trypanocide for domestic livestock. Nonetheless, preliminary research indicated that the substance was quite effective against trypanosome and Babesia species

. .This might be because it has a lower incidence of toxicity than other trypanocides and a higher therapeutic index in most cattle, and being active against trypanosomes that are resistant to other trypanocides used in cattle The recommended therapeutic dose is 3·5 mg kg−1 body weight for AAT due to T. congolense and T. vivax (7 mg kg−1 may be recommended against resistant isolates) and 7 mg kg−1 is indicated for AAT due to T. brucei and for surra, administered by intramuscular or subcutaneous injection Diminazene is only applied as a curative agent and is not used for prophylaxis, as it is rapidly metabolized and excreted Diminazene residues may persist for several weeks in the edible tissues of cattle and other food-producing animals, especially in the liver and kidney, whereas the drug levels in milk peak at 6 hours  and fall to below detection limits after 48 hours. For this reason it is advised that cattle and sheep destined for human consumption are subject to a 21–35 days pre-slaughter withdrawal from drug, while a 3-day milk withdrawal period is recommended

Isometamidium Chloride
For the treatment of Trypanosoma congolense infections in cattle, isometamidium chloride (Samorin R, RMB Animal Health Ltd.) is one of the top medications used both therapeutically and preventatively. Cattle have complete prophylaxis for 4 months after receiving an intramuscular (IM) injection of 1.0 mg kg-1 isometamidium chloride against fully sensitive trypanosome populations. While several hypothesized theories from experimental finding results, the mechanism of resistance to isometamidium chloride is less apparent. Populations of T. congolense that are resistant to drugs show lower levels of drug accumulation According to Peregrine et al. (1997), resistance to isometamidium is mostly linked to cross-resistance to homidium, leading one to hypothesize that two structurally comparable drugs may share an absorption mechanism while having slightly different distributions within trypanosomes. Homidium is significantly more widely distributed throughout the trypanosome, whereas isometamidium is primarily concentrated in the kinetoplast

Conclusion
The fact that treated animals may have relapse following chemotherapy is one effect of medication resistance to trypanosomes. However, not all relapses can be attributable to resistance; some may occur as a result of underdosing, reinfection, or the trypanosomes emerging from tissues outside the range of the trypanocidal medication. The final point is especially important for members of the Trypanozoon subgenus, such as T. evansi, because these trypanosomes are known to localize in extra-vascular tissues, including the central nervous system (CNS), particularly in the course of an infection. Also, farmers should avoid treating the animals themselves without the aid of a veterinary doctor, so as to avoid under dosing ,overdosing and buildup of resistance.