Statistical approaches to understanding between and within host dynamics of infectious disease agent replication Open Access

Coates, Jessica (Spring 2022)

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Despite the design of highly effective antibiotics and vaccines, infectious diseases still cause a major burden on public health. Infectious diseases account for three of the ten major causes of death in the United States and globally infectious diseases can be attributed to over 17 million deaths per year. Because of an increase in antibiotic resistance and decreased vaccine effectiveness for multiple vaccine preventable diseases, there is a need to better understand the dynamics of infectious disease replication under antibiotic stress and in highly vaccinated populations. To better understand these dynamics, this work aimed to explore two unique cases: (1) the within host dynamics of E. coli replication in the presence of bacteriostatic and bactericidal antibiotics and (2) the between host dynamics of mumps transmission in US populations with a high vaccine coverage. Given the usefulness of statistical approaches to understanding infectious disease dynamics, we utilized data derived from traditional experimental biology to construct a mathematical model describing the birth and death processes of bacteria exposed to antibiotics. This work demonstrated that bactericidal and bacteriostatic antibiotics have differing effects on the growth dynamics of bacteria that can be manipulated to increase the likelihood of bacterial clearance. In a second study, we utilized observational data collected through a systematic review to estimate the effective reproduction number for mumps outbreaks in the United States post the introduction of a two-dose vaccination recommendation. This work highlighted the heterogeneity in transmission dynamics for different populations with similar vaccination coverage and provided foundational evidence about the potential effectiveness of non-pharmaceutical interventions in controlling mumps outbreaks. Together this work adds to the body of work focused on understanding the importance of within and between host dynamics of infectious agent replication. Additionally, the work provides novel insight that may aid in the design of future studies. This is particularly important because as we develop a better understanding of the dynamics of infectious agent replication, it improves our ability to reduce the burden caused by infectious diseases on human health.  

Table of Contents

Chapter I. Introduction. 9

Introduction. 13

The Gaps in Knowledge. 15

The Questions. 18

Questions on within-host dynamics of infectious disease reproduction. 18

Questions on between-host dynamics of infectious disease reproduction. 19

Outline of The Thesis and Chapter Summaries. 19

References. 21

Chapter II: Antibiotic-induced population fluctuations and stochastic clearance of bacteria. 24

Abstract 24

Introduction. 26

Results. 28

Contrasting trends in plating efficiency for bacteriostatic and bactericidal drugs. 28

A subsequent plate assay reveals a lack of heritable resistance. 30

Bactericidal drugs induce stochastic fluctuations in population dynamics. 30

The effects of bactericidal drugs on cell growth and death. 32

A simple, stochastic model of the population dynamics accounts for stochastic clearance of bacterial populations. 33

A population with large inoculum size is subject to stochastic clearance at sub-MIC drug concentrations. 35

Alteration of the extinction probability to facilitate bacterial eradication at sub-MIC drug concentrations. 38

Extending the growth-reduction strategy to antibiotic-resistant strains. 40

Discussion. 41

Materials and methods. 46

Bacterial strains and culture. 46

Plate assay. 47

Antibiotics. 47

Time-Lapse microscopy. 47

Replicate culture using a microtiter plate. 48

Acknowledgements. 49

References. 49

Chapter III: Mumps transmission in United States in the post-vaccine era: A systematic review.. 86

Abstract 86

Introduction. 87

Objective and Overview of Systematic Review.. 89

Methods. 89

Search methods for identification of studies. 90

Threats to Internal Validity. 91

Measures of transmission dynamics. 92

Results. 93

Narrative Synthesis. 96

Narrative Synthesis for studies after the 2006 resurgence. 98

Risk of Bias. 99

Threats to Internal Validity. 99

Estimating how transmission dynamics differ by setting. 100

Discussion. 101

Conclusions. 104

Implications for practice. 104

Implications for research. 104

Acknowledgments. 105

References. 105

Chapter IV: Discussion. 111

Introduction. 111

Summary of Major Findings. 112

Recommendations for future studies. 113

References. 116

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