Typhoid Fever
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- ItemRestrictedInvestigating effects of topoisomerase mutations on topoisomerase-ciprofloxacin interaction in Salmonella typhi isolated in Blantyre(Kamuzu University of Health Sciences, 2021-09-20) Matambo, ErnestIntroduction:: Typhoid fever accounts for about 135, 000 deaths in adults and children in south Asia, central and southern Africa. The recommended antibiotic treatment of typhoid fever in Malawi is the fluoroquinolone ciprofloxacin, however, Salmonella enterica subspecies enterica serovar Typhi (S. Typhi) decreased susceptibility to ciprofloxacin has been detected in Blantyre, Malawi. S. Typhi can become resistant to fluoroquinolones by two mechanisms; either due to the acquisition of plasmid mediated resistance genes or mutations in gyrA, gyrB, parC and parE genes in topoisomerase II and IV. This study will use in silico methods to identify mutations in gyrA, gyrB, parC and parE genes in S. Typhi from Blantyre and to investigate the effects of topoisomerase II and IV mutations on topoisomerase-ciprofloxacin interaction. Main objective:: To investigate the effect of gyrA, gyrB, parC and parE mutations on ciprofloxacintopoisomerase interaction in S. Typhi isolated in Blantyre. Specific objectives: i. To identify mutations in Quinolone Resistance Determining Region of S. Typhi with decreased ciprofloxacin susceptibility isolated in Blantyre ii. To describe effects of mutations in gyrA, gyrB, parC and parE genes on their protein structure in S. Typhi with decreased ciprofloxacin susceptibility isolated in Blantyre iii. To compare folding energy of topoisomerase protein structure of S. Typhi with decreased ciprofloxacin susceptibility to topoisomerase protein structure of ciprofloxacin-sensitive S. Typhi iv. To compare ciprofloxacin-topoisomerase interaction in topoisomerase of S. Typhi with decreased ciprofloxacin susceptibility to ciprofloxacin-sensitive S. Typhi Methodology:: This will be a retrospective study. Reads of S. Typhi with reduced susceptibility to ciprofloxacin (n=14) and of ciprofloxacin sensitive S. Typhi (n=14) will be assembled using de novo assembly. Topoisomerase II and IV genes will then be extracted from the assembled genomes. Topoisomerase II and IV gene mutations will be identified in the genomes of S. Typhi with decreased susceptibility to ciprofloxacin by comparing the gene sequences to the CT18 reference genome. The topoisomerase II and IV gene sequences will be translated into protein sequences and then their protein structures predicted. The protein structures will be analysed for structural differences in the S. Typhi with decreased ciprofloxacin susceptibility and ciprofloxacin-sensitive S. Typhi. Folding energy between S. Typhi with decreased ciprofloxacin susceptibility and ciprofloxacin-sensitive S. Typhi protein structures will be compared. Bonding energy with ciprofloxacin between the two groups of protein structures will also be compared. Expected findings and their dissemination Expected findings are that there will be mutations in topoisomerase II and IV gene sequences and that the mutations will be in the ciprofloxacin binding pockets of the predicted protein structures in the S. Typhi with decreased ciprofloxacin susceptibility. Folding energy is expected to be low in protein structures without mutations as compared to protein structures with mutations. Protein structures with mutations will have high binding energy as compared to those without mutations. The study findings and write up will be submitted to COMREC, Kamuzu University of Health Sciences Library and to a peer-reviewed journal for publication.
- ItemRestrictedAn Investigation of Factors Associated With Recurring Typhoid Fever Epidemics in Neno by Treza Laston(2022-03-10) Laston, TrezaProblem: Typhoid fever is endemic in Malawi with more than 16,000 cases per year nationwide. Malawi’s burden of typhoid is most heavily borne by children under 15 years of age. Available data shows a rise in cases following an increase in drug resistance. While typhoid is rarely fatal, the recovery is long and difficult. The disease takes time, money, and productivity from those infected and their families, and is associated with numerous, long term complications. Starting in 2013, the incidence of typhoid has significantly increased in Malawi. Neno district in Southern Malawi with a total population of about 150,000 people has experienced recurring typhoid fever epidemics. On May 2, 2009, an outbreak of typhoid fever began in rural villages along the Malawi- Mozambique border resulting in 748 illnesses and 44 deaths by September 2010. Another outbreak was reported in Neno District as reported by Nyasa Times claiming five lives and 56 suspected cases with 41 confirmed positive. Despite numerous interventions done by the Ministry of Health including distribution of Water Guard (WG) for in-home water treatment, education on safe drinking water, hand washing, personal hygiene and food safety, cases of typhoid fever have continued. This study will investigate factors associated with recurring typhoid fever epidemics in Neno and why it has affected the same district/area.
- ItemRestrictedVacc-iNTS Invasive Non-Typhoidal salmonellosis cost of illness study and cost effectiveness(Kamuzu University of Health Sciences, 2021-03-15) Gordon, MelitaType of research: This is a cost of illness and cost of effective analysis study. It is a prospective facility-based cohort study to determine the individual, healthcare provider, and societal economic burden of non-invasive typhoidal Salmonella (iNTS). This is a multisite study in Sub-Saharan Africa that includes Malawi, Burkina Faso Ghana. Problem : iNTS disease poses a substantial economic burden on poor families as well as depletes already limited health care resources. Economic burden of iNTS disease can be better understood by cost of illness (COI) studies and the lack of iNTs Typhoid Fever (TF) COI data is considered a major knowledge gap. As such, data from this study is essential for measuring the cost-effectiveness of vaccination or other disease preventative interventions which will help set priorities, guide policies, and allocate resources accordingly. Objectives: The primary objectives of this study is are to estimate the cost of illness of laboratory confirmed iNTS disease. and to estimate the cost effectiveness of GMMA-based iNTS vaccine introduction in Ghana, Burkina Faso and Malawi. Secondary objectives will estimate the excess costs of drug resistant iNTS disease in comparison with drug susceptible iNTS . and to estimate the cost effectiveness of GMMA-based iNTS vaccine introduction in Ghana, Burkina Faso and Malawi. Methodology There are two health economic components under proposed COI study, health facility costing and patient out of pocket costing (Figure 1). The health facility costing will be a one-time activity, whereas patient out of pocket costing will involve prospective follow-up with a serial cross-sectional survey of incident cases. These health economic studies are embedded into existing iNTS case surveillance and will use the same platform set-up for surveillance. The COI study will involve recruitment of blood culture confirmed iNTS cases. Consented laboratory confirmed blood culture positive cases will be enrolled soon after their blood culture results are available. At the time of first COI survey contact, cases will be interviewed after providing written informed consent to collect their expenditures and loss of income until the previous day. A second interview will be conducted between 10-20 days from the blood sample collection day to collect subsequent costs and loss of income. If the subject continues to feel sick, a third interview will be conducted 4 weeks from the blood sample collection day (day 28-30). We expect that most subjects will have 2 to 3 interviews, however if subjects continue to be sick, the last interview will be collected on 90th day. Expected findings and dissemination The International Vaccine Institute(IVI) will prepare one or more summary manuscripts reporting cost of illness of laboratory confirmed cases (iNTS) along with country investigators. Authorships and their order will be determined based on individual contributions to the study. Site investigators will be included as co-authors in order decided by their contributions. Following the publication of an initial article the project’s principal investigator and project coordinator will discuss publication scenarios with site representatives, help identify the lead scientists who will be responsible for drafting of the manuscript and provide scientific oversight for each possible publication. Authorships and their order will be determined based on individual contributions to the studies. Research findings will be disseminated locally through scientific group meetings, research and group meetings, research and progress meetings at the College Of medicine and MLW and nationally through the annual College of Medicine research dissemination conference. Results will also be reported to College of Medicine Research Ethics Committee (COMREC). Peer reviewed publication of findings is anticipated. We anticipate the following constraints in the study: Delay in completing the planned activities on time due to travel restriction or general hindrance caused by the COVID-19 situation, slow enrolment due to insufficient number of iNTS disease cases or in general we may have too few cases and if COVID-19 continues into 2021 study staff visiting and interviewing patients may be at risk.