Computational Model to Quantify the Growth of Antibiotic Resistant Bacteria in Wastewater

Abstract

Though wastewater and sewage systems are known to be a significant reservoir of antibiotic resistant bacterial populations and periodic outbreaks of drug resistant infection, there is little quantitative understanding of the drivers behind resistant population growth in these settings. In order to fill this gap in quantitative understanding of outbreaks of antibiotic resistant infections in wastewater, we have developed a mathematic model synthesizing many of the known drivers of antibiotic resistance in these settings in order to predict the growth of resistant populations in different environmental scenarios. A number of these drivers of drug resistant infection outbreak including antibiotic residue concentration, antibiotic interaction and synergy, chromosomal mutation and horizontal gene transfer, have not previously been integrated into a single computational model. Our integrated model shows that low levels of antibiotic residues present in wastewater can lead to the increased development of resistant populations, and the dominant mechanism of resistance acquisition in these populations is horizontal gene transfer rather than chromosomal mutations. Additionally, we found that synergistic antibiotic interactions can cause increased resistant population growth. Our study shows that the effects of antibiotic interaction are observable even at the low antibiotic concentrations present in wastewater settings. These findings, consistent with recent experimental and field studies, provide new quantitative knowledge on the evolution of antibiotic resistant bacterial reservoirs, and the model developed herein can be adapted for use as a prediction tool in public health policy making, particularly in low income settings where water sanitation issues remain widespread and disease outbreaks continue to undermine public health efforts.SignificanceThe rate at which antimicrobial resistance (AMR) has developed and spread throughout the world has increased in recent years, and it is suggested that at the current rate, several million people may die by 2050 due to AMR. One major reservoir of resistant bacterial populations that has been linked to outbreaks of drug resistant bacterial infections, but is not well understood, is in wastewater settings, where antibiotic pollution is often present. Using ordinary differential equations incorporating several known drivers of resistance in wastewater, we find that interactions between antibiotic residues and horizontal gene transfer significantly affect the growth of resistant bacterial reservoirs.

Effects of Antibiotic Interaction on Antimicrobial Resistance Development in Wastewater

“…The model used in this paper is based on a previously developed model of the growth of antibiotic resistant bacterial populations in wastewater that builds on prior studies and extends to incorporate a variety of critical inputs which can be broadly classified into bacterial parameters, environmental parameters and antibiotic parameters (11). Bacteria specific input factors include the growth rates of antibiotic susceptible and resistant strains and mutation rates in response to subinhibitory concentrations of antibiotic.…”

“…Eq Set 1. Sensitive and resistant populations under selective pressure from antimicrobial combination therapy, adapted from Sutradhar et al 2021 11 1)…”

“…Wastewater specifically has been shown to be a reservoir of resistant pathogens, often stemming from the antibiotic pollution present in runoff from industrial and agricultural sources (10). Furthermore, computational modeling of wastewater has shown that even low concentrations of antibiotic residues can lead to the development of AMR (11). This is particularly of concern in low-income communities which can often have open sewer systems and little access to wastewater treatment, putting them at particular risk for deadly drug-resistant outbreaks.…”

“…Previously, we have developed a computational model of resistance acquisition in continuous flow environments based on known mechanisms of bacterial growth and mutation as well as experimental validation (11). However, experimental validation of the model was limited to systems with only one antibiotic residue.…”

Nosocomial Infections: Pathogenicity, Resistance and Novel Antimicrobials

“…Gene transfer by each of the three mechanisms is favored between closely related organisms, but can occur between phylogenetically distant organisms [59]. Reservoirs of antibiotic-resistant organisms in hospitals have been well documented [60,61], as have transmission routes between these reservoirs [62,63], but the rates of horizontal transfer in clinical environments and the impacts of HGT on disease frequency remain unknown or speculative.…”