Amy Hurford

Linking antimicrobial prescribing to antimicrobial resistance in the ICU: before and after an antimicrobial stewardship program.

Antimicrobials are an effective treatment for many types of infections, but their overuse promotes the spread of resistant microorganisms that defy conventional treatments and complicate patient care. In 2009, an antimicrobial stewardship program was implemented at Mount Sinai Hospital (MSH, Toronto, Canada). Components of this program were to alter the fraction of patients prescribed antimicrobials, to shorten the average duration of treatment, and to alter the types of antimicrobials prescribed. These components were incorporated into a mathematical model that was compared to data reporting the number of patients colonized with Pseudomonas aeruginosa and the number of patients colonized with antimicrobial-resistant P. aeruginosa first isolates before and after the antimicrobial stewardship program. Our analysis shows that the reported decrease in the number of patients colonized was due to treating fewer patients, while the reported decrease in the number of patients colonized with resistant P. aeruginosa was due to the combined effect of treating fewer patients and altering the types of antimicrobials prescribed. We also find that shortening the average duration of treatment was unlikely to have produced any noticeable effects and that further reducing the fraction of patients prescribed antimicrobials would most substantially reduce P. aeruginosa antimicrobial resistance in the future. The analytical framework that we derive considers the effect of colonization pressure on infection spread and can be used to interpret clinical antimicrobial resistance data to assess different aspects of antimicrobial stewardship within the ecological context of the intensive care unit.

A model for sea lice (Lepeophtheirus salmonis) dynamics in a seasonally changing environment

Sea lice (Lepeophtheirus salmonis) are a significant source of monetary losses on salmon farms. Sea lice exhibit temperature-dependent development rates and salinity-dependent mortality, but to date no deterministic models have incorporated these seasonally varying factors. To understand how environmental variation and life history characteristics affect sea lice abundance, we derive a delay differential equation model and parameterize the model with environmental data from British Columbia and southern Newfoundland. We calculate the lifetime reproductive output for female sea lice maturing to adulthood at different times of the year and find differences in the timing of peak reproduction between the two regions. Using a sensitivity analysis, we find that sea lice abundance is more sensitive to variation in mean annual water temperature and mean annual salinity than to variation in life history parameters. Our results suggest that effective sea lice management requires consideration of site-specific temperature and salinity patterns and, in particular, that the optimal timing of production cycles and sea lice treatments might vary between regions.

Mechanistic movement models to understand epidemic spread

An overlooked aspect of disease ecology is considering how and why animals come into contact with one and other resulting in disease transmission. Mathematical models of disease spread frequently assume mass-action transmission, justified by stating that susceptible and infectious hosts mix readily, and foregoing any detailed description of host movement. Numerous recent studies have recorded, analysed and modelled animal movement. These movement models describe how animals move with respect to resources, conspecifics and previous movement directions and have been used to understand the conditions for the occurrence and the spread of infectious diseases when hosts perform a type of movement. Here, we summarize the effect of the different types of movement on the threshold conditions for disease spread. We identify gaps in the literature and suggest several promising directions for future research. The mechanistic inclusion of movement in epidemic models may be beneficial for the following two reasons. Firstly, the estimation of the transmission coefficient in an epidemic model is possible because animal movement data can be used to estimate the rate of contacts between conspecifics. Secondly, unsuccessful transmission events, where a susceptible host contacts an infectious host but does not become infected can be quantified. Following an outbreak, this enables disease ecologists to identify ‘near misses’ and to explore possible alternative epidemic outcomes given shifts in ecological or immunological parameters. This article is part of the themed issue ‘Opening the black box: re-examining the ecology and evolution of parasite transmission’.

Benefits and unintended consequences of antimicrobial de-escalation: Implications for stewardship programs

Sequential antimicrobial de-escalation aims to minimize resistance to high-value broad-spectrum empiric antimicrobials by switching to alternative drugs when testing confirms susceptibility. Though widely practiced, the effects de-escalation are not well understood. Definitions of interventions and outcomes differ among studies. We use mathematical models of the transmission and evolution of Pseudomonas aeruginosa in an intensive care unit to assess the effect of de-escalation on a broad range of outcomes, and clarify expectations. In these models, de-escalation reduces the use of high-value drugs and preserves the effectiveness of empiric therapy, while also selecting for multidrug-resistant strains and leaving patients vulnerable to colonization and superinfection. The net effect of de-escalation in our models is to increase infection prevalence while also increasing the probability of effective treatment. Changes in mortality are small, and can be either positive or negative. The clinical significance of small changes in outcomes such as infection prevalence and death may exceed more easily detectable changes in drug use and resistance. Integrating harms and benefits into ranked outcomes for each patient may provide a way forward in the analysis of these tradeoffs. Our models provide a conceptual framework for the collection and interpretation of evidence needed to inform antimicrobial stewardship.

How to measure the impacts of antibiotic resistance and antibiotic development on empiric therapy: new composite indices

Objectives We aimed to construct widely useable summary measures of the net impact of antibiotic resistance on empiric therapy. Summary measures are needed to communicate the importance of resistance, plan and evaluate interventions, and direct policy and investment. Design, setting and participants As an example, we retrospectively summarised the 2011 cumulative antibiogram from a Toronto academic intensive care unit. Outcome measures We developed two complementary indices to summarise the clinical impact of antibiotic resistance and drug availability on empiric therapy. The Empiric Coverage Index (ECI) measures susceptibility of common bacterial infections to available empiric antibiotics as a percentage. The Empiric Options Index (EOI) varies from 0 to ‘the number of treatment options available’, and measures the empiric value of the current stock of antibiotics as a depletable resource. The indices account for drug availability and the relative clinical importance of pathogens. We demonstrate meaning and use by examining the potential impact of new drugs and threatening bacterial strains. Conclusions In our intensive care unit coverage of device-associated infections measured by the ECI remains high (98%), but 37–44% of treatment potential measured by the EOI has been lost. Without reserved drugs, the ECI is 86–88%. New cephalosporin/β-lactamase inhibitor combinations could increase the EOI, but no single drug can compensate for losses. Increasing methicillin-resistant Staphylococcus aureus (MRSA) prevalence would have little overall impact (ECI=98%, EOI=4.8–5.2) because many Gram-positives are already resistant to β-lactams. Aminoglycoside resistance, however, could have substantial clinical impact because they are among the few drugs that provide coverage of Gram-negative infections (ECI=97%, EOI=3.8–4.5). Our proposed indices summarise the local impact of antibiotic resistance on empiric coverage (ECI) and available empiric treatment options (EOI) using readily available data. Policymakers and drug developers can use the indices to help evaluate and prioritise initiatives in the effort against antimicrobial resistance.

Determinants of the Final Size and Case Rate of Nosocomial Outbreaks

Different nosocomial pathogen species have varying infectivity and durations of infectiousness, while the transmission route determines the contact rate between pathogens and susceptible patients. To determine if the pathogen species and transmission route affects the size and spread of outbreaks, we perform a meta-analysis that examines data from 933 outbreaks of hospital-acquired infection representing 14 pathogen species and 8 transmission routes. We find that the mean number of cases in an outbreak is best predicted by the pathogen species and the mean number of cases per day is best predicted by the species-transmission route combination. Our fitted model predicts the largest mean number of cases for Salmonella outbreaks (22.3) and the smallest mean number of cases for Streptococci outbreaks (8.5). The largest mean number of cases per day occurs during Salmonella outbreaks spread via the environment (0.33) and the smallest occurs for Legionella outbreaks spread by multiple transmission routes (0.005). When combined with information on the frequency of outbreaks these findings could inform the design of infection control policies in hospitals.

Skewed temperature dependence affects range and abundance in a warming world

Population growth metrics such as R0 are usually asymmetric functions of temperature, with cold-skewed curves arising when the positive effects of a temperature increase outweigh the negative effects, and warm-skewed curves arising in the opposite case. Classically, cold-skewed curves are interpreted as more beneficial to a species under climate warming, because coldskewness implies increased population growth over a larger proportion of the species’ fundamental thermal niche than warm-skewness. However, inference based on the shape of the fitness curve alone, and without considering the synergistic effects of net reproduction, density, and dispersal may yield an incomplete understanding of climate change impacts. We formulate a moving-habitat integrodifference equation model to evaluate how fitness curve skewness affects species’ range size and abundance during climate warming. In contrast to classic interpretations, we find that climate warming adversely affects populations with cold-skewed fitness curves, positively affects populations with warm-skewed curves and has relatively little or mixed effects on populations with symmetric curves. Our results highlight the necessity of considering the synergistic effects of fitness curve skewness, density, and dispersal in climate change impact analyses, and that the common approach of mapping changes only in R0 may be misleading.

The evolution of molecular mimicry in parasites: a mathematical model

Parasite strains that are molecular mim¬ics are more likely to evade the immune system. When parasites evade a host’s the im¬mune system, their numbers grow, and these parasites are readily spread to new hosts. But, if molecular mimics are more transmissible, why is molecular mimicry then not more com-mon?