Theoretical considerations and empirical predictions of the pharmaco- and population dynamics of heteroresistance.

Antibiotics are considered one of the most important contributions to clinical medicine in the last century. Due to the use and overuse of these drugs, there have been increasing frequencies of infections with resistant pathogens. One form of resistance, heteroresistance, is particularly problematic; pathogens appear sensitive to a drug by common susceptibility tests. However, upon exposure to the antibiotic, resistance rapidly ascends, and treatment fails. To quantitatively explore the processes contributing to the emergence and ascent of resistance during treatment and the waning of resistance following cessation of treatment, we develop two distinct mathematical and computer-simulation models of heteroresistance. In our analysis of the properties of these models, we consider the factors that determine the response to antibiotic-mediated selection. In one model, heteroresistance is progressive, with each resistant state sequentially generating a higher resistance level. In the other model, heteroresistance is non-progressive, with a susceptible population directly generating populations with different resistance levels. The conditions where resistance will ascend in the progressive model are narrower than those of the non-progressive model. The rates of reversion from the resistant to the sensitive states are critically dependent on the transition rates and the fitness cost of resistance. Our results demonstrate that the standard test used to identify heteroresistance is insufficient. The predictions of our models are consistent with empirical results. Our results demand a reevaluation of the definition and criteria employed to identify heteroresistance. We recommend that the definition of heteroresistance should include a consideration of the rate of return to susceptibility.

Decision Making Within and Outside Standard Operating Procedures: Paradoxical Use of Operational Discretion in Firefighters.

OBJECTIVE: To understand how firefighters' use of rules (i.e., standard operating procedures [SOPs]) and deliberative decision making (i.e., operational discretion [OD]) interacts with acute stress. BACKGROUND: Current operational guidance for UK firefighters combines the provision of SOPs, for routine incidents, with the use of OD, under prescribed conditions (e.g., when there is a risk to human life). However, our understanding of the use of SOPs and OD is limited. METHODS: Incident commanders (ICs; n = 43) responded to simulated emergency incidents, which either licensed the use of OD or required use of a SOP. Video footage of IC behavior was used to code their response as involving a SOP or OD, while levels of acute stress were assessed using a blood-based measure and self-report. RESULTS: ICs were less likely to use OD selectively in the simulated emergency incident that licensed its use than in the one for which use of an SOP was appropriate; IC command level did not affect this pattern of results; and the incident that licensed OD resulted in more acute stress than the incident that required use of a SOP. CONCLUSION: SOPs and OD were not used in the manner prescribed by current operational guidance in simulated emergency incidents. APPLICATION: These results suggest that firefighter training in SOPs and OD should be augmented alongside personal resilience training, given the impact of stress on health and wellbeing, but also to improve the deployment of SOPs and OD under stress.

Subjective and objective survey of office lighting: effects on alertness, comfort, satisfaction, and safety.

BACKGROUND: Lighting is one of the workplace factors that can relevantly impact workers' health, performance, safety, and job satisfaction. Brightness, natural light and color temperature are the factors that affect the quality of lighting. This study involved subjective and objective evaluation of office lighting and its effects on workers' alertness, comfort, satisfaction, safety, and performance in a prominent government office. METHODS: Visual comfort, alertness, performance, safety and satisfaction were assessed subjectively using the questionnaires and rating scales. Moreover, illuminance, color temperature of light sources, and natural light availability were evaluated objectively. RESULTS:  The findings of this study indicated that the use of natural light in the workplace could increase the illuminance and color temperature of light in the workplace and improve alertness, visual comfort, satisfaction and worker's preference. Conclusions: To improve the quality of lighting in the workplace, factors affecting it, such as the color temperature and the availability of natural light, should be considered.

An investigation of the effects of different shift schedules on the fatigue and sleepiness of officers on oil tankers during cargo handling operations.

Cargo handling is an operation, which requires a high level of performance from the officer of the watch (OOW). This study aimed to investigate the effect of different shift schedules on sleep quality, cognitive performance, and sleepiness of 139 OOWs on oil tankers with 4on-8off shifts, during the first shift of cargo handling. Sleep quality (Pittsburgh Sleep Quality Index (PSQI)), level of sleepiness (the Karolinska Sleepiness Scale (KSS)), Psychomotor Vigilance Task (PVT), and Arrow Flanker task performance were examined. The results showed that OOWs with (00:00-04:00, 12:00-16:00) and (04:00-08:00, 16:00-20:00) shifts had impaired cognitive performance and higher sleepiness during the cargo handling operation, and they also experienced impaired sleep quality. The results demonstrated that the circadian rhythm and homeostatic sleep drive have a greater impact on cognitive performance and sleepiness than time on shifts. These results suggest that allocating rest hours immediately before the cargo handling operation may reduce the risk of fatigue. Practitioner Summary: To the best of our knowledge, this maritime field study shows for the first time the prevalence of seafarers' sleepiness and cognitive performance while on duty during cargo handling, using a pre-post shift comparison between three different shifts. The results show the negative effects of keeping watch at night on sleep quality, sleepiness, and the impaired cognitive performance both in the day and the night shifts.

Use of Imaging to Optimise Prostate Cancer Tumour Volume Assessment for Focal Therapy Planning.

PURPOSE OF REVIEW: Rapid advances in imaging of the prostate have facilitated the development of focal therapy and provided a non-invasive method of estimating tumour volume. Focal therapy relies on an accurate estimate of tumour volume for patient selection and treatment planning so that the optimal energy dose can be delivered to the target area(s) of the prostate while minimising toxicity to surrounding structures. This review provides an overview of different imaging modalities which may be used to optimise tumour volume assessment and critically evaluates the published evidence for each modality. RECENT FINDINGS: Multi-parametric MRI (mp-MRI) has become the standard tool for patient selection and guiding focal therapy treatment. The current evidence suggests that mp-MRI may underestimate tumour volume, although there is a large variability in results. There remain significant methodological challenges associated with pathological processing and accurate co-registration of histopathological data with mp-MRI. Advances in different ultrasound modalities are showing promise but there has been limited research into tumour volume estimation. The role of PSMA PET/CT is still evolving and further investigation is needed to establish if this is a viable technique for prostate tumour volumetric assessment. mp-MRI provides the necessary tumour volume information required for selecting patients and guiding focal therapy treatment. The potential for underestimation of tumour volume should be taken into account and an additional margin applied to ensure adequate treatment coverage. At present, there are no other viable image-based alternatives although advances in new technologies may refine volume estimations in the future.

Ethnicity, work-related stress and subjective reports of health by migrant workers: a multi-dimensional model.

OBJECTIVES: This study integrates different aspects of ethnicity and work-related stress dimensions (based on the Demands-Resources-Individual-Effects model, DRIVE [Mark, G. M., and A. P. Smith. 2008. "Stress Models: A Review and Suggested New Direction." In Occupational Health Psychology, edited by J. Houdmont and S. Leka, 111-144. Nottingham: Nottingham University Press]) and aims to test a multi-dimensional model that combines individual differences, ethnicity dimensions, work characteristics, and perceived job satisfaction/stress as independent variables in the prediction of subjectives reports of health by workers differing in ethnicity. DESIGN: A questionnaire consisting of the following sections was submitted to 900 workers in Southern Italy: for individual and cultural characteristics, coping strategies, personality behaviours, and acculturation strategies; for work characteristics, perceived job demands and job resources/rewards; for appraisals, perceived job stress/satisfaction and racial discrimination; for subjective reports of health, psychological disorders and general health. To test the reliability and construct validity of the extracted factors referred to all dimensions involved in the proposed model and logistic regression analyses to evaluate the main effects of the independent variables on the health outcomes were conducted. RESULTS: Principal component analysis (PCA) yielded seven factors for individual and cultural characteristics (emotional/relational coping, objective coping, Type A behaviour, negative affectivity, social inhibition, affirmation/maintenance culture, and search identity/adoption of the host culture); three factors for work characteristics (work demands, intrinsic/extrinsic rewards, and work resources); three factors for appraisals (perceived job satisfaction, perceived job stress, perceived racial discrimination) and three factors for subjective reports of health (interpersonal disorders, anxious-depressive disorders, and general health). Logistic regression analyses showed main effects of specific individual and cultural differences, work characteristics and perceived job satisfaction/stress on the risk of suffering health problems. CONCLUSION: The suggested model provides a strong framework that illustrates how psychosocial and individual variables can influence occupational health in multi-cultural workplaces.

Task Engagement and Attentional Resources.

OBJECTIVE: Two studies tested multivariate models of relationships between subjective task engagement and vigilance. The second study included a stress factor (cold infection). Modeling tested relationships between latent factors for task engagement and vigilance, and the role of engagement in mediating effects of cold infection. BACKGROUND: Raja Parasuraman's research on vigilance identified several key issues, including the roles of task factors, arousal processes, and individual differences, within the framework of resource theory. Task engagement is positively correlated with performance on various attentional tasks and may serve as a marker for resource availability. METHOD: In the first study, 229 participants performed simultaneous and successive vigilance tasks. In the second study, 204 participants performed a vigilance task and a variable-foreperiod simple reaction-time task on two separate days. On the second day, 96 participants performed while infected with a naturally occurring common cold. Task engagement was assessed in both studies. RESULTS: In both studies, vigilance decrement in hit rate was observed, and task performance led to loss of task engagement. Cold infection also depressed both vigilance and engagement. Fitting structural equation models indicated that simultaneous and successive tasks should be represented by separate latent factors (Study 1), and task engagement fully mediated the impact of cold infection on vigilance but not reaction time (Study 2). CONCLUSIONS: Modeling individual differences in task engagement elucidates the role of resources in vigilance and underscores the relevance of Parasuraman's vision of the field. APPLICATION: Assessment of task engagement may support diagnostic monitoring of operators performing tasks requiring vigilance.

Female urinary incontinence and wellbeing: results from a multi-national survey.

BACKGROUND: Previous research has shown that the severity of symptoms of urinary incontinence impacts on quality of life and wellbeing. The aim of this article is to investigate the relationship between female urinary incontinence and mental wellbeing. This involved analyses comparing those with UI and those without to determine whether any differences in wellbeing were modified by demographic factors, specific wellbeing domain, or exercise and frequency of sex. Following this, further analyses compared sub-groups of those with UI (based on the impact of the UI) to determine which characteristics were important in influencing wellbeing. METHODS: An internet survey of women with UI, aged between 45 and 60 years, has been previously reported and this article reports secondary analyses of that data. A sample from 4 countries: the UK, France, Germany and the USA. Two thousand four hundred three women completed the survey, 1203 with UI and 1200 who did not report UI. The main outcome measures were the scores from the Warwick-Edinburgh Mental Wellbeing Scale (WEMWBS). RESULTS: The results showed that lower wellbeing is observed in UI. This effect is observed in all aspects of wellbeing and most sub-groups of UI sufferers. Lifestyle influences wellbeing and those with UI who exercise less frequently or have sex infrequently are especially likely to report lower wellbeing. Wellbeing decreases as a function of the indirect measures of severity of UI and reductions in HRQol. Again, these changes reflect all aspects of wellbeing measured by WEMWBS. CONCLUSIONS: The results show that women with UI, aged 45-60 years, report lower wellbeing. This effect was not modified by demographic factors and was apparent in most of the domains measured by the WEMWBS. The reduced wellbeing was related to the impact of the UI on behaviour, embarrassment associated with it, and frequency of leakage.

Impact of a Pharmacist-Initiated Vancomycin Monitoring Program.

OBJECTIVES: Evaluate the clinical impact of pharmacist-initiated vancomycin monitoring and dosing in a long-term care setting. DESIGN: Single-center, pretest, post-test design. SETTING: Rutland Nursing Home, Brooklyn, New York. PARTICIPANTS: Nursing facility residents treated with intravenous vancomycin (N = 198). OUTCOME MEASURES: The primary objective is to determine the incidence of acute kidney injury (AKI) a year before and a year after implementation of a pharmacist-initiated vancomycin-monitoring protocol. The secondary objectives are percentage of serum drug levels in therapeutic range and compliance with laboratory testing for monitoring of nephrotoxicity. RESULTS: The overall incidence of AKI decreased from 16.3% (8/49) to 4.7% (7/149) (P = 0.013). Compliance with weekly monitoring for nephrotoxicity via serum creatinine and blood urea nitrogen improved from 76% (37/49) to 95% (141/149) (P ≤ 0.001). Compliance with weekly vancomycin level monitoring improved from 71% (35/49) to 85% (126/149) (P = 0.041). Percentage of vancomycin trough levels in the therapeutic range of 10-20 mcg/mL were shown to have no difference between two groups, but vancomycin levels > 20 mcg/mL decreased from 31% (15/49) to 17% (26/149) (P = 0.048). CONCLUSION: Implementation of pharmacist-driven vancomycin monitoring significantly improved monitoring compliance of vancomycin serum levels and kidney function as well as reduced the incidence of AKI in the long-term care setting.

The impact of urinary incontinence on health-related quality of life (HRQoL) in a real-world population of women aged 45-60 years: results from a survey in France, Germany, the UK and the USA.

OBJECTIVE: To develop a clear understanding of the relationship between severity of urinary incontinence (UI) and health-related quality of life (HRQoL) and mental well-being in a population of women of working age with the requisite demands of a busy, active life. SUBJECTS AND METHODS: A survey of women with UI, aged between 45 and 60 years, was conducted via the internet in the UK, France, Germany and USA between 1 and 30 September 2013. Validated outcome measures were used to assess symptoms and the impact of UI on activities of daily life, HRQoL, and mental well-being: The International Consultation on Incontinence Modular Questionnaire Short Form; (ICIQ-UI Short Form); the ICIQ-Lower Urinary Tract Symptoms Quality of Life; (ICIQ-LUTSqol); the Warwick-Edinburgh Mental Well-being Scale (WEMWBS). The relationships between UI, HRQoL and mental well-being were analysed using analyses of variance and regression. RESULTS: The survey was completed by 1203 women with UI with an average age of 52.7 years. Based upon responses to the ICIQ-UI Short Form about the amount of urine that leaks, respondents were categorised as having light (n = 1023, 87%), medium (n = 134, 11%), or severe UI (n = 20, 2%). The scores on the ICIQ-UI Short Form increased with severity [mean (sd) scores: light UI 7.9 (3.4), medium UI 13.8 (2.9), and severe UI 18.3 (3.9)], as did the impact on HRQoL, assessed using the ICIQ-LUTSqol [mean (sd) scores: light UI 30.6 (7.3), medium UI 41.0 (11.2), and severe UI 56.9 (17.6)]. Mental well-being decreased with severity of UI, the mean (se) WEMWBS scores were: light UI 48.3 (10.1), medium UI 44.5 (9.5), and severe UI 39.9 (16.2). CONCLUSION: In women with UI, aged 45-60 years, UI symptoms directly affect HRQoL, which subsequently impacts negatively on mental well-being.

The Tradeoffs Between Persistence and Mutation Rates at Sub-Inhibitory Antibiotic Concentrations in Staphylococcus aureus.

The rational design of the antibiotic treatment of bacterial infections employs these drugs to reach concentrations that exceed the minimum needed to prevent the replication of the target bacteria. However, within a treated patient, spatial and physiological heterogeneity promotes antibiotic gradients such that the concentration of antibiotics at specific sites is below the minimum needed to inhibit bacterial growth. Here, we investigate the effects of sub-inhibitory antibiotic concentrations on three parameters central to bacterial infection and the success of antibiotic treatment, using in vitro experiments with Staphylococcus aureus and mathematical-computer simulation models. Our results, using drugs of six different classes, demonstrate that exposure to sub-inhibitory antibiotic concentrations not only alters the dynamics of bacterial growth but also increases the mutation rate to antibiotic resistance and decreases the rate of production of persister cells thereby reducing the persistence level. Understanding this trade-off between mutation rates and persistence levels resulting from sub-inhibitory antibiotic exposure is crucial for optimizing, and mitigating the failure of, antibiotic therapy.

A bacteriophage-based validation of a personal protective equipment doffing procedure to be used with high-consequence pathogens.

OBJECTIVE: To determine if the high-level personal protective equipment used in the treatment of high-consequence infectious diseases is effective at stopping the spread of pathogens to healthcare personnel (HCP) while doffing. BACKGROUND: Personal protective equipment (PPE) is fundamental to the safety of HCPs. HCPs treating patients with high-consequence infectious diseases use several layers of PPE, forming complex protective ensembles. With high-containment PPE, step-by-step procedures are often used for donning and doffing to minimize contamination risk to the HCP, but these procedures are rarely empirically validated and instead rely on following infection prevention best practices. METHODS: A doffing protocol video for a high-containment PPE ensemble was evaluated to determine potential contamination pathways. These potential pathways were tested using fluorescence and genetically marked bacteriophages. RESULTS: The experiments revealed existing protocols permit contamination pathways allowing for transmission of bacteriophages to HCPs. Updates to the doffing protocols were generated based on the discovered contamination pathways. This updated doffing protocol eliminated the movement of viable bacteriophages from the outside of the PPE to the skin of the HCP. CONCLUSIONS: Our results illustrate the need for quantitative, scientific investigations of infection prevention practices, such as doffing PPE.

The Internet and Loneliness.

The internet and related media play key roles in education, work, and leisure. It could be argued that people have better interpersonal interactions because of social media, which could reduce loneliness. But documented internet use patterns suggest that the internet increases loneliness. Studies conducted prior to and during the COVID-19 pandemic demonstrate an association between what's called "internet addiction" and loneliness, although findings vary with participant demographics and frequency and types of internet use. There is a need to conduct longitudinal research to determine the direction of causality and whether what we define as "balanced" internet behavior positively affects well-being.

Associations between Autistic and ADHD Traits and the Well-Being and Mental Health of University Students.

Research on autism and ADHD continues to increase, as does the research on well-being and mental health. There is a growing need to understand what factors impact mental health and well-being, and the question arises as to what factors impact mental health and well-being in autism and ADHD. The existing literature focuses on two different aspects when it comes to the well-being and mental health of autism in students. One aspect focuses on mental health and well-being in diagnosed neurodivergent individuals, and the other aspect focuses on associations between autistic and ADHD traits and mental health and well-being. In order to understand the impact on mental health in autism, an online survey using the Qualtrics platform was given to a sample of 430 university students. The survey used the well-being process questionnaire, the autism spectrum quotient, the ADHD self-report scale, and the strengths and difficulties questionnaire. The results showed significant correlations between anxiety, depression, and autistic and ADHD traits (all correlations > 0.2). These variables were also correlated with the well-being and SDQ outcomes and well-being predictors (all correlations > 0.2). The regression analyses showed significant associations between well-being outcomes and predictor variables and anxiety and depression, whereas the effects of autistic and ADHD traits were restricted to the SDQ outcomes (hyperactivity, conduct, and peer problems). Regression analyses were also conducted to determine whether a variable formed by combining autistic traits, ADHD, anxiety, and depression scores was a significant predictor of well-being and SDQ outcomes. The combined variable was associated with all outcome variables except the prosocial variable. This study provides the basis for further research for understanding the interaction between well-being, mental health, autism, and ADHD.

Psychosocial Work Conditions as Determinants of Well-Being in Jamaican Police Officers: The Mediating Role of Perceived Job Stress and Job Satisfaction.

Policing is considered a high-stress occupation due to the demanding nature of the job. Addressing police stress requires a detailed understanding of how psychosocial risk factors influence various aspects of their well-being. Moreover, an analysis of the direct effects of work conditions and the mediating effects of cognitive appraisals is also warranted. Using the Demands-Resources-Individual Effects (DRIVE) model of work-related stress this study investigated the direct effects of work conditions on well-being and also examined the intermediate role of perceived job stress and job satisfaction in the relationship between work conditions and well-being. Five hundred and seventy-eight police officers from the Jamaica Constabulary Force (J.C.F.) completed the questionnaire. Data were analyzed using hierarchical regressions and the Hayes Process tool for mediation analysis. Both perceived job stress and satisfaction mediated the relationship between work conditions and general physical health. Perceived job stress was an indirect pathway through which work conditions influenced psychological distress, whereas job satisfaction was not a significant mediator. In contrast, job satisfaction mediated the relationship between work conditions and positive well-being, but perceived job stress did not. These findings provide significant evidence for periodically monitoring and auditing perceptions of stress and job satisfaction, as they are likely precursors to subsequent health problems.

Exploring the Relationship Between Work Stress and Work-related Rumination.

Current studies lack adequate analysis of the antecedents of the two forms of work-related rumination. However, understanding the relationship between different types of stress and the two forms of rumination is of profound significance for eliminating the influence of negative rumination. In this project, three studies were conducted to investigate the cumulative and immediate effects of challenge and hindrance stress on affective rumination and problem-solving rumination based on one-time, two-time points and daily measurements. Participants were 1109, 605 and 111 employees from a variety of jobs in Chinese mainland. The results showed the relationship between hindrance stress and affective rumination varies over different time course. There was no significant correlation between hindrance stress and problem-solving rumination over any time course. The relationship between challenge stress and two forms of work-related rumination varies over different time course. The results of this study suggest that the antecedent analysis of work-related rumination should not only give attention to the type of work stress, but also consider the time of work stress when analyzing its aftereffects.

Reducing Work Withdrawal Behaviors When Faced with Work Obstacles: A Three-Way Interaction Model.

Work withdrawal behavior is a type of negative reaction when employees face obstacles at work. Its negative impact on individuals and organizations has caught the attention of academic circles and managers. In this study, data from 596 full-time employees were collected using two timepoint measurements one month apart. The internal mechanism of the link between obstructive stress and job withdrawal behavior was analyzed, and the combined effects of work control and cognitive flexibility on the negative effects of obstructive stress were analyzed in terms of the work demand-control-personal model. The results showed that negative work rumination played a complete mediating role between obstructive stress and work withdrawal behavior, and cognitive flexibility, obstructive stress, and work control had a significant three-way interaction. The results suggest that more attention should be paid to the role of employee cognition to avoid employees' withdrawal behavior in the face of work obstacles. In addition, when providing work resources to employees, the organization should also consider ensuring that work resources can be fully utilized to play a positive role in buffering work obstacles.

Development of an emergency medicine pharmacy intensity score tool.

PURPOSE: Emergency medicine pharmacists (EMPs) have been demonstrated to have a positive impact on patient outcomes in a variety of clinical scenarios in the emergency department (ED), yet their distribution across the nation is suboptimal. An emergency medicine pharmacy intensity score tool (EMPIST) would not only facilitate the quantification of EMP staffing needs and ideal resource deployment times, but would also allow practitioners to triage patient care activities. The purpose of this investigation was to develop an EMPIST and evaluate its relationship to EMP activities. METHODS: This was a multicenter, prospective, observational analysis of an EMPIST developed by practicing EMPs. EMPs prospectively documented their clinical activities during usual care for patients in their ED. Spearman's rank-order correlation was used to determine any correlation between the EMPIST and pharmacist activities. RESULTS: In total, 970 EMP activities and 584 EMPIST items were documented in 352 patients by 7 EMPs across 7 different EDs. The most commonly documented EMP interventions performed were bedside monitoring (12.7%), initiation of nonantimicrobial therapy (12.6%), and antimicrobial therapy initiation and streamlining (10.6%). The total EMPIST was found to significantly correlate with EMP activities, and this correlation was consistent across both "diagnostic/presentation" and "medication" items (P < 0.001 for all comparisons). CONCLUSION: The EMPIST significantly correlated with EMP activities, with consistent correlation across all subgroups. Its utilization has the potential to enhance bedside clinical practice and optimize the deployment of limited EMP services. Additional investigations are needed to examine the validity of this tool and identify any relationship it may have to patient outcomes.

What's the Matter with MICs: Bacterial Nutrition, Limiting Resources, and Antibiotic Pharmacodynamics.

The MIC of an antibiotic required to prevent replication is used both as a measure of the susceptibility/resistance of bacteria to that drug and as the single pharmacodynamic parameter for the rational design of antibiotic treatment regimes. MICs are experimentally estimated in vitro under conditions optimal for the action of the antibiotic. However, bacteria rarely grow in these optimal conditions. Using a mathematical model of the pharmacodynamics of antibiotics, we make predictions about the nutrient dependency of bacterial growth in the presence of antibiotics. We test these predictions with experiments in broth and a glucose-limited minimal media with Escherichia coli and eight different antibiotics. Our experiments question the sufficiency of using MICs and simple pharmacodynamic functions as measures of the pharmacodynamics of antibiotics under the nutritional conditions of infected tissues. To an extent that varies among drugs: (i) the estimated MICs obtained in rich media are greater than those estimated in minimal media; (ii) exposure to these drugs increases the time before logarithmic growth starts, their lag; and (iii) the stationary-phase density of E. coli populations declines with greater sub-MIC antibiotic concentrations. We postulate a mechanism to account for the relationship between sub-MICs of antibiotics and these growth parameters. This study is limited to a single bacterial strain and two types of culture media with different nutritive content. These limitations aside, the results of our study clearly question the use of MIC as the unique pharmacodynamic parameter to develop therapeutically oriented protocols. IMPORTANCE For studies of antibiotics and how they work, the most-often used measurement of drug efficacy is the MIC. The MIC is the concentration of an antibiotic needed to inhibit bacterial growth. This parameter is critical to the design and implementation of antibiotic therapy. We provide evidence that the use of MIC as the sole measurement for antibiotic efficacy ignores important aspects of bacterial growth dynamics. Before now, there has not been a nexus between bacteria, the conditions in which they grow, and the MIC. Most importantly, few studies have considered sub-MICs of antibiotics, despite their clinical importance. Here, we explore these concentrations in-depth, and we demonstrate MIC to be an incomplete measure of how an infection will interact with a specific antibiotic. Understanding the critiques of MIC is the first of many steps needed to improve infectious disease treatment.

The Evolution of Heteroresistance via Small Colony Variants in Escherichia coli Following Long Term Exposure to Bacteriostatic Antibiotics.

Traditionally, bacteriostatic antibiotics are agents able to arrest bacterial growth. Despite being unable to kill bacterial cells, when they are used clinically the outcome of these drugs is frequently as effective as when a bactericidal drug is used. We explore the dynamics of Escherichia coli after exposure to two ribosome-targeting bacteriostatic antibiotics, chloramphenicol and azithromycin, for thirty days. The results of our experiments provide evidence that bacteria exposed to these drugs replicate, evolve, and generate a sub-population of small colony variants (SCVs) which are resistant to multiple drugs. These SCVs contribute to the evolution of heteroresistance and rapidly revert to a susceptible state once the antibiotic is removed. Stated another way, exposure to bacteriostatic drugs selects for the evolution of heteroresistance in populations previously lacking this trait. More generally, our results question the definition of bacteriostasis as populations exposed to bacteriostatic drugs are replicating despite the lack of net growth.