Determinants of maternal colonization with multidrug-resistant gram-negative bacteria

Bulabula, Andre Nyandwe Hamama (2020-03)

Thesis (PhD)--Stellenbosch University, 2020.

Thesis

ENGLISH ABSTRACT : This doctoral research explored the topic of maternal colonization with multidrug-resistant Gram-negative bacilli (MDR-GNB) in Africa, using analytical cross-sectional studies to generate novel data and systematic reviews and meta-analyses to synthesize existing data. Maternal colonization is an established risk factor for neonatal colonization, which is a precursor to neonatal infection (the third leading cause of neonatal deaths in Africa). Understanding the factors contributing to maternal colonization with MDR-GNB in Africa, will inform the development of preventive interventions and ultimately contribute to reduction of neonatal infection burden. Through a systematic review and meta-analysis, we underscored the major knowledge gaps regarding the burden of and risk factors for maternal colonization with MDR-GNB in Africa. The meta-analysis allowed us to provide a first estimate of the prevalence of maternal colonization with extended-spectrum beta-lactamases producing Enterobacteriaceae (ESBL-E) among pregnant and postpartum women in Africa (17%), which was 2 to 3-fold higher than that described from high-income countries. Utilizing an analytical cross-sectional study design, we generated unique data describing the prevalence of maternal colonization with antimicrobial resistance (AMR) genes in a South African cohort of 651 peripartum women. Cefotaxime-M15 (CTX-M15) and New Delhi Metallo-beta-lactamase (NDM) genes were isolated from 12.9% and 2.2% of specimens respectively. Communal taps as the primary water source was the only independent predictor of maternal colonization with CTX-M15. Poverty-related factors (lower educational achievement, low income group and rural residence), and a clinical factor (primiparous status), were independent predictors of maternal colonization with carbapenem-resistant pathogens. Comorbidities like HIV infection and diabetes, or exposures such as recent antibiotic use, did not predict maternal colonization with AMR genes. The knowledge, attitudes and practices regarding antibiotic use during pregnancy were assessed in a cohort of 301 pregnant South African women. Women with higher mean knowledge score (K-score) had lower reported proportions of antibiotic self-medication compared to women with lower mean K-scores. High monthly household income was an independent predictor of self-medication with The relationship between the density of hospital environmental contamination with AMR genes and colonization proportions in 180 hospitalized peripartum women and 92 neonates, was prospectively assessed. The level of hospital environmental contamination with AMR genes was low (5.8%); similarly, the number of colonized patients was small (2.8% of the peripartum women and 9.8% of the neonates), limiting the study’s power to determine a clear link between environmental contamination and patient colonization. Finally, in a second systematic review and meta-analysis, we produced a synthesis of molecular evidence linking MDR-GNB transmission from colonized mothers to their neonates. Although limited by the number and quality of studies, molecular evidence supports an overall 27% transmission proportion for MDR- and/or ESBL Enterobacteriaceae from colonized mothers to their infants, resulting in neonatal colonization. Further high-quality research is needed to determine the risk factors that promote mother-to-infant MDR-GNB transmission and evidence to link maternal MDR-GNB colonization and subsequent neonatal infection. This doctoral thesis has produced new findings on the magnitude of and risk factors for maternal colonization with MDR-GNB in an African context. The novel data will inform the development of interventions to prevent colonization with MDR-GNB in mothers and subsequently reduce neonatal infection.

AFRIKAANSE OPSOMMING : Hierdie doktorale ondersoek het die onderwerp van moederkolonisasie met multidrugtiewe weerstandige Gram-negatiewe basille (MDR-GNB) in Afrika ondersoek, met behulp van analitiese deursnitstudies om nuwe data en sistematiese oorsigte en meta-analises te genereer om bestaande data te sintetiseer. Moederkolonisasie is 'n gevestigde risikofaktor vir neonatale kolonisasie, wat 'n voorloper is vir neonatale infeksie (die derde grootste oorsaak van neonatale sterftes in Afrika). Deur die faktore wat bydra tot die moederkolonisasie met MDR-GNB in Afrika te verstaan, sal die ontwikkeling van voorkomende ingrypings ingelig word en uiteindelik bydra tot die vermindering van neonatale infeksielas. Deur 'n stelselmatige oorsig en meta-analise het ons die belangrikste leemtes in die kennis oor die las en risikofaktore vir moederlike kolonisasie met MDR-GNB in Afrika onderstreep. Die metaanalise het ons in staat gestel om 'n eerste skatting te gee van die voorkoms van moederlike kolonisasie met ESBL-E onder swanger en postpartum vroue in Afrika (17%), wat 2 tot 3 keer meer is as wat beskryf is uit lande met 'n hoë inkomste. Met behulp van 'n analitiese deursnitstudie-ontwerp, het ons unieke data gegenereer wat die voorkoms van moederkolonisasie met AMR-gene in 'n Suid-Afrikaanse groep van 651 peripartumvroue beskryf (CTX-M15- en NDM-gene is onderskeidelik van 12,9% en 2,2% van die monsters geïsoleer). Gemeenskaplike krane as die primêre waterbron was die enigste onafhanklike voorspeller van moederlike kolonisasie met CTX-M15. Armoede-verwante faktore (laer opvoedkundige prestasie, lae-inkomstegroep en landelike woning), en kliniese faktore (primariële status en laat aanbieding vir eerste besoek aan die voorgeboortesorg (ANC)) was onafhanklike voorspellers van moederlike kolonisasie met carbapenem-weerstandige patogene. Komorbiditeite soos MIV-infeksie en diabetes, of blootstellings soos die onlangse gebruik van antibiotika, het nie moederkolonisasie met AMR-gene voorspel nie. Die kennis, houdings en praktyke rakende antibiotiese gebruik tydens swangerskap is beoordeel in 'n groep van 301 swanger Suid-Afrikaanse vroue. Vroue met 'n hoër gemiddelde kennis (K-telling) het 'n laer gerapporteerde aantal antibiotiese selfmedikasie gehad in vergelyking met vroue met 'n laer gemiddelde K-telling. Die maandelikse huishoudelike inkomste was 'n onafhanklike voorspeller van selfmedikasie met antibiotika. Die verband tussen die digtheid van besoedeling in die hospitaal met AMR-gene en kolonisasietariewe by 180 vroulike peripartumvroue en 92 pasgeborenes is beoordeel. Die vlak van besoedeling in die hospitaal met AMR-gene was laag (5,8%); Op dieselfde manier was die aantal gekoloniseerde pasiënte klein (2,8% van die vroulike peripartum en 9,8% van die pasgeborenes), wat die studie se vermoë beperk het om 'n duidelike verband tussen die omgewingskontaminasie en pasiëntkolonisasie te bepaal. Uiteindelik, in 'n tweede sistematiese oorsig en meta-analise, het ons 'n sintese van molekulêre bewyse vervaardig wat MDR-GNB-oordrag van gekoloniseerde moeders na hul pasgeborenes verbind. Alhoewel dit beperk is deur die aantal en kwaliteit van die studies, ondersteun molekulêre bewyse 'n algehele oordragskoers van 27% vir MDR- en / of ESBL Enterobacteriaceae van gekoloniseerde moeders na hul babas, wat lei tot neonatale kolonisasie. Verdere navorsing van hoë gehalte is nodig om die risikofaktore te bepaal wat die oordrag van moeder-tot-baba-MDR-GNB bevorder en bewyse om die MDR-GNB-kolonisasie van die moeder en die daaropvolgende neonatale infeksie te koppel. Hierdie doktorale proefskrif het nuwe bevindings opgelewer oor die omvang en risikofaktore vir moederlike kolonisasie met MDR-GNB in 'n Afrika-konteks. Die nuwe gegewens sal die ontwikkeling van ingrypings om kolonisasie met MDR-GNB by moeders te voorkom inlig, en neonatale infeksie verminder.

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