-
International Journal of Antimicrobial... Mar 2024India is on track to eliminate malaria by 2030 but emerging resistance to first-line antimalarials is a recognised threat. Two instances of rapid development, spread,... (Meta-Analysis)
Meta-Analysis
BACKGROUND
India is on track to eliminate malaria by 2030 but emerging resistance to first-line antimalarials is a recognised threat. Two instances of rapid development, spread, and natural selection of drug-resistant mutant parasites in India (chloroquine across the country and artesunate + sulfadoxine-pyrimethamine [AS+SP] in the northeastern states) translated into drug policy changes for Plasmodium falciparum malaria in 2010 and 2013, respectively. Considering these rapid changes in the SP drug resistance-conferring mutation profile of P. falciparum, there is a need to systematically monitor the validated mutations in Pfdhfr and Pfdhps genes across India alongside AS+SP therapeutic efficacy studies. There has been no robust, systematic countrywide surveillance reported for these parameters in India, hence the current study was undertaken.
METHODS
Studies that reported data on WHO-validated SP resistance markers in P. falciparum across India from 2008 to January 2023 were included. Five major databases, PubMed, Web of Science, Scopus, Embase, and Google Scholar, were exhaustively searched. Individual and pooled prevalence estimates of mutations were obtained through random- and fixed-effect models. Data were depicted using forest plots created with a 95% confidence interval. The study is registered with PROSPERO (CRD42021236012).
RESULTS
A total of 37 publications, and 533 Pfdhfr and 134 Pfdhps National Centre of Biotechnology Information (NCBI) DNA sequences were included from >4000 samples. The study included information from 80 districts, 21 states and 3 union territories (UTs) from India. The two PfDHFR mutations, C59R (62%) and S108N (74%), were the most prevalent mutations (pooled estimates 61% and 71%, respectively) and appeared to be stabilised/fixed. Although rarest overall, the prevalence of I164L was observed to be as high as 32%. The PfDHFR double mutants were the most prevalent overall (51%; pooled 42%). The prevalence of triple and quadruple mutations was 6% and 5%, respectively, and is an immediate concern for some states. The most prevalent PfDHPS mutation was A437G (39%), followed by K540E (25%) and A581G (12%). There was a low overall prevalence of PfDHFR/PfDHPS quintuple and sextuple mutations but surveillance for these mutations is critical for some areas.
CONCLUSION
The analyses span the two critical policy changes, highlight the areas of concern, and guide policymakers in strategising and refining the anti-malaria drug policy for malaria elimination. The results of the analyses also highlight the SP-resistance hot spots, critical gaps and challenges, and indicate that focal and local malaria genetic surveillance (including drug-resistance markers) is needed until malaria is successfully eliminated.
Topics: Humans; Plasmodium falciparum; Pyrimethamine; Malaria, Falciparum; Antimalarials; India; Artesunate; Drug Combinations; Sulfadoxine
PubMed: 38154659
DOI: 10.1016/j.ijantimicag.2023.107071 -
Journal of Parasitic Diseases :... Jun 2024Toxoplasmosis, caused by , is a zoonotic disease that affects a wide range of warm-blooded animals, including humans. The parasite undergoes both sexual and asexual... (Review)
Review
Toxoplasmosis, caused by , is a zoonotic disease that affects a wide range of warm-blooded animals, including humans. The parasite undergoes both sexual and asexual reproduction in intermediate hosts (humans and animals) and definitive hosts (cats). Transmission in humans occurs through consuming oocyst-contaminated water, fruits, vegetables, and raw or undercooked meats. In Bangladesh, several factors contribute to an increased risk of contracting toxoplasmosis. The parasite is reported to cause diseases among livestock such as goats and sheep in this country, and it has also been associated with some human illnesses. Toxoplasmosis prevalence varies significantly worldwide, with developing countries like Bangladesh experiencing higher rates. Diagnostic methods include both conventional non-DNA-based tests and molecular detection techniques, while treatment options involve using antiparasitic drugs like sulfadiazine and pyrimethamine. To control toxoplasmosis, essential steps include improving sanitation, promoting safe food handling, and educating the public about risks related to cat ownership and undercooked meat consumption. Implementing prenatal screening and treatment is also important. With the growing popularity of pet ownership in urban areas, it becomes essential to emphasize the veterinary and public health significance of toxoplasmosis in Bangladesh. This article comprehensively reviews various aspects of toxoplasmosis, with a specific focus on the situation in Bangladesh.
PubMed: 38840887
DOI: 10.1007/s12639-024-01664-4 -
Eye (London, England) May 2024Ocular toxoplasmosis is the most common cause of infectious posterior uveitis. Available literature is still conflicting regarding the incidence of recurrence during... (Review)
Review
Ocular toxoplasmosis is the most common cause of infectious posterior uveitis. Available literature is still conflicting regarding the incidence of recurrence during pregnancy as various calculations were employed in the different published studies. Although earlier reports have suggested a difference in presentation and an increase in severity during pregnancy, newer studies appear to show otherwise. Further diagnostic testing, including serologic and intraocular fluid sampling, may be indicated to increase the diagnostic accuracy in this special population of patients. The management of ocular toxoplasmosis during pregnancy is challenging as the foetus is additionally considered in the choice of treatment. Traditionally preferred anti-toxoplasmosis regimens containing antifolate drugs, such as pyrimethamine and trimethoprim-sulfamethoxazole, cannot be used routinely in pregnant patients, especially during the first trimester. This review includes literature on alternative treatments for ocular toxoplasmosis during pregnancy, including spiramycin and intravitreal treatment options.
Topics: Humans; Toxoplasmosis, Ocular; Pregnancy; Female; Antiprotozoal Agents; Pregnancy Complications, Parasitic; Pregnancy Complications, Infectious; Spiramycin; Anti-Bacterial Agents; Intravitreal Injections
PubMed: 38191658
DOI: 10.1038/s41433-023-02916-y -
Indian Journal of Public Health 2023Seasonal malaria chemoprevention (SMC) is an important public health intervention that is being used to reduce the burden of malaria in sub-Saharan Africa. (Review)
Review
BACKGROUND
Seasonal malaria chemoprevention (SMC) is an important public health intervention that is being used to reduce the burden of malaria in sub-Saharan Africa.
OBJECTIVES
This study aimed to evaluate the implementation of SMC and pharmacovigilance practices in under-five children in Kebbi State, Nigeria.
MATERIALS AND METHODS
The methodology involved a comprehensive review of tools for managing SMC commodities, training data collectors, and fieldwork to evaluate all local government area (LGA) stores, the central medical store (CMS), and selected health facilities based on the sample size determined. Data were collected using SurveyCTO software and analyzed using MS Excel. Twenty-one data reviewers visited the CMS, 21 LGA stores, and 315 health facilities.
RESULTS
Our study uncovered significant inaccuracies in documentation, which led to many commodities needing to be more effectively accounted for regarding sources. Data triangulation showed inconsistencies between tools and physical counts that do not match the quantities on inventory control cards. Most primary health-care (PHC) staff in charge of SMC have been formally trained in pharmacovigilance. About 75% (237) of PHCs referred cases of adverse drug reactions (ADRs) to a secondary health-care facility, while 14% (45) treated the symptoms of the ADR with another drug, and 7% (21) took no action, and the reaction resolved on its own.
CONCLUSIONS
This study provides insight into the challenges and opportunities for improving the implementation of SMC and pharmacovigilance practices in Kebbi State, Nigeria, and has important implications for other settings with similar challenges.
Topics: Child, Preschool; Humans; Infant; Antimalarials; Chemoprevention; India; Malaria; Nigeria; Pharmacovigilance; Seasons
PubMed: 37929374
DOI: 10.4103/ijph.ijph_577_23 -
Antimicrobial Agents and Chemotherapy Dec 2023Malaria molecular surveillance remains critical in detecting and tracking emerging parasite resistance to anti-malarial drugs. The current study employed molecular...
Malaria molecular surveillance remains critical in detecting and tracking emerging parasite resistance to anti-malarial drugs. The current study employed molecular techniques to determine species prevalence and characterize the genetic diversity of and molecular markers of sulfadoxine-pyrimethamine resistance in humans and wild mosquito populations in Cameroon. mosquito collections and parasitological survey were conducted in villages to determine species infection, and genomic phenotyping of anti-folate resistance was accomplished by sequencing the dihydrofolate-reductase () and dihydropteroate-synthase () genes of naturally circulating and isolates. The malaria prevalence in Elende was 73.5% with the 5-15 years age group harboring significant (27%) and (19%) infections. The polymorphism breadth of the pyrimethamine-associated marker revealed a near fixation (94%) of the triple-mutant -AI. The backbone mediating sulfadoxine resistance reveals a high frequency of the KAA alleles (20.8%). Similarly, the NKSSFI haplotype (78.4%) was predominantly detected in the asexual blood stage. In contrast, the - occured at 37.2% frequency. The combined quadruple NKSSFI_ KAA (31.9%) was the major circulating haplotype with similar frequency in humans and mosquitoes. This study highlights the increasing frequency of the parasite mostly common in asymptomatic individuals with apparent infection. Interventions directed at reducing malaria transmission such as the scaling-up of SP are favoring the emergence and spread of multiple drug-resistant alleles between the human and mosquito host systems.
Topics: Animals; Humans; Pyrimethamine; Sulfadoxine; Anopheles; Alleles; Cameroon; Antimalarials; Malaria, Falciparum; Drug Combinations; Plasmodium falciparum; Malaria; Drug Resistance; Tetrahydrofolate Dehydrogenase
PubMed: 37947766
DOI: 10.1128/aac.00588-23 -
International Journal of Antimicrobial... Jul 2023A major threat to the goal of eliminating malaria, particularly in Southeast Asia, is the spread of Plasmodium falciparum resistant to artemisinin-based combination...
A major threat to the goal of eliminating malaria, particularly in Southeast Asia, is the spread of Plasmodium falciparum resistant to artemisinin-based combination therapies. P218 is a drug candidate designed to combat antifolate-sensitive and -resistant parasites. However, there is no evidence that P218 is effective against artemisinin-resistant P. falciparum. This report investigated the susceptibilities of 10 parasite isolates from Southeast Asia to P218 and other antimalarial drugs. All isolates with different levels of artemisinin resistance were genetically distinct from one another, although common haplotypes associated with antimalarial resistance were identified. All isolates were highly resistant to pyrimethamine, and none of them were significantly less sensitive to P218 than the pyrimethamine-resistant laboratory strain V1/S. Significant differences in sensitivity to other types of antimalarials (mefloquine, atovaquone and chloroquine) compared with V1/S were found for some isolates, although the differences were not clinically relevant. P218 is thus efficacious against multi-drug (including artemisinin-resistant P. falciparum.
Topics: Humans; Antimalarials; Artemisinins; Drug Resistance; Folic Acid Antagonists; Malaria, Falciparum; Plasmodium falciparum; Pyrimethamine
PubMed: 37160237
DOI: 10.1016/j.ijantimicag.2023.106838 -
BMC Medical Genomics Jul 2023Despite advances in treatment, recurrence and mortality rates from breast cancer (BrCa) continue to rise, clinical effectiveness is limited, and prognosis remains...
BACKGROUND
Despite advances in treatment, recurrence and mortality rates from breast cancer (BrCa) continue to rise, clinical effectiveness is limited, and prognosis remains disappointing, especially for patients with HER2-positive, triple-negative, or advanced breast cancer. Based on cuproptosis-related long noncoding RNAs (CRLs), this study aims to create a predictive signature to assess the prognosis in patients with BrCa.
METHODS
The related CRLs RNA-seq data clinicopathological data were collected from The Cancer Genome Atlas (TCGA) database, and the predictive model was constructed after correlation analysis. Subsequently, we examined and validated connections and changes in the CRLs model with prognostic features (including risk curves, ROC curves and nomograms), pathway and functional enrichment, tumor mutation (TMB), tumor immune dysfunction and exclusion (TIDE) and treatment sensitivity.
RESULTS
A prediction model formula composed of 5 CRLs was obtained, and divided breast cancer patients into high and low risk subgroups according to the obtained risk scores. The results showed that the overall survival (OS) of patients in the high-risk group was lower than that in the low-risk group, and the AUC of all samples at 1, 3 and 5 years were 0.704, 0.668 and 0.647, respectively. It was indicated that CRLs prognostic model could independently predict prognostic indicators of BrCa patients. In addition, analysis of gene set enrichment, immune function, TMB, and TIDE showed that these differentially expressed CRLs had a wealth of related pathways and functions, and might be closely related to immune response and immune microenvironment. Additionally, TP53 was found to have the highest mutation frequency in high-risk group (40%), while PIK3CA was found to have the highest mutation frequency in low-risk group (42%), which might become new targets for targeted therapy. Finally, we compared susceptibility to anticancer agents to identify potential treatment options for breast cancer. Lapatinib, Sunitinib, Phenformin, Idelalisib, Ruxolitinib, Cabozantinib were more sensitive to patients in the low-risk group, while Sorafenib, Vinorelbine, Pyrimethamine were more sensitive to patients in high-risk group, namely, these drugs could potentially be used in the future to treat breast cancer patients grouped according to the risk model.
CONCLUSION
This study identified CRLs associated with breast cancer and provided a tailored tool for predicting prognosis, immune response, and drug sensitivity in patients with BrCa.
Topics: Humans; Female; Breast Neoplasms; RNA, Long Noncoding; Prognosis; Risk Factors; Immunity; Apoptosis; Tumor Microenvironment
PubMed: 37422644
DOI: 10.1186/s12920-023-01590-z -
RSC Medicinal Chemistry Feb 2024The emergence of drug resistance against the frontline antimalarials is a major challenge in the treatment of malaria. In view of emerging reports on drug-resistant...
The emergence of drug resistance against the frontline antimalarials is a major challenge in the treatment of malaria. In view of emerging reports on drug-resistant strains of against artemisinin combination therapy, a dire need is felt for the discovery of novel compounds acting against novel targets in the parasite. In this study, we identified a novel series of quinolinepiperazinyl-aryltetrazoles (QPTs) targeting the blood stage of . anti-plasmodial activity screening revealed that most of the compounds showed IC < 10 μM against chloroquine-resistant INDO strain, with the most promising lead compounds 66 and 75 showing IC values of 2.25 and 1.79 μM, respectively. Further, compounds 64-66, 68, 75-77 and 84 were found to be selective (selectivity index >50) in their action against over a mammalian cell line, with compounds 66 and 75 offering the highest selectivity indexes of 178 and 223, respectively. Explorations into the action of lead compounds 66 and 75 revealed their selective cidal activity towards trophozoites and schizonts. In a ring-stage survival assay, 75 showed cidal activity against the early rings of artemisinin-resistant Cam3.1. Further, 66 and 75 in combination with artemisinin and pyrimethamine showed additive to weak synergistic interactions. Of these two lead molecules, only 66 restricted rise in the percentage of parasitemia to about 10% in -infected mice with a median survival time of 28 days as compared to the untreated control, which showed the percentage of parasitemia >30%, and a median survival of 20 days. Promising antimalarial activity, high selectivity, and additive interaction with artemisinin and pyrimethamine indicate the potential of these compounds to be further optimized chemically as future drug candidates against malaria.
PubMed: 38389888
DOI: 10.1039/d3md00417a -
Tropical Medicine & International... Jun 2024Seasonal malaria chemoprevention using sulfadoxine-pyrimethamine plus amodiaquine (sulfadoxine-pyrimethamine plus amodiaquine on Day 1 and amodiaquine on both Day 2 and...
Impact of seasonal malaria chemoprevention based on the number of medicines doses received on malaria burden among children aged 3-59 months in Nigeria: A propensity score-matched analysis.
BACKGROUND
Seasonal malaria chemoprevention using sulfadoxine-pyrimethamine plus amodiaquine (sulfadoxine-pyrimethamine plus amodiaquine on Day 1 and amodiaquine on both Day 2 and Day 3) is delivered to children aged 3-59 months in areas of highly season malaria transmission. While the overall population-level impact of seasonal malaria chemoprevention on malaria control has been documented in various countries and time periods, there is no clear evidence regarding seasonal malaria chemoprevention impact based on the number of medicine doses children receive in one cycle in routine programmatic conditions.
METHODS
Data were extracted from Nigeria's routinely collected seasonal malaria chemoprevention end-of-round coverage surveys (2021, 2022). We matched seasonal malaria chemoprevention-targeted children who received specific numbers of seasonal malaria chemoprevention medicines with those who did not receive any doses of seasonal malaria chemoprevention medicines (non-sulfadoxine-pyrimethamine plus amodiaquine) using multiple sets of propensity score matches. We performed multilevel logistic regression for each matched group to evaluate the association between the number of doses of seasonal malaria chemoprevention medicines and monthly confirmed malaria cases (caregiver-reported malaria infection diagnosed by rapid diagnostic test at a health facility following the penultimate cycle of seasonal malaria chemoprevention).
RESULTS
Among 21,621 SMC-targeted children, 9.7% received non-sulfadoxine-pyrimethamine plus amodiaquine, 0.5% received only Day 1 sulfadoxine-pyrimethamine plus amodiaquine, 1.0% received Day 1 sulfadoxine-pyrimethamine plus amodiaquine and either Day 2 amodiaquine or Day 3 amodiaquine (sulfadoxine-pyrimethamine plus amodiaquine + amodiaquine), and 88.8% received Day 1 sulfadoxine-pyrimethamine plus amodiaquine and both Day 2 and Day 3 amodiaquine (sulfadoxine-pyrimethamine plus amodiaquine + amodiaquine + amodiaquine). Children receiving only Day 1 sulfadoxine-pyrimethamine plus amodiaquine did not have significant lower odds of rapid diagnostic tests-confirmed malaria than those receiving non-sulfadoxine-pyrimethamine plus amodiaquine (OR 0.77, 0.42-1.42). However, children receiving sulfadoxine-pyrimethamine plus amodiaquine + amodiaquine had significantly lower odds of rapid diagnostic tests-confirmed malaria than those receiving non-sulfadoxine-pyrimethamine plus amodiaquine (OR 0.42, 95% CI 0.28-0.63). Similarly, children receiving sulfadoxine-pyrimethamine plus amodiaquine + amodiaquine + amodiaquine also had significantly lower odds of rapid diagnostic test-confirmed malaria than those receiving non-sulfadoxine-pyrimethamine plus amodiaquine (OR 0.54, 95% CI 0.47-0.62).
CONCLUSION
Adherence to at least one daily dose of amodiaquine administration following receipt of Day 1 sulfadoxine-pyrimethamine plus amodiaquine by eligible children is crucial to ensure the effectiveness of seasonal malaria chemoprevention. This demonstrates the importance of enhancing caregiver awareness regarding the importance of amodiaquine and identifying barriers toward amodiaquine administration at the community level.
PubMed: 38842452
DOI: 10.1111/tmi.14019 -
Acta Crystallographica. Section D,... Aug 2023Candida auris has emerged as a global health problem with a dramatic spread by nosocomial transmission and a high mortality rate. Antifungal therapy for C. auris...
Candida auris has emerged as a global health problem with a dramatic spread by nosocomial transmission and a high mortality rate. Antifungal therapy for C. auris infections is currently limited due to widespread resistance to fluconazole and amphotericin B and increasing resistance to the front-line drug echinocandin. Therefore, new treatments are urgently required to combat this pathogen. Dihydrofolate reductase (DHFR) has been validated as a potential drug target for Candida species, although no structure of the C. auris enzyme (CauDHFR) has been reported. Here, crystal structures of CauDHFR are reported as an apoenzyme, as a holoenzyme and in two ternary complexes with pyrimethamine and cycloguanil, which are common antifolates, at near-atomic resolution. Preliminary biochemical and biophysical assays and antifungal susceptibility testing with a variety of classical antifolates were also performed, highlighting the enzyme-inhibition rates and the inhibition of yeast growth. These structural and functional data might provide the basis for a novel drug-discovery campaign against this global threat.
Topics: Humans; Antifungal Agents; Candida auris; Tetrahydrofolate Dehydrogenase; Folic Acid Antagonists; Microbial Sensitivity Tests; Candidiasis, Invasive; Saccharomyces cerevisiae
PubMed: 37428844
DOI: 10.1107/S2059798323004709