Antimicrobial Resistance as Risk Factor for Recurrent Bacteremia after Staphylococcus aureus, Escherichia coli, or Klebsiella spp. Community-Onset Bacteremia.

We investigated links between antimicrobial resistance in community-onset bacteremia and 1-year bacteremia recurrence by using the clinical data warehouse of Europe's largest university hospital group in France. We included adult patients hospitalized with an incident community-onset Staphylococcus aureus, Escherichia coli, or Klebsiella spp. bacteremia during 2017-2019. We assessed risk factors of 1-year recurrence using Fine-Gray regression models. Of the 3,617 patients included, 291 (8.0%) had >1 recurrence episode. Third-generation cephalosporin (3GC)-resistance was significantly associated with increased recurrence risk after incident Klebsiella spp. (hazard ratio 3.91 [95% CI 2.32-6.59]) or E. coli (hazard ratio 2.35 [95% CI 1.50-3.68]) bacteremia. Methicillin resistance in S. aureus bacteremia had no effect on recurrence risk. Although several underlying conditions and infection sources increased recurrence risk, 3GC-resistant Klebsiella spp. was associated with the greatest increase. These results demonstrate a new facet to illness induced by 3GC-resistant Klebsiella spp. and E. coli in the community setting.

Care pathways of sepsis survivors: sequelae, mortality and use of healthcare services in France, 2015-2018.

BACKGROUND: Individuals who survive sepsis are at high risk of chronic sequelae, resulting in significant health-economic costs. Several studies have focused on aspects of healthcare pathways of sepsis survivors but comprehensive, longitudinal overview of their pathways of care are scarce. The aim of this retrospective, longitudinal cohort study is to identify sepsis survivor profiles based on their healthcare pathways and describe their healthcare consumption and costs over the 3 years following their index hospitalization. METHODS: The data were extracted from the French National Hospital Discharge Database. The study population included all patients above 15 years old, with bacterial sepsis, who survived an incident hospitalization in an acute care facility in 2015. To identify survivor profiles, state sequence and clustering analyses were conducted over the year following the index hospitalization. For each profile, patient characteristics and their index hospital stay and sequelae were described, as well as use of care and its associated monetary costs, both pre- and post-sepsis. RESULTS: New medical (79.2%), psychological (26.9%) and cognitive (18.5%) impairments were identified post-sepsis, and 65.3% of survivors were rehospitalized in acute care. Cumulative mortality reached 36.6% by 3 years post-sepsis. The total medical cost increased by 856 million € in the year post-sepsis. Five patient clusters were identified: home (65.6% of patients), early death (12.9%), late death (6.8%), short-term rehabilitation (11.3%) and long-term rehabilitation (3.3%). Survivors with early and late death clusters had high rates of cancer and primary bacteremia and experienced more hospital-at-home care post-sepsis. Survivors in short- or long-term rehabilitation clusters were older, with higher percentage of septic shock than those coming back home, and had high rates of multiple site infections and higher rates of new psychological and cognitive impairment. CONCLUSIONS: Over three years post-sepsis, different profiles of sepsis survivors were identified with different mortality rates, sequels and healthcare services usage and cost. This study confirmed the importance of sepsis burden and suggests that strategies of post-discharge care, in accordance with patient profile, should be further tested in order to reduce sepsis burden.

One-year hospital readmission for recurrent sepsis: associated risk factors and impact on 1-year mortality-a French nationwide study.

BACKGROUND: Sepsis is a complex health condition, leading to long-term morbidity and mortality. Understanding the risk factors for recurrent sepsis, as well as its impact on mid- and long-term mortality among other risk factors, is essential to improve patient survival. METHODS: A risk factor analysis, based on French nationwide medico-administrative data, was conducted on a cohort of patients above 15 years old, hospitalized with an incident sepsis in metropolitan France between 1st January 2018 and 31st December 2018 and who survived their index hospitalization. Two main analyses, focusing on outcomes occurring 1-year post-discharge, were conducted: a first one to assess risk factors for recurrent sepsis and a second to assess risk factors for mortality. RESULTS: Of the 178017 patients surviving an incident sepsis episode in 2018 and included in this study, 22.3% died during the 1-year period from discharge and 73.8% had at least one hospital readmission in acute care, among which 18.1% were associated with recurrent sepsis. Patients aged between 56 and 75, patients with cancer and renal disease, with a long index hospital stay or with mediastinal or cardiac infection had the highest odds of recurrent sepsis. One-year mortality was higher for patients with hospital readmission for recurrent sepsis (aOR 2.93; 99% CI 2.78-3.09). Among all comorbidities, patients with cancer (aOR 4.35; 99% CI 4.19-4.52) and dementia (aOR 2.02; 99% CI 1.90-2.15) had the highest odds of 1-year mortality. CONCLUSION: Hospital readmission for recurrent sepsis is one of the most important risk factors for 1-year mortality of septic patients, along with age and comorbidities. Our study suggests that recurrent sepsis, as well as modifiable or non-modifiable other risk factors identified, should be considered in order to improve patient care pathway and survival.

Unraveling the seasonal epidemiology of pneumococcus.

Infections caused by Streptococcus pneumoniae-including invasive pneumococcal diseases (IPDs)-remain a significant public health concern worldwide. The marked winter seasonality of IPDs is a striking, but still enigmatic aspect of pneumococcal epidemiology in nontropical climates. Here we confronted age-structured dynamic models of carriage transmission and disease with detailed IPD incidence data to test a range of hypotheses about the components and the mechanisms of pneumococcal seasonality. We find that seasonal variations in climate, influenza-like illnesses, and interindividual contacts jointly explain IPD seasonality. We show that both the carriage acquisition rate and the invasion rate vary seasonally, acting in concert to generate the marked seasonality typical of IPDs. We also find evidence that influenza-like illnesses increase the invasion rate in an age-specific manner, with a more pronounced effect in the elderly than in other demographics. Finally, we quantify the potential impact of seasonally timed interventions, a type of control measures that exploit pneumococcal seasonality to help reduce IPDs. Our findings shed light on the epidemiology of pneumococcus and may have notable implications for the control of pneumococcal infections.

Antibiotic prescriptions and risk factors for antimicrobial resistance in patients hospitalized with urinary tract infection: a matched case-control study using the French health insurance database (SNDS).

BACKGROUND: Antibiotic resistance is increasing among urinary pathogens, resulting in worse clinical and economic outcomes. We analysed factors associated with antibiotic-resistant bacteria (ARB) in patients hospitalized for urinary tract infection, using the comprehensive French national claims database. METHODS: Hospitalized urinary tract infections were identified from 2015 to 2017. Cases (due to ARB) were matched to controls (without ARB) according to year, age, sex, infection, and bacterium. Healthcare-associated (HCAI) and community-acquired (CAI) infections were analysed separately; logistic regressions were stratified by sex. RESULTS: From 9460 cases identified, 6468 CAIs and 2855 HCAIs were matched with controls. Over a 12-months window, the risk increased when exposure occurred within the last 3 months. The following risk factors were identified: antibiotic exposure, with an OR reaching 3.6 [2.8-4.5] for men with CAI, mostly associated with broad-spectrum antibiotics; surgical procedure on urinary tract (OR 2.0 [1.5-2.6] for women with HCAI and 1.3 [1.1-1.6] for men with CAI); stay in intensive care unit > 7 days (OR 1.7 [1.2-2.6] for men with HCAI). Studied co-morbidities had no impact on ARB. CONCLUSIONS: This study points out the critical window of 3 months for antibiotic exposure, confirms the impact of broad-spectrum antibiotic consumption on ARB, and supports the importance of prevention during urological procedures, and long intensive care unit stays.

Self- and parent-reported Quality of Life 7 years after severe childhood traumatic brain injury in the Traumatisme Grave de l'Enfant cohort: associations with objective and subjective factors and outcomes.

PURPOSE: To investigate self- and parent-reported Health-Related Quality-of-Life (HRQoL) and their associations after severe childhood traumatic brain injury (TBI) in the Traumatisme Grave de l'Enfant (TGE) cohort. METHODS: Self- (n = 34) and/or parent-reports (n = 25) of HRQoL were collected for 38 participants (age 7-22 years) 7 years after severe childhood TBI. The collected data included sociodemographic characteristics, injury severity indices, and overall disability and functional outcome at 3-months, 1- and 2-years post-injury. At 7-years post-injury, data were collected in the TBI group and in a control group (n = 33): overall disability (Glasgow Outcome Scale Extended), intellectual ability (IQ), and questionnaires assessing HRQoL (Pediatric Quality of Life Inventory), executive functions (Behavior Rating Inventory of Executive Functions), behavior (Child Behavior Checklist), fatigue (Multidimensional Fatigue Scale) and participation (Child and Adolescent Scale of Participation). RESULTS: Parent- and self-reports of HRQoL were significantly lower in the TBI group than in the control group. Parent-rated HRQoL was not associated with objectively assessed factors, whereas self-reported HRQoL was associated with gender (worse in females) and initial functional outcome. All questionnaire scores completed by the same informant (self or parent) were strongly inter-correlated. CONCLUSIONS: Reported HRQoL 7-years after severe childhood TBI is low compared to controls, weakly or not-related to objective factors, such as injury severity indices, clinically assessed functional outcomes, or IQ, but strongly related to reports by the same informant of executive deficits, behavior problems, fatigue, and participation.

Self- and Parent-Reported Fatigue 7 Years After Severe Childhood Traumatic Brain Injury: Results of the Traumatisme Grave de l'Enfant Prospective Longitudinal Study.

OBJECTIVE: To investigate presence of and factors associated with self- and parent-reported fatigue 7 years after severe childhood traumatic brain injury (TBI) in the prospective longitudinal study TGE (Traumatisme Grave de l'Enfant-severe childhood trauma). METHODS: Self-reports and/or parent reports on the Multidimensional Fatigue Scale were collected for 38 participants (aged 7-22 years) 7 years after severe childhood TBI, and 33 controls matched for age, gender, and parental educational level. The data collected included sociodemographic characteristics, age at injury and injury severity scores, overall disability (Glasgow Outcome Scale Extended), intellectual outcome (Wechsler scales), and questionnaires assessing executive functions, health-related quality of life, behavior, and participation. RESULTS: Fatigue levels were significantly worse in the TBI than in the control group, especially for cognitive fatigue. Correlations of reported fatigue with age at injury, gender, TBI severity, and intellectual ability were moderate and often not significant. Fatigue was significantly associated with overall level of disability (Glasgow Outcome Scale Extended) and with all questionnaires completed by the same informant. CONCLUSION: High levels of fatigue were reported by 30% to 50% of patients 7 years after a severe childhood TBI. Reported fatigue explained more than 60% of the variance of reported health-related quality of life by the same informant (patient or parent).

Association of Pneumococcal Conjugate Vaccine Coverage With Pneumococcal Meningitis: An Analysis of French Administrative Areas, 2001-2016.

Geographic variations of invasive pneumococcal disease incidence and serotype distributions were observed after pneumococcal conjugate vaccine introduction at regional levels and among French administrative areas. The variations could be related to regional vaccine coverage (VC) variations that might have direct consequences for vaccination-policy impact on invasive pneumococcal disease, particularly pneumococcal meningitis (PM) incidence. We assessed vaccine impact from 2001 to 2016 in France by estimating the contribution of regional VC differences to variations of annual local PM incidence. Using a mixed-effect Poisson model, we showed that, despite some variations of VC among administrative areas, vaccine impact on vaccine-serotype PM was homogeneously confirmed among administrative areas. Compared with the prevaccine era, the cumulative VC impact on vaccine serotypes led, in 2016, to PM reductions ranging among regions from 87% (25th percentile) to 91% (75th percentile) for 7-valent pneumococcal conjugate vaccine serotypes and from 58% to 63% for the 6 additional 13-valent pneumococcal conjugate vaccine serotypes. Nonvaccine-serotype PM increases from the prevaccine era ranged among areas from 98% to 127%. By taking into account the cumulative impact of growing VC and VC differences, our analyses confirmed high vaccine impact on vaccine-serotype PM case rates and suggest that VC variations cannot explain PM administrative area differences.

Characterizing and Comparing the Seasonality of Influenza-Like Illnesses and Invasive Pneumococcal Diseases Using Seasonal Waveforms.

The seasonalities of influenza-like illnesses (ILIs) and invasive pneumococcal diseases (IPDs) remain incompletely understood. Experimental evidence indicates that influenza-virus infection predisposes to pneumococcal disease, so that a correspondence in the seasonal patterns of ILIs and IPDs might exist at the population level. We developed a method to characterize seasonality by means of easily interpretable summary statistics of seasonal shape-or seasonal waveforms. Nonlinear mixed-effects models were used to estimate those waveforms based on weekly case reports of ILIs and IPDs in 5 regions spanning continental France from July 2000 to June 2014. We found high variability of ILI seasonality, with marked fluctuations of peak amplitudes and peak times, but a more conserved epidemic duration. In contrast, IPD seasonality was best modeled by a markedly regular seasonal baseline, punctuated by 2 winter peaks in late December to early January and January to February. Comparing ILI and IPD seasonal waveforms, we found indication of a small, positive correlation. Direct models regressing IPDs on ILIs provided comparable results, even though they estimated moderately larger associations. The method proposed is broadly applicable to diseases with unambiguous seasonality and is well-suited to analyze spatially or temporally grouped data, which are common in epidemiology.

Revealing the Micro-scale Signature of Endemic Zoonotic Disease Transmission in an African Urban Setting.

The development of novel approaches that combine epidemiological and genomic data provides new opportunities to reveal the spatiotemporal dynamics of infectious diseases and determine the processes responsible for their spread and maintenance. Taking advantage of detailed epidemiological time series and viral sequence data from more than 20 years reported by the National Reference Centre for Rabies of Bangui, the capital city of Central African Republic, we used a combination of mathematical modeling and phylogenetic analysis to determine the spatiotemporal dynamics of rabies in domestic dogs as well as the frequency of extinction and introduction events in an African city. We show that although dog rabies virus (RABV) appears to be endemic in Bangui, its epidemiology is in fact shaped by the regular extinction of local chains of transmission coupled with the introduction of new lineages, generating successive waves of spread. Notably, the effective reproduction number during each wave was rarely above the critical value of 1, such that rabies is not self-sustaining in Bangui. In turn, this suggests that rabies at local geographic scales is driven by human-mediated dispersal of RABV among sparsely connected peri-urban and rural areas as opposed to dispersion in a relatively large homogenous urban dog population. This combined epidemiological and genomic approach enables development of a comprehensive framework for understanding disease persistence and informing control measures, indicating that control measures are probably best targeted towards areas neighbouring the city that appear as the source of frequent incursions seeding outbreaks in Bangui.

Estimation of exposure-attributable fractions from time series: A simulation study.

Burden analysis in public health often involves the estimation of exposure-attributable fractions from observed time series. When the entire population is exposed, the association between the exposure and outcome must be carefully modelled before the attributable fractions can be estimated. This article derives asymptotic convergences for the estimation of attributable fractions for commonly used time series models (ARMAX, Poisson, negative binomial, and Serfling), using for the most part the delta method. For the Poisson regression, the estimation of the attributable fraction is achieved by a Monte Carlo algorithm, taking into account both an estimation and a prediction error. A simulation study compares these estimations in the case of an epidemic exposure and highlights the importance of thorough analysis of the data: When the outcome is generated under an additive model, the additive models are satisfactory, and the multiplicative models are poor, and vice versa. However, the Serfling model performs poorly in all cases. Of note, a misspecification in the form or delay of the association between the exposure and the outcome leads to mediocre estimation of the attributable fraction. An application to the fraction of French outpatient antibiotic use attributable to influenza between 2003 and 2010 illustrates the asymptotic convergences. This study suggests that the Serfling model should be avoided when estimating attributable fractions while the model of choice should be selected after careful investigation of the association between the exposure and outcome.

An agent-based model simulation of influenza interactions at the host level: insight into the influenza-related burden of pneumococcal infections.

BACKGROUND: Host-level influenza virus-respiratory pathogen interactions are often reported. Although the exact biological mechanisms involved remain unelucidated, secondary bacterial infections are known to account for a large part of the influenza-associated burden, during seasonal and pandemic outbreaks. Those interactions probably impact the microorganisms' transmission dynamics and the influenza public health toll. Mathematical models have been widely used to examine influenza epidemics and the public health impact of control measures. However, most influenza models overlooked interaction phenomena and ignored other co-circulating pathogens. METHODS: Herein, we describe a novel agent-based model (ABM) of influenza transmission during interaction with another respiratory pathogen. The interacting microorganism can persist in the population year round (endemic type, e.g. respiratory bacteria) or cause short-term annual outbreaks (epidemic type, e.g. winter respiratory viruses). The agent-based framework enables precise formalization of the pathogens' natural histories and complex within-host phenomena. As a case study, this ABM is applied to the well-known influenza virus-pneumococcus interaction, for which several biological mechanisms have been proposed. Different mechanistic hypotheses of interaction are simulated and the resulting virus-induced pneumococcal infection (PI) burden is assessed. RESULTS: This ABM generates realistic data for both pathogens in terms of weekly incidences of PI cases, carriage rates, epidemic size and epidemic timing. Notably, distinct interaction hypotheses resulted in different transmission patterns and led to wide variations of the associated PI burden. Interaction strength was also of paramount importance: when influenza increased pneumococcus acquisition, 4-27% of the PI burden during the influenza season was attributable to influenza depending on the interaction strength. CONCLUSIONS: This open-source ABM provides new opportunities to investigate influenza interactions from a theoretical point of view and could easily be extended to other pathogens. It provides a unique framework to generate in silico data for different scenarios and thereby test mechanistic hypotheses.

Comparing antibiotic consumption between two European countries: are packages an adequate surrogate for prescriptions?

Defined daily doses (DDD) are the gold standard indicator for quantifying prescriptions. Since 2014, the European Centre for Disease Prevention and Control (ECDC) has also been using the number of packages per 1,000 inhabitants per day (ipd), as a surrogate for prescriptions, to report antibiotic consumption in the community and to perform comparisons between European Union (EU) countries participating in the European Surveillance of Antimicrobial Consumption Network (ESAC-Net). In 2015, consumption was reported to range across Europe from 1.0 to 4.7 packages per 1,000 ipd. Our analysis showed that consumption of antibiotics for systemic use per 1,000 ipd was on average 1.3 times greater in France than in Belgium when considering prescriptions in the numerator, 2.5 times greater when considering packages and 1.2 times greater when considering DDD. As long as the same metrics are used over time, antibiotic consumption data aggregated and disseminated by ECDC are useful for assessing temporal trends at the European level and within individual countries; these data may also be used for benchmarking across EU countries. While DDD - although imperfect - are the most widely accepted metric for this purpose, antibiotic packages do not appear suitable for comparisons between countries and may be misleading.

Impact of pneumococcal conjugate vaccines on pneumococcal meningitis cases in France between 2001 and 2014: a time series analysis.

BACKGROUND: Pneumococcal meningitis (PM) is a major invasive pneumococcal disease. Two pneumococcal conjugate vaccines (PCVs) have been introduced in France: PCV7 was recommended in 2003 and replaced in 2010 by PCV13, which has six additional serotypes. The impact of introducing those vaccines on the evolution of PM case numbers and serotype distributions in France from 2001 to 2014 is assessed herein. METHODS: Data on 5166 Streptococcus pneumoniae strains isolated from cerebrospinal fluid between 2001 and 2014 in the 22 regions of France were obtained from the National Reference Center for Pneumococci. The effects of the different vaccination campaigns were estimated using time series analyses through autoregressive moving-average models with exogenous variables ("flu-like" syndromes incidence) and intervention functions. Intervention functions used 11 dummy variables representing each post vaccine epidemiological period. The evolution of serotype distributions was assessed for the entire population and the two most exposed age groups (<5 and > 64 years old). RESULTS: For the first time since PCV7 introduction in 2003, total PM cases decreased significantly after starting PCV13 use: -7.1 (95% CI, -10.85 to -3.35) cases per month during 2013-2014, and was confirmed in children < 5 years old (-3.5; 95% CI, -4.81 to -2.13) and adults > 64 years old (-2.0; 95% CI, -3.36 to -0.57). During 2012-2014, different non-vaccine serotypes emerged: 12F, 24F in the entire population and children, 6C in the elderly; serotypes 3 and 19F persisted in the entire population. CONCLUSIONS: Unlike other European countries, the total PM cases in France declined only after introduction of PCV13. This suggests that vaccine pressure alone does not explain pneumococcal epidemiological changes and that other factors could play a role. Serotype distribution had changed substantially compared to the pre-vaccine era, as in other European countries, but very differently from the US. A highly reactive surveillance system is thus necessary not only to monitor evolutions due to vaccine pressure and to verify the local serotypic appropriateness of new higher-valent pneumococcal vaccines, but also to recognise and prevent unexpected changes due to other internal or external factors.

Nonsteroidal Anti-Inflammatory Drug without Antibiotics for Acute Viral Infection Increases the Empyema Risk in Children: A Matched Case-Control Study.

OBJECTIVE: To investigate the risk factors of empyema after acute viral infection and to clarify the hypothesized association(s) between empyema and some viruses and/or the use of nonsteroidal anti-inflammatory drugs (NSAIDs). STUDY DESIGN: A case-control study was conducted in 15 centers. Cases and controls were enrolled for a source population of children 3-15 years of age with acute viral infections between 2006 and 2009. RESULTS: Among 215 empyemas, 83 cases (children with empyema and acute viral infection within the 15 preceding days) were included, and 83 controls (children with acute viral infection) were matched to cases. Considering the intake of any drug within 72 hours after acute viral infection onset and at least 6 consecutive days of antibiotic use and at least 1 day of NSAIDs exposure, the multivariable analysis retained an increased risk of empyema associated with NSAIDs exposure (aOR 2.79, 95% CI 1.4-5.58, P = .004), and a decreased risk associated with antibiotic use (aOR 0.32, 95% CI 0.11-0.97, P = .04). The risk of empyema associated with NSAIDs exposure was greater for children not prescribed an antibiotic and antibiotic intake diminished that risk for children given NSAIDs. CONCLUSIONS: NSAIDs use during acute viral infection is associated with an increased risk of empyema in children, and antibiotics are associated with a decreased risk. The presence of antibiotic-NSAIDs interaction with this risk is suggested. These findings suggest that NSAIDs should not be recommended as a first-line antipyretic treatment during acute viral infections in children.

Burden of bacterial resistance among neonatal infections in low income countries: how convincing is the epidemiological evidence?

BACKGROUND: Antibiotic resistance is a threat in developing countries (DCs) because of the high burden of bacterial disease and the presence of risk factors for its emergence and spread. This threat is of particular concern for neonates in DCs where over one-third of neonatal deaths may be attributable to severe infections and factors such as malnutrition and HIV infection may increase the risk of death. Additional, undocumented deaths due to severe infection may also occur due to the high frequency of at-home births in DCs. METHODS: We conducted a systematic review of studies published after 2000 on community-acquired invasive bacterial infections and antibiotic resistance among neonates in DCs. Twenty-one articles met all inclusion criteria and were included in the final analysis. RESULTS: Ninety percent of studies recruited participants at large or university hospitals. The majority of studies were conducted in Sub-Saharan Africa (n=10) and the Indian subcontinent (n=8). Neonatal infection incidence ranged from 2.9 (95% CI 1.9-4.2) to 24 (95% CI 21.8-25.7) for 1000 live births. The three most common bacterial isolates in neonatal sepsis were Staphylococcus aureus, Escherichia coli, and Klebsiella. Information on antibiotic resistance was sparse and often relied on few isolates. The majority of resistance studies were conducted prior to 2008. No conclusions could be drawn on Enterobacteriaceae resistance to third generation cephalosporins or methicillin resistance among Staphylococcus aureus. CONCLUSIONS: Available data were found insufficient to draw a true, recent, and accurate picture of antibiotic resistance in DCs among severe bacterial infection in neonates, particularly at the community level. Existing neonatal sepsis treatment guidelines may no longer be appropriate, and these data are needed as the basis for updated guidelines. Reliable microbiological and epidemiological data at the community level are needed in DCs to combat the global challenge of antibiotic resistance especially among neonates among whom the burden is greatest.

Outpatient antibiotic use in France between 2000 and 2010: after the nationwide campaign, it is time to focus on the elderly.

Antibiotic overconsumption is the main force driving the emergence of multidrug-resistant bacterial strains. To promote better antibiotic use in France, a nationwide campaign has been run every year from October to March since 2002. In 2007, it was shown that winter outpatient antibiotic consumption had decreased by 26.5% compared to the 2000-2002 baseline period. Here, we quantified outpatient antibiotic use between 2000 and 2010 as a follow-up analysis of the nationwide campaign. Reimbursed outpatient antibiotic prescriptions were extracted from computerized French National Health Insurance databases. Entire series and age group and antibiotic class analyses were computed. Time series analyses used autoregressive moving-average models with exogenous variables and intervention functions. Two periods were considered: October to March "campaign" periods and April to September "warm" periods. Compared to the precampaign (2000-2002) baseline period, the numbers of weekly antibiotic prescriptions per 1,000 inhabitants during campaign periods decreased until winter 2006 to 2007 (-30% [95% confidence interval {CI}, -36.3 to -23.8%]; P < 0.001) and then stabilized except for individuals >60 years of age, for whom prescriptions reached the precampaign level. During the warm periods from April to September, no significant differences were estimated compared to the baseline level for the entire series, but seniors had an increasing trend that became significant as of 2005, reaching +21% (95% CI, +12.9 to +29.6%) in 2009 (P < 0.0001). These results highlight the need for a better understanding of antibiotic use by the elderly, requiring research with targeted and tailored public health actions for this population.

Hospital Burden of All-Cause Pneumonia and Nonbacteremic Pneumococcal Pneumonia in Adults in France Between 2013 and 2019.

Background: Community-acquired pneumonia (CAP) is associated with significant morbidity and mortality. The study objective was to describe the hospital burden of pneumonia in the adult population in France. Methods: This retrospective study was conducted from the National Health Insurance Database. All hospitalizations for pneumonia (all-cause) between 2013 and 2019 were included. Different risk categories for patients were established based on pneumococcal vaccine recommendations by French health authorities. Results: A total of 2 199 240 episodes of CAP were registered over the study period (annual mean, 314 177 [standard deviation, 17 818.6]); 75% occurred in patients aged ≥65 years, among whom 47% were not classified in the moderate- or high-risk categories recommended for French pneumococcal vaccination. The incidence of CAP increased with age (117.9, 395.3, and 1916.7 per 100 000 for the age groups 18-49, 50-64, and ≥65 years, respectively, in 2019). Furthermore, being at risk of pneumococcal disease resulted in more severe outcomes, including longer episode duration (mean, 14 days in low-risk vs 17 days in high-risk patients) and higher risk of referral to critical care units (from 20% to 27%), of rehospitalization up to 180 days (from 39% to 67%), of in-hospital death (from 12% to 19%), and of 1-year mortality (from 26% to 49%). Conclusions: This study establishes the incidence of CAP in adults in France, describes the significant burden of disease, and highlights the need for better prevention policies.

Assessing pneumococcal meningitis association with viral respiratory infections and antibiotics: insights from statistical and mathematical models.

Pneumococcus is an important human pathogen, highly antibiotic resistant and a major cause of bacterial meningitis worldwide. Better prevention requires understanding the drivers of pneumococcal infection incidence and antibiotic susceptibility. Although respiratory viruses (including influenza) have been suggested to influence pneumococcal infections, the underlying mechanisms are still unknown, and viruses are rarely considered when studying pneumococcus epidemiology. Here, we propose a novel mathematical model to examine hypothetical relationships between Streptococcus pneumoniae meningitis incidence (SPMI), acute viral respiratory infections (AVRIs) and antibiotic exposure. French time series of SPMI, AVRI and penicillin consumption over 2001-2004 are analysed and used to assess four distinct virus-bacteria interaction submodels, ascribing the interaction on pneumococcus transmissibility and/or pathogenicity. The statistical analysis reveals strong associations between time series: SPMI increases shortly after AVRI incidence and decreases overall as the antibiotic-prescription rate rises. Model simulations require a combined impact of AVRI on both pneumococcal transmissibility (up to 1.3-fold increase at the population level) and pathogenicity (up to threefold increase) to reproduce the data accurately, along with diminished epidemic fitness of resistant pneumococcal strains causing meningitis (0.97 (0.96-0.97)). Overall, our findings suggest that AVRI and antibiotics strongly influence SPMI trends. Consequently, vaccination protecting against respiratory virus could have unexpected benefits to limit invasive pneumococcal infections.