The Challenge of Parasite Control
Eric S. Loker, Bruce V. Hofkin in Parasitology, 2023
Drug resistance emerges when drug use creates an environment for the pathogen that favors the selection of resistance. Similarly, drug resistance can be reversed when we create environments in which such resistance loses its selective advantage. The example of chloroquine use in the central African nation of Malawi is illustrative. Owing to heavy chloroquine use, the prevalence of the resistant PfCRT genotype in P. falciparum reached 85% in 1992. In 1993, chloroquine was removed from the market in Malawi because of its limited efficacy. After chloroquine was withdrawn, chloroquine-resistant parasites then lost their selective advantage over sensitive strains and a decline in resistance ensued. By 2000, the prevalence of the resistant genotype was only 13%. These promising results have since been mirrored in a number of other African countries from which chloroquine was withdrawn between 1998 and 2008. Figure 9.23 highlights one such example.
Treatment and prevention of malaria
David A Warrell, Herbert M Gilles in Essential Malariology, 2017
Recently, there has been renewed interest in the idea of using antimalarial drugs in combination. There is an obvious parallel with developments in the chemotherapy of tuberculosis (TB) and cancer, for which monotherapy resulted in the rapid development of drug resistance. The theory is based on the concept that drug resistance in infecting organisms arises from the selection of mutations in functional genes as a direct consequence of exposure of microbe populations to the drug. Where two drugs with different mechanisms of action are used together, the chance of a double mutation arising, and being selected, is far lower than the chance of selection of the individual mutations. This theory assumes that resistance to all antimalarial drugs is essentially mutation-dependent, but that it is not necessary to define the precise mutations involved. In TB and cancer chemotherapy this concept is paramount, and characterizes all treatments. In malaria chemotherapy, the threat of resistance was appreciated almost 100 years ago and the concept of combination therapy promoted, notably by Wallace Peters, but, for various reasons, this has so far not been successfully implemented.
Colonization, Infection, and Resistance in the Critical Care Unit
Cheston B. Cunha, Burke A. Cunha in Infectious Diseases and Antimicrobial Stewardship in Critical Care Medicine, 2020
Sixty-five percent of all healthcare-associated infections (HAIs) occur in the CCU [10]. In the CCU, colonization with healthcare-associated pathogens such as Staphylococcus aureus, enterococci, gram-negative organisms, and Clostrioides difficile is associated with increased risk of infection. In addition, hospitalized patients in the CCU are at higher risk of colonization with multidrug-resistant (MDR) pathogens. Infections caused by MDR pathogens are associated with worse patient outcomes, including increased morbidity, mortality, healthcare costs, and increased hospital lengths of stay when compared with infections by more drug-sensitive pathogens [11]. Methicillin-resistant Staphylococcus aureus (MRSA), vancomycin-resistant Enterococcus (VRE), and MDR gram-negative bacteria (MDR-GN), including extended spectrum beta-lactamase-producing Enterobacteriaceae (ESBL), carbapenem-resistant Enterobacteriaceae (CRE), MDR Pseudomonas, and MDR Acinetobacter, have been the most commonly drug-resistant pathogens reported in the United States [12]. In a large point-prevalence study from around the world, MDR-GN now account for 62% of CCU infections [7].
Pharmacotherapy for artemisinin-resistant malaria
Published in Expert Opinion on Pharmacotherapy, 2021
Erik Koehne, Ayola Akim Adegnika, Jana Held, Andrea Kreidenweiss
Antimicrobial drug resistance is usually understood as the occurrence of bacteria, viruses, pathogens, etc. that evade killing or attenuation by a chemotherapeutic drug and continue to survive and propagate in the infected individual, maintaining the presence of the potential disease (based on the assumption of adequate dosing, pharmacokinetics, initial parasite biomass, and accounting for reinfection). The first observations of artemisinin resistance were made in 2008 in Cambodia [13,14] when the time to P. falciparum clearance following seven days artesunate monotherapy was prolonged beyond three days and some malaria patients were still parasitemic on day 28 follow-up, although most patients were cured. The WHO defines clinical artemisinin resistance as ‘delayed parasite clearance following treatment with an artemisinin-based monotherapy or with an artemisinin-based combination therapy’ [8]. This is also labeled as ‘artemisinin partial resistance’ and is suspected when 10% (or more) of malaria patients present with a parasitemia at day three or have a parasite clearance half-life beyond five hours. However, this clinical phenotype does not necessarily lead to a treatment failure commonly assessed 28 or 42 days after treatment start (timing depends on the half-life of the ACT partner drug). A failure following ACT treatment rather occurs because of an underlying resistance to the ACT partner drug that may or may not be accompanied by a partial artemisinin resistance event in the circulating P. falciparum strains [15].
Intratumoral Pi deprivation benefits chemoembolization therapy via increased accumulation of intracellular doxorubicin
Published in Drug Delivery, 2022
Yang-Feng Lv, Zhi-Qiang Deng, Qiu-Chen Bi, Jian-Jun Tang, Hong Chen, Chuan-Sheng Xie, Qing-Rong Liang, Yu-Hua Xu, Rong-Guang Luo, Qun Tang
Drug resistance is a complex phenomenon that can result from numerous mechanisms. Elevated efflux of anticancer agents by ATP-dependent pumps decreased intracellular drug accumulation, which has been the major reason for resistance of tumors, including HCC, to chemotherapy (Lockhart et al., 2003; Marin et al., 2009; Bar-Zeev et al., 2017; Marin et al., 2020). The resistance caused by abnormally high rates of drug efflux could be either intrinsic or acquired after drug administration. Those pumps responsible for drug efflux are transmembrane transporters, primarily from the ATP binding cassette (ABC) transporter superfamily, such as P-glycoprotein (P-gp; ABCB1; MDR1), breast cancer resistance protein (BCRP; ABCG2), and multidrug resistance-associated protein 1 (MRP1; ABCC1). Specifically, in the case of HCC, all three of these proteins are indicative of HCC progression, and inhibition of their expression contributes to better chemotherapy (Huang et al., 1992; Soini et al., 1996; Nies et al., 2001; Vander Borght et al., 2008; Sukowati et al., 2012; Huang et al., 2013). Targeting these transporters has been proposed for decades but is still far from being applied to the bedside.
Insights into apoptotic proteins in chemotherapy: quantification techniques and informing therapy choice
Published in Expert Review of Proteomics, 2018
Mechanisms mediating drug resistance are multifaceted. Rapid developments in proteomic technologies enabled to simultaneously identify multiple proteins in drug-resistant cancers [58,59]. Therapy resistance is often associated with an impaired ability of cancer cells to undergo apoptosis. Hence, understanding the molecular mechanisms of apoptosis induction and their modes of impairment may be useful to develop novel strategies to improve treatment outcomes. The precise estimation of a patient’s tumor sensitivity to apoptosis is, however, difficult to attain. ‘Redundant’ signaling molecules, alternative pathway branches and feedback or feed-forward loops challenge our understanding of whether and how deficiencies in genes and proteins impact apoptosis signaling. Similarly, patient-specific genetic or epigenetic factors and the tumor’s microenvironment complicate prediction of therapy responses in individual patients.
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