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The Challenge of Parasite Control
Published in Eric S. Loker, Bruce V. Hofkin, Parasitology, 2023
Eric S. Loker, Bruce V. Hofkin
Anti-malaria treatment and prophylaxis have a long history (Figure 9.17). Today, one of the most frequently used antimalarial drugs for prophylaxis is a combination of atovaquone and proguanil, known commercially as Malarone®. Atovaquone is a ubiquinone analog, which preferentially inhibits the electron transport chain in Plasmodium and other apicomplexans. Laboratory results demonstrate that it is 200 times more active against the Plasmodium electron transport chain than it is against that of mammals, presumably because of differences in the electron transport chain components of apicomplexans and vertebrates. Thus, with a high therapeutic index, atovaquone is reasonably safe to use. Proguanil is metabolized within the host to cycloguanil, which inhibits dihydrofolate reductase, an enzyme involved in the conversion of dihydrofolate into tetrahydrofolate, a required step ultimately leading to the production of thymidine nucleotides. As such, proguanil inhibits nucleic acid synthesis. Its relative safety may result from its preferential inhibition of the parasite enzyme.
A Pharmacological Appraisal of Antimalarial Plant Species
Published in Namrita Lall, Medicinal Plants for Cosmetics, Health and Diseases, 2022
Mahwahwatse J. Bapela, Precious B. Ramontja, Mcebisi J. Mabuza
Antifolates include two classes of antimalarial drugs that interfere with folate metabolism, a pathway essential for DNA replication and protein synthesis of malaria parasites. They specifically target two enzymes involved in the biosynthesis of tetrahydrofolate, the dihydropteroate synthase (DHPS) and dihydrofolate reductase (DHFR) (Rudrapal, 2011). Sulphonamides, sulphadoxine (Figure 18.3), sulphones, dapsone and sulphalene act as competitive inhibitors against DHPS, thereby preventing the formation of dihydropteroate. The second class includes proguanil, chloroproguanil, cycloguanil and pyrimethamine, which inhibit DHFR, consequently preventing the reduction of dihydrofolate (DHF) to tetrahydrofolic acid (THF). The combination of both classes of antifolates proved to have a synergistic effect against malaria, though clinical resistance developed quickly, compromising their use in many malaria-endemic areas (Heinberg and Kirkman, 2015). Atovaquone (Figure 18.3) is a hydroxynaphthoquinone that is used in combination with proguanil for prophylaxis and therapy of asymptomatic malaria. It is active against all Plasmodium species, inhibiting the exoerythrocytic stage in humans and the oocyst development in the mosquitoes. It acts by inhibiting the mitochondrial electron transport chain, thereby leading to a breakdown of the mitochondrial membrane potential (Barton et al., 2010). The prevalence of mutations of the cytochrome b gene has resulted in therapy failure of atovaquone (Siregar et al., 2015).
Atovaquone
Published in M. Lindsay Grayson, Sara E. Cosgrove, Suzanne M. Crowe, M. Lindsay Grayson, William Hope, James S. McCarthy, John Mills, Johan W. Mouton, David L. Paterson, Kucers’ The Use of Antibiotics, 2017
Reports of the potency of atovaquone against other microorganisms followed soon after its initial development as an anti-malarial agent. The first such reports concerned Pneumocystis jirovecii (Hughes et al., 1990) and documented its successful use for treatment of human immunodeficiency virus (HIV)–infected Pneumocystis jirovecii pneumonia (PCP) patients (Dohn et al., 1991) and in patients with Toxoplasma gondii infection (Araujo et al., 1991). Subsequently, useful activity was reported against Leishmania donovani infection (Croft et al., 1992), babesiosis (Hughes and Oz, 1995), and micro-sporidiosis (Anwar-Bruni et al., 1996). However, there are suggestions that resistance to atovaquone may also develop in these infections (Pfefferkorn et al., 1993; Walker and Meshnick, 1998; Baatz et al., 2006).
Management strategies for human babesiosis
Published in Expert Review of Anti-infective Therapy, 2020
Robert P. Smith, Klaus-Peter Hunfeld, Peter J Krause
About three quarters of patients on clindamycin and quinine develop side effects, especially nausea, gastrointestinal upset, transient or permanent hearing impairment, vertigo, and QTc prolongation [37,38,62,96]. These effects can be so severe that the regimen has to be discontinued or the dosage decreased in about a third of those on the combination [34]. Typical adverse effects associated with atovaquone and azithromycin include diarrhea, nausea, transaminase elevations, headache, and rash. Dose dependent reversible hearing impairment has been reported, and rarely, QTc prolongation [37,96]. Uncommonly, antimicrobial failure may result from development of resistance to azithromycin and atovaquone while on long-term therapy [41–43,64,78]. The genetic causes of resistance to atovaquone and to azithromycin have been identified [43,44]. Because humans are dead end hosts and natural hosts are not treated with antibiotic, it is unlikely resistance will increase over time. It is important to emphasize that the development of resistance to single antimicrobials demonstrates that monotherapy should be avoided if possible. Development of resistance to atovaquone and azithromycin requires a change to clindamycin and quinine or to empiric regimens with other antimicrobial agents. These include, (i) atovaquone plus azithromycin plus clindamycin, (ii) atovaquone plus clindamycin, (iii) atovaquone/proguanil plus azithromycin, and (iv) atovaquone plus azithromycin plus clindamycin plus quinine. There are limited data to support the use of these combinations [41].
Malaria medicines to address drug resistance and support malaria elimination efforts
Published in Expert Review of Clinical Pharmacology, 2018
Jane Achan, Julia Mwesigwa, Chinagozi Precious Edwin, Umberto D’alessandro
Historically, the response to a failing first-line treatment has been changing the national treatment policy to an alternative treatment or creation of subnational treatment policies. More recently, this approach has been used to varying degrees of success in response to artemisinin resistance. In 2012, dihydroartemisinin-piperaquine (DP) replaced artesunate-mefloquine as the first-line therapy for both P. falciparum and P. vivax malaria in Cambodia, except in Pailin where, given the poor DP efficacy [68], atovaquone-proguanil (AP) was selected for P. falciparum malaria [69]. In southeastern Thailand, AP was also used on a wide scale to temporarily reduce artemisinin drug pressure given its documented good efficacy and safety profile [70]. However, this may not have been a good choice given previously well-documented resistance to atovaquone in this area [71] that would impact on the long-term therapeutic efficacy of AP. In such scenarios, continuous surveillance is necessary to monitor drug efficacy and ensure that early signals of resistance are detected given the potential similarities in mechanisms of action of the selected drugs and those for which resistance has been reported.
Pneumocystis jirovecii: a review with a focus on prevention and treatment
Published in Expert Opinion on Pharmacotherapy, 2021
R. Benson Weyant, Dima Kabbani, Karen Doucette, Cecilia Lau, Carlos Cervera
The largest advantage of atovaquone is its favorable side-effect profile when compared to other anti-pneumocystis drugs. For one, it is safe to use in those with G6PD deficiencies and it also provides prophylaxis against toxoplasmosis. Common adverse effects of atovaquone are rash, headache, GI upset, and rarely elevation of hepatic transaminases. Importantly, atovaquone does not cause marrow suppression or hemolysis. The bioavailability of atovaquone is doubled when ingested with fatty foods and patients should be counseled on this [64]. Similarly, the drug may be less effective in patients with GI conditions or transplant patients with intestinal graft-versus-host disease.