Roads have important impacts on social and ecological processes that in turn have impacts on health [35
]. The relationship between roads and disease has been examined for a variety of infectious diseases including HIV, malaria, dengue and diarrhoeal disease [29
]. Here, we provide data from a 5 year regional-scale observational study showing that roads can also impact the spread of resistant bacteria. Focusing on E. coli
resistance to amp–sxt, the most common pairing of antibiotics observed, we found a higher prevalence of antibiotic-resistant bacteria in villages along the road compared with more remote villages. These results are consistent with those of other researchers, who have found higher levels of AR organisms in sites with greater anthropogenic influence [39
However, we found no relationship between antibiotic use and remoteness, which probably relates to the presence of both governmental and non-governmental organizations that deliver medical care, including antibiotics, throughout the region. Given its homogeneous distribution along the remoteness gradient, we employed a village-level transmission model to better understand how antibiotic use impacts prevalence patterns at a regional scale. Our model analysis suggests that at the regional-scale individual antibiotic use serves to modify the effect of two potentially important processes: the transmission of E. coli
from person to person mediated through environmental pathways, and the introduction of E. coli
from outside the region owing to the movement patterns of people into and out of the region [29
]. As antibiotic use rates decrease across the region, the differential rate of introduction becomes a more important determinant of our observed prevalence patterns. Transmission becomes an important determinant when antibiotic use increases; i.e. antibiotic use amplifies transmission. Thus, antibiotic use has a regional-scale impact that differs from those impacts that are derived from only considering the individual-level scale.
At the individual scale, experimental evidence suggests that resistant bacteria can be out-competed by their sensitive counterparts [43
]. The implication of this is that once the pressure of antibiotics is removed, the population of resistant bacteria may decrease relatively quickly, making an individual's antibiotic use act primarily as a main effect on his/her probability of colonization with a resistant strain. However, at the community level, the effect of antibiotic use is more complex. Evidence suggests that the fitness costs of resistance can be very low [44
], and therefore the subsequent slow decline in the prevalence of resistant bacteria once the antibiotic use ceases, provides continued opportunity for resistant organisms to spread from host to host, from host to the environment and from the environment to the host. Therefore, interplay between antibiotic use, disease transmission rate and rate of introduction from the environment must be considered when characterizing drivers of population-level prevalence of resistant bacteria.
Our analysis suggests that the antibiotic use rate acts to modify the impact of the transmission rate and outside introduction rate, indicating that the effect of antibiotic use rate on community-level prevalence cannot be thought of in isolation. When antibiotic use is high (e.g. ρ
= 0.01, antibiotics per person per day), the bacteria resistant to the antibiotic being used is selected for within the individual, thereby making it more likely for a transmission event to involve a resistant organism. Under these conditions, transmission becomes a major driver of AR prevalence, with outside introduction having a comparatively very small effect. When antibiotic use is low (e.g. ρ
= 0.001, antibiotics per person per day), most transmission events involve sensitive bacteria, rendering the transmission rate impotent as a driver of AR prevalence (). In this setting, oral exposure, which occurs through ingestion of bacteria into the gastrointestinal tract, is the primary driver of prevalence; this exposure comes from a variety of sources including introduction from outside the region. Many studies have demonstrated that AR can spread between individuals sharing the same home [47
], day care centre [48
] or even community [50
]. For enteric organisms both transmission and outside introduction occurs through water, sanitation, hygiene and food pathways— modes of spread especially strong in agricultural settings [51
] and developing countries [52
]. The transmission of bacteria can occur through these pathways in developed countries as well, albeit at lower rates.
Typical models of AR are set in controlled environments such as hospitals, and focus on the competitive advantage given to resistant bacteria through antibiotic use. In such models, invasion of resistant bacteria from the outside is ignored, potentially because the focus of hospital settings is on the large amounts of antibiotic use and how they are optimally prescribed (e.g. [13
]). On the other hand, in a community setting, the invasion and the spread of resistant bacteria are an important determinant of prevalence. The inclusion of the rate of introduction of antibiotics and its interaction with transmission and antibiotic use, therefore, is a central piece of our analysis.
The complete understanding of the dynamics of AR spread in the context of social and ecological changes can only be obtained through a systematic and ecological perspective as presented in this study. Our data and analysis support the proposal that understanding the mechanisms of the evolution and the spread of resistant bacteria require a consideration of the ecological dynamics that shape microbial population structure [22
]. These dynamics are mediated through factors that determine selection pressures, routes of transmission and the invasion of resistant bacteria [22
], which may overwhelm the direct effects of individual antibiotic use in determining the emergence and dissemination of AR across communities or regions. In our study region, the major driver of selection pressure and routes of transmission appears to be a new network of roads, which have strong influence on the social and ecological environment and in turn on the health of communities [37
]. Roads may affect the evolution and the spread of resistant bacteria by influencing the use of antibiotics in the human population, changing hygiene and sanitation and introducing resistant bacteria when people travel or migrate into a region.