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- Brown, Nick, 1961-
(författare)
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Unresolved Controversies in Child Pneumonia in low and middle income Countries
- 2021
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- There has been a fall globally in pneumonia-related fatality in children during the Millennium Development and early Sustainable Development Goal era.However, pneumonia remains the single largest contributor to mortality with issues including antibiotic resistance, pollution, a change in infective epidemiology, equipoise over effects of adjunctive treatments and identification of sick, decompensating children. This thesis examines 4 of these controversies as original research.Theme 1; two papers, 1 and 2: The first discusses the background motivation. The second a large randomized, non-inferiority controlled trial undertaken (‘RETAPP’) in a suburban slum area of Karachi, Pakistan. Oral amoxicillin treatment was compared with placebo, in the treatment of WHO-defined, uncomplicated, fast breathing pneumonia.Theme 2 (paper 3) The role of indoor air pollution and poverty in recurrent fast breathing pneumonia: a nested case control study.Theme 3 (paper 4). The role of adjunctive use of zinc to standard treatment in children with severe pneumonia: a systematic review and meta-analysis of randomised controlled trials.Theme 4 (paper 5). Recognition of the child with severe respiratory illness using the Clinical Respiratory Score in the emergency department Results: In the RETAPP study, 4,002 randomised children were enrolled. There was a significant difference in treatment failure rates in the amoxicillin and placebo groups (2.6 % vs 4.9 %). The number needed to treat was high at 44, and mortality very low and similar in both groups, discussion points for policy makers.There does not appear to be an enhanced risk with Indoor Air Pollution in recurrence of pneumonia. The only predictor was household poverty: external pollution could be a factor.Adjunctive zinc confers no additional advantage to children with severe pneumonia.The clinical respiratory score is a highly sensitive, but non-specific marker for severe illness.Conclusions: The small, though significant, differences in treatment failure rates in fast breathing pneumonia are likely to have implications for setting of management.The role of environmental predictors needs to turn to poverty and external pollution.Zinc has no role as an adjunctive treatment. The clinical respiratory score has excellent predictive value for severe illness.
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| 2. |
- Mhamilawa, Lwidiko E, 1988-
(författare)
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New strategies and tools for Plasmodium falciparum case management and surveillance in the era of imminent resistance to artemisinin-based combination therapy in Tanzania.
- 2020
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- Artemether-lumefantrine has been an efficacious first line treatment for uncomplicated Plasmodium falciparum malaria in Tanzania since its introduction in 2006. Interest has developed in understanding the observation of high residual PCR determined positivity rates on day 3 after supervised artemether-lumefantrine treatment in the magnitude of almost 30% in previous assessments from 2015 in Bagamoyo district, Tanzania. Deep sequencing has recently been used to study these Bagamoyo parasites with delayed clearance, and the clearance times by PCR of some P. falciparum sub-populations were similar to artemisinin resistant parasites in Myanmar as assessed by microscopy, albeit lacking the described mutations in the Kelch13 propeller gene associated with artemisinin resistance. Moreover, molecular epidemiological studies from Bagamoyo, have shown temporal selection of lumefantrine associated genetic tolerance/resistance markers (pfmdr1 - N86, 184F, D1246 and pfcrt - K76) in the parasite population following wide scale use of artemether-lumefantrine but without signs of compromised treatment efficacy. On the other hand, traditional epidemiological studies have reported that imported malaria cases in Zanzibar from Tanzania mainland contribute to regressing the malaria elimination efforts in this pre-elimination part of the country.This PhD project explored efficacy and safety of extending the artemether-lumefantrine regimen from standard 3 days to 6 days and adding single low dose primaquine (0.25mg/kg) as a new strategy that can be used in order to protect the therapeutic lifespan of artemether-lumefantrine. Also, whole-genome sequencing was used to study genomic epidemiology of P. falciparum population between Tanzania mainland and Zanzibar.The results revealed that extended artemether-lumefantrine treatment did not have superior efficacy in the current context of artemether-lumefantrine sensitive P. falciparum parasites. However, the safety profile was excellent and similar to standard 3 days treatment. Parasite detection by molecular methods was 84% on day 3 after artemether-lumefantrine treatment. Meanwhile, significant decreases in the effective population sizes were inferred in both Tanzania mainland and Zanzibar parasite populations, that coincide with a period of decreasing malaria transmission in Tanzania. The parasite population from Tanzania mainland and Zanzibar were found to be connected, implying importation of cases from high transmission mainland to pre elimination regions of Zanzibar.Utility of these results is during exploring options of alternative artemisinin-based combination therapy regimens to protect their therapeutic efficacy in an era of imminent artemisinin resistance in sub Saharan Africa. Moreover, the genomic epidemiological findings in this project may be of interest for malaria elimination programs, in the incorporation of molecular tools in future malaria elimination strategies and resistance surveillance, in the context of understanding importation of malaria from high to low transmission regions.
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| 3. |
- Allwell-Brown, Gbemisola
(författare)
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Antibiotic use among children in low- and middle-income countries : Studies on global trends, and contextual determinants of antibiotic prescribing in Eastern Uganda
- 2022
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- This thesis aimed to systematically map trends in reported antibiotic use (RAU) among sick under-five children across low- and middle-income countries (LMICs) in 2005-2017, and, to understand the contextual determinants of antibiotic prescribing in Eastern Uganda. Based on 132 national surveys from 73 LMICs, and using Bayesian linear regression models, trends in RAU among sick under-five children (with symptoms of fever, diarrhoea or cough with fast/difficult breathing) across LMICs in 2005-2017 were mapped by WHO region, World Bank country income group, symptom complaint (Study-I), and by the following user characteristics: rural/urban residence, maternal education, household wealth and source of care (Study-II). To provide context, Study-III investigated patterns and contextual determinants of antibiotic prescribing for febrile under-five outpatients (FUO) attending 37 primary and secondary healthcare facilities across Bugisu, a sub-region in Eastern Uganda, based on a healthcare facility survey, and a two-year retrospective review of outpatient registers from January 2019-December 2020. To further strengthen the understanding of contextual determinants of antibiotic prescribing, in Study-IV, 10 focus group discussions and 10 in-depth interviews were conducted with 85 healthcare providers across primary and secondary healthcare facilities in Bugisu, and analysed using thematic analysis.A modest (17%) relative increase in RAU for sick under-five children across LMICs in 2005-2017 was found, with about 43% of the children reportedly receiving antibiotics for their illness in 2017. Low-income, African, and South-East Asian countries consistently recorded the lowest RAU for sick under-five children. Within LMICs, RAU for sick under-five children increased across all user groups in 2005-2017 but remained lowest among the poorest children, those living in rural areas, and having mothers with the lowest education levels. In Bugisu, 62.2% of FUO in surveyed healthcare facilities received antibiotic prescriptions. Amoxicillin and co-trimoxazole accounted for two-thirds of all antibiotic prescriptions. Cotrimoxazole and ampicillin/cloxacillin were prescribed, despite not being indicated in any of the reported conditions in Study-III. Among other interrelated factors across multiple levels of the health system, availability of antibiotics and diagnostics within healthcare facilities, caregiver demands, and governance at national and sub-national levels were important health worker considerations in antibiotic prescribing for febrile under-five patients.These studies suggest that inequitable access to antibiotics remains a challenge between and within LMICs. Yet, misuse and wastage of antibiotics persists in the same populations with the greatest lack of access to antibiotics and formal healthcare services. A health systems strengthening approach is required to improve antibiotic stewardship and overall quality of care in LMICs.
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