Mariano Ciccolini

Small regulatory RNA-induced growth rate heterogeneity of Bacillus subtilis.

Isogenic bacterial populations can consist of cells displaying heterogeneous physiological traits. Small regulatory RNAs (sRNAs) could affect this heterogeneity since they act by fine-tuning mRNA or protein levels to coordinate the appropriate cellular behavior. Here we show that the sRNA RnaC/S1022 from the Gram-positive bacterium Bacillus subtilis can suppress exponential growth by modulation of the transcriptional regulator AbrB. Specifically, the post-transcriptional abrB-RnaC/S1022 interaction allows B. subtilis to increase the cell-to-cell variation in AbrB protein levels, despite strong negative autoregulation of the abrB promoter. This behavior is consistent with existing mathematical models of sRNA action, thus suggesting that induction of protein expression noise could be a new general aspect of sRNA regulation. Importantly, we show that the sRNA-induced diversity in AbrB levels generates heterogeneity in growth rates during the exponential growth phase. Based on these findings, we hypothesize that the resulting subpopulations of fast- and slow-growing B. subtilis cells reflect a bet-hedging strategy for enhanced survival of unfavorable conditions.

Efficient surveillance for healthcare-associated infections spreading between hospitals

Significance Early detection of new or novel variants of nosocomial pathogens (such as hospital-acquired methicillin-resistant Staphylococcus aureus) is a public health priority. However, surveillance effort is often limited by financial and practical constraints. Although this is widely recognized, no good evidence base exists to inform the design of efficient hospital-based surveillance systems. We address the key questions of how many and which hospitals should be included in such a surveillance system. Using hospital admissions data from England and The Netherlands, we model the spread of a pathogen among the network of hospitals connected by the movement of patients between them. We show how it is possible to design hospital-based surveillance systems that deliver earlier detection times for reduced effort. Early detection of new or novel variants of nosocomial pathogens is a public health priority. We show that, for healthcare-associated infections that spread between hospitals as a result of patient movements, it is possible to design an effective surveillance system based on a relatively small number of sentinel hospitals. We apply recently developed mathematical models to patient admission data from the national healthcare systems of England and The Netherlands. Relatively short detection times are achieved once 10–20% hospitals are recruited as sentinels and only modest reductions are seen as more hospitals are recruited thereafter. Using a heuristic optimization approach to sentinel selection, the same expected time to detection can be achieved by recruiting approximately half as many hospitals. Our study provides a robust evidence base to underpin the design of an efficient sentinel hospital surveillance system for novel nosocomial pathogens, delivering early detection times for reduced expenditure and effort.

Disease transmission on fragmented contact networks: Livestock-associated Methicillin-resistant Staphylococcus aureus in the Danish pig-industry

Animal trade in industrialised livestock-production systems creates a complex, heterogeneous, contact network that shapes between-herd transmission of infectious diseases. We report the results of a simple mathematical model that explores patterns of spread and persistence of livestock-associated Methicillin-resistant Staphylococcus aureus (LA-MRSA) in the Danish pig-industry associated with this trade network. Simulations show that LA-MRSA can become endemic sustained by animal movements alone. Despite the extremely low predicted endemic prevalence, eradication may be difficult, and decreasing within-farm prevalence, or the time it takes a LA-MRSA positive farm to recover a negative status, fails to break long-term persistence. Our results suggest that a low level of non-movement induced transmission strongly affects MRSA dynamics, increasing endemic prevalence and probability of persistence. We also compare the model-predicted risk of 291 individual farms becoming MRSA positive, with results from a recent Europe-wide survey of LA-MRSA in holdings with breeding pigs, and find a significant correlation between contact-network connectivity properties and the model-estimated risk measure.

Using an index-based approach to assess the population-level appropriateness of empirical antibiotic therapy

OBJECTIVES The population-level appropriateness of empirical antibiotic therapy can be conventionally measured by ascertainment of treatment coverage. This method involves a complex resource-intensive case-by-case assessment of the prescribed antibiotic treatment and the resistance of the causative microorganism. We aimed to develop an alternative approach based, instead, on the use of routinely available surveillance data. METHODS We calculated a drug effectiveness index by combining three simple aggregated metrics: relative frequency of aetiological agents, level of resistance and relative frequency of antibiotic use. To evaluate the applicability of our approach, we used this metric to estimate the population-level appropriateness of guideline-compliant and non-guideline-compliant empirical treatment regimens in the context of the Dutch national guidelines for complicated urinary tract infections. RESULTS The drug effectiveness index agrees within 5% with results obtained with the conventional approach based on a case-by-case ascertainment of treatment coverage. Additionally, we estimated that the appropriateness of 2008 antibiotic prescribing regimens would have declined by up to 4% by year 2011 in the Netherlands due to the emergence and expansion of antibiotic resistance. CONCLUSIONS The index-based framework can be an alternative approach to the estimation of point values and counterfactual trends in population-level empirical treatment appropriateness. In resource-constrained settings, where empirical prescribing is most prevalent and comprehensive studies to directly measure appropriateness may not be a practical proposition, an index-based approach could provide useful information to aid in the development and monitoring of antibiotic prescription guidelines.

O085: A network-based approach using intra-hospital patient transfers to identify high-risk wards during nosocomial outbreaks

Initial detection of a nosocomial outbreak can sometimes occur only after a considerable time has passed since the appearance of the index case(s). During this high-risk period from emergence to detection, within-hospital patient movements can disseminate the nosocomial pathogen to different admission wards. Following outbreak detection, a rapid, robust estimate of potentially exposed wards is of crucial importance in order to focus the implementation of infection prevention measures.

P183: A multi-pronged approach to unravel rhinovirus transmission in a children’s hospital: towards effective infection control.

Human rhinovirus (HRV) is associated with serious respiratory illness, particularly in patients with pulmonary comorbidities. Little is known about nosocomial transmission of HRV. A good understanding of the hospital epidemiology of HRV is required to evaluate the effect of infection control strategies.