OutbreakFlow: Model-based Bayesian inference of disease outbreak dynamics with invertible neural networks and its application to the COVID-19 pandemics in Germany.

Mathematical models in epidemiology are an indispensable tool to determine the dynamics and important characteristics of infectious diseases. Apart from their scientific merit, these models are often used to inform political decisions and interventional measures during an ongoing outbreak. However, reliably inferring the epidemical dynamics by connecting complex models to real data is still hard and requires either laborious manual parameter fitting or expensive optimization methods which have to be repeated from scratch for every application of a given model. In this work, we address this problem with a novel combination of epidemiological modeling with specialized neural networks. Our approach entails two computational phases: In an initial training phase, a mathematical model describing the epidemic is used as a coach for a neural network, which acquires global knowledge about the full range of possible disease dynamics. In the subsequent inference phase, the trained neural network processes the observed data of an actual outbreak and infers the parameters of the model in order to realistically reproduce the observed dynamics and reliably predict future progression. With its flexible framework, our simulation-based approach is applicable to a variety of epidemiological models. Moreover, since our method is fully Bayesian, it is designed to incorporate all available prior knowledge about plausible parameter values and returns complete joint posterior distributions over these parameters. Application of our method to the early Covid-19 outbreak phase in Germany demonstrates that we are able to obtain reliable probabilistic estimates for important disease characteristics, such as generation time, fraction of undetected infections, likelihood of transmission before symptom onset, and reporting delays using a very moderate amount of real-world observations.

Transmission of Klebsiella pneumoniae carbapenemase (KPC)-producing Klebsiella pneumoniae: the role of infection control.

BACKGROUND: The worldwide spread of carbapenemase-producing Gram-negative bacteria (GNB) in healthcare settings is worrying. Of particular concern is the occurrence of Klebsiella pneumoniae carbapenemase (KPC)-producing Klebsiella pneumoniae (KP). In recent years, several guidelines and recommendations have focused on the control of carbapenem-resistant GNB. It remains, however, unknown to what extent individual infection control measures are effective. Our aim was to critically review the recent evidence regarding the effectiveness of measures to control KPC-KP spread in healthcare settings. METHODS: Critical review of the literature aiming to evaluate, in accordance with published recommendations, all available studies reporting infection control (IC) measures to control KPC-KP published in the past 5 years. RESULTS: Among 11 included studies, the majority consisted of outbreak reports, where application of measures was reported in the absence of control groups. Variability was observed related to the frequency of application of recommended measures for control of KPC-KP. Additional measures were recorded, such as environmental sampling and staff screening, whereas compliance with hand hygiene was measured in relatively few studies. Finally, mortality in patients harbouring KPC-KP was notable, reaching 42.9% of included patients. CONCLUSIONS: Despite successful control of KPC-KP spread during outbreaks, the impact of individual IC measures is difficult to assess, as the quality of published evidence is low and controlled intervention studies are lacking. The distribution of studies, the number of reported cases and the high mortality rates, clearly show that KPC-KP remains a major healthcare problem worldwide.

Tracing clinically-relevant antimicrobial resistances in Acinetobacter baumannii-calcoaceticus complex across diverse environments: A study spanning clinical, livestock, and wastewater treatment settings.

Acinetobacter baumannii has become a prominent nosocomial pathogen, primarily owing to its remarkable ability to rapidly acquire resistance to a wide range of antimicrobial agents and its ability to persist in diverse environments. However, there is a lack of data on the molecular epidemiology and its potential implications for public health of A. baumannii strains exhibiting clinically significant resistances that originate from non-clinical environments. Therefore, the genetic characteristics and resistance mechanisms of 80 A. baumannii-calcoaceticus (ABC) complex isolates, sourced from environments associated with poultry and pig production, municipal wastewater treatment plants (WWTPs), and clinical settings, were investigated. In total, our study classified 54 isolates into 29 previously described sequence types (STs), while 26 isolates exhibited as-yet-unassigned STs. We identified a broad range of A. baumannii STs originating from poultry and pig production environments (e.g., ST10, ST238, ST240, ST267, ST345, ST370, ST372, ST1112 according to Pasteur scheme). These STs have also been documented in clinical settings worldwide, highlighting their clinical significance. These findings also raise concerns about the potential zoonotic transmission of certain STs associated with livestock environments. Furthermore, we observed that clinical isolates exhibited the highest diversity of antimicrobial resistance genes (ARGs). In contrast to non-clinical isolates, clinical isolates typically carried a significantly higher number of ARGs, ranging from 10 to 15. They were also the exclusive carriers of biocide resistance genes and acquired carbapenemases (blaOXA-23, blaOXA-58, blaOXA-72, blaGIM-1, blaNDM-1). Additionally, we observed that clinical strains displayed an increased capacity for carrying plasmids and undergoing genetic transformation. This heightened capability could be linked to the intense selective pressures commonly found within clinical settings. Our study provides comprehensive insights into essential aspects of ABC isolates originating from livestock-associated environments and clinical settings. We explored their resistance mechanisms and potential implications for public health, providing valuable knowledge for addressing these critical issues.

Monocentric observational cohort study to investigate the transmission of third-generation cephalosporin-resistant Enterobacterales in a neonatal intensive care unit in Heidelberg, Germany.

Third-generation cephalosporin-resistant Enterobacterales is a major threat for newborns in neonatal intensive care units (NICUs). The route of acquisition in a non-outbreak setting should be investigated to implement adequate infection prevention measures. To identify risk factors for colonization with and to investigate the transmission pattern of third-generation cephalosporin-resistant Enterobacterales in a NICU setting. This monocentric observational cohort study in a tertiary NICU in Heidelberg, Germany, enrolled all hospitalized neonates screened for cephalosporin-resistant Enterobacterales. Data were collected from 1 January 2018 to 31 December 2021. Weekly screening by rectal swabs for colonization with third-generation cephalosporin-resistant Enterobacterales was performed for all newborns until discharge. Whole-genome sequencing was performed for molecular characterization and transmission analysis. In total, 1,287 newborns were enrolled. The median length of stay was 20 (range 1-250) days. Eighy-eight infants (6.8%) were colonized with third-generation cephalosporin-resistant Enterobacterales. Low birth weight [<1500 g (adjusted odds ratio, 5.1; 95% CI 2.2-11.5; P < 0.001)] and longer hospitalization [per 30 days (adjusted odds ratio, 1.7; 95% CI 1.5-2.0; P < 0.001)] were associated with colonization or infection with drug-resistant Enterobacterales in a multivariate analysis. Enterobacter cloacae complex was the most prevalent third-generation cephalosporin-resistant Enterobacterales detected, 64.8% (59 of 91). Whole-genome sequencing, performed for the available 85 of 91 isolates, indicated 12 transmission clusters involving 37 patients. This cohort study suggests that transmissions of third-generation cephalosporin-resistant Enterobacterales in newborns occur frequently in a non-outbreak NICU setting, highlighting the importance of surveillance and preventive measures in this vulnerable patient group. IMPORTANCE Preterm newborns are prone to infections. Therefore, infection prevention should be prioritized in this vulnerable patient group. However, outbreaks involving drug-resistant bacteria, such as third-generation resistant Enterobacterales, are often reported. Our study aims to investigate transmission and risk factors for acquiring third-generation cephalosporin-resistant Enterobacterales in a non-outbreak NICU setting. Our data indicated that premature birth and low birth weight are significant risk factors for colonization/infection with third-generation cephalosporin-resistant Enterobacterales. Furthermore, we could identify putative transmission clusters by whole-genome sequencing, highlighting the importance of preemptive measures to prevent infections in this patient collective.

Viral load of SARS-CoV-2 in surgical smoke in minimally invasive and open surgery: a single-center prospective clinical trial.

At the beginning of the COVID-19 pandemic, it was assumed that SARS-CoV-2 could be transmitted through surgical smoke generated by electrocauterization. Minimally invasive surgery (MIS) was targeted due to potentially higher concentrations of the SARS-CoV-2 particles in the pneumoperitoneum. Some surgical societies even recommended open surgery instead of MIS to prevent the potential spread of SARS-CoV-2 from the pneumoperitoneum. This study aimed to detect SARS-CoV-2 in surgical smoke during open and MIS. Patients with SARS-CoV-2 infection who underwent open surgery or MIS at Heidelberg University Hospital were included in the study. A control group of patients without SARS-CoV-2 infection undergoing MIS or open surgery was included for comparison. The trial was approved by the Ethics Committee of Heidelberg University Medical School (S-098/2021). The following samples were collected: nasopharyngeal and intraabdominal swabs, blood, urine, surgical smoke, and air samples from the operating room. An SKC BioSampler was used to sample the surgical smoke from the pneumoperitoneum during MIS and the approximate surgical field during open surgery in 15 ml of sterilized phosphate-buffered saline. An RT-PCR test was performed on all collected samples to detect SARS-CoV-2 viral particles. Twelve patients with proven SARS-CoV-2 infection underwent open abdominal surgery. Two SARS-CoV-2-positive patients underwent an MIS procedure. The control group included 24 patients: 12 underwent open surgery and 12 MIS. One intraabdominal swab in a patient with SARS-CoV-2 infection was positive for SARS-CoV-2. However, during both open surgery and MIS, none of the surgical smoke samples showed any detectable viral particles of SARS-CoV-2. The air samples collected at the end of the surgical procedure showed no viral particles of SARS-CoV-2. Major complications (CD ≥ IIIa) were more often observed in SARS-CoV-2 positive patients (10 vs. 4, p = 0.001). This study showed no detectable viral particles of SARS-CoV-2 in surgical smoke sampled during MIS and open surgery. Thus, the discussed risk of transmission of SARS-CoV-2 via surgical smoke could not be confirmed in the present study.

Forecasting local hospital bed demand for COVID-19 using on-request simulations.

Accurate forecasting of hospital bed demand is crucial during infectious disease epidemics to avoid overwhelming healthcare facilities. To address this, we developed an intuitive online tool for individual hospitals to forecast COVID-19 bed demand. The tool utilizes local data, including incidence, vaccination, and bed occupancy data, at customizable geographical resolutions. Users can specify their hospital's catchment area and adjust the initial number of COVID-19 occupied beds. We assessed the model's performance by forecasting ICU bed occupancy for several university hospitals and regions in Germany. The model achieves optimal results when the selected catchment area aligns with the hospital's local catchment. While expanding the catchment area reduces accuracy, it improves precision. However, forecasting performance diminishes during epidemic turning points. Incorporating variants of concern slightly decreases precision around turning points but does not significantly impact overall bed occupancy results. Our study highlights the significance of using local data for epidemic forecasts. Forecasts based on the hospital's specific catchment area outperform those relying on national or state-level data, striking a better balance between accuracy and precision. These hospital-specific bed demand forecasts offer valuable insights for hospital planning, such as adjusting elective surgeries to create additional bed capacity promptly.

Is virtual reality suitable for hand hygiene training in health care workers? Evaluating an application for acceptability and effectiveness.

BACKGROUND: For effective prevention of nosocomial transmissions continuous training and motivation of health care workers (HCW) are essential to maintain and increase compliance with high rates of hand hygiene. The use of Virtual Reality (VR) seems to be a contemporary and interesting approach for hand hygiene training in HCW. Nevertheless, HCW should be asked for their preferences as intrinsic motivation is essential for compliance with hand hygiene and training success should be evaluated. METHODS: A prospective, cross-controlled trial was conducted at two wards in a tertiary care hospital comparing a conventional lecture for hand hygiene to the use of VR. Both interventions were assigned at ward level. Primary outcome was HCW acceptance, which was verified in a third ward, secondary outcomes were hand rub consumption and compliance to indications for hand hygiene as proposed by WHO. RESULTS: In summary, 81 trainings were conducted, 48 VR trainings and 33 trainings by lecture. VR training was well accepted by HCW with a mean score in all items from 3.9 to 4.3 (out of 5). While most HCW (69%) would prefer VR teaching rather than a lecture for hand hygiene education, only 4% preferred the traditional lecture. 400 observations of hand hygiene indications were made, 50 before intervention and 50 after each intervention at the three wards. Mean proportion of correct and indication-appropriate performances was 81% before intervention, 87% after VR training (p = 0.12), and 95% after lecture (p = 0.04). Hand rub consumption did not change significantly in any group. CONCLUSIONS: Due to the high acceptance of VR technology among healthcare workers, it can be considered an interesting addition to conventional lectures for teaching hand hygiene. However, the hypothesis that VR teaching has a higher impact on hand rub use and hand hygiene compliance than a conventional lecture cannot be confirmed.

Cross-site collaboration on infection prevention and control research-room for improvement? A 7-year comparative study in five European countries.

BACKGROUND: The spread of SARS-CoV-2, multidrug-resistant organisms and other healthcare-associated pathogens represents supra-regional challenges for infection prevention and control (IPC) specialists in every European country. To tackle these problems, cross-site research collaboration of IPC specialists is very important. This study assesses the extent and quality of national research collaborations of IPC departments of university hospitals located in Austria, England, France, Germany, and the Netherlands, identifies network gaps, and provides potential solutions. METHODS: Joint publications of IPC heads of all university hospitals of the included countries between 1st of June 2013 until 31st of May 2020 were collected by Pubmed/Medline search. Further, two factors, the journal impact factor and the type/position of authorship, were used to calculate the Scientific Collaboration Impact (SCI) for all included sites; nationwide network analysis was performed. RESULTS: In five European countries, 95 sites and 125 responsible leaders for IPC who had been in charge during the study period were identified. Some countries such as Austria have only limited national research cooperations, while the Netherlands has established a gapless network. Most effective collaborating university site of each country were Lille with an SCI of 1146, Rotterdam (408), Berlin (268), Sussex (204), and Vienna/Innsbruck (18). DISCUSSION: The present study indicates major differences and room for improvement in IPC research collaborations within each country and underlines the potential and importance of collaborating in IPC.

Effect of didecyl dimethyl ammonium chloride-impregnated washcloth wipe whole-body bathing on catheter-related blood stream infections and central venous line-associated infections in adult intensive care units.

OBJECTIVE: To investigate the effect of daily whole-body bathing (WBB) using disposable washcloth wipes/caps impregnated with an antiseptic solution containing the quaternary ammonium base compound didecyl dimethyl ammonium chloride (DDAC). METHODS: A prospective double-blind randomized crossover trial was conducted to compare WBB of adult intensive care unit (ICU) patients with washcloth wipes/caps impregnated with either regular cleanser/shampoo or the antiseptic DDAC. The clinical trial was performed in a medical ICU (MICU) and a surgical ICU (SICU). The study period was divided into two 6-month intervals with alternating treatment regimens. RESULTS: A total of 1540 ICU patients (total length of ICU stay 10 470 days) were included in the trial. Compared to controls, DDAC bathing was found to be associated with reduced incidence rates per 1000 patient days for central-venous-line-associated infections (CLAIs) caused by Gram-positive bacteria (GPB) from 16.39 (95%CI 13.1-20.3) in the control group to 7.28 (95%CI 5.2-9.9) in the intervention group (p 0.01). A stratified analysis by unit showed that the incidence rates of CLAI due to GPB were reduced by the intervention in both the MICU and the SICU from 21.2 (95%CI 15.8-27.7) to 9.3 (95%CI 5.8-14.1) (p < 0.01) and from 12.1 (95%CI 8.3-17.0) to 5.7 (95%CI 3.4-9.1) (p 0.01), respectively. There was a trend towards reduction in catheter-related bloodstream infections (CRBSIs) and bloodstream infections (BSIs); however, this did not reach statistical significance due to carry-over effects and small numbers. CONCLUSIONS: Given the growing need for new concepts to prevent and control healthcare-associated infections, DDAC may be a new and promising agent for WBB of ICU patients.

Does the Reprocessing of Endoscopes Have to Take Place Immediately after Pre-Cleaning? A First Evaluation.

BACKGROUND/AIMS: The recommendations on the time interval between pre-cleaning and reprocessing of endoscopes differ in international guidelines, with a low level of evidence. The aim of this study was to investigate the influence of postponing reprocessing on the reprocessing quality after pre-cleaning the flexible endoscopes. METHODS: We reprocessed 124 standardized test tubes simulating endoscope channels after soiling and contamination and determined the reprocessing performance. In addition, we examined contaminated gastroscopes, colonoscopes, and bronchoscopes. The duration of interim storage after pre-cleaning was 16 h for 100 test tubes and up to 24 h for 18 endoscopes. We determined the residual protein content and germ load as markers for cleaning and disinfection performance. In addition, we determined biofilm formation by photometry of crystal violet staining. RESULTS: All test tubes and flexible endoscopes showed residual protein content and germ load significantly below legally prescribed threshold values, independent of the interval between pre-cleaning and reprocessing. CONCLUSION: Our findings indicate that flexible endoscopes could be stored overnight after pre-cleaning without any influence on the quality of reprocessing. While ensuring patient safety, this could simplify logistical processes and enable cost savings.

Surveillance for Colonization, Transmission, and Infection With Methicillin-Susceptible Staphylococcus aureus in a Neonatal Intensive Care Unit.

Importance: Staphylococcus aureus is one of the leading causes of infections in neonatal intensive care units (NICUs). Most studies in this patient group focus on methicillin-resistant S aureus or the outbreak setting, whereas data for methicillin-susceptible S aureus are limited. Objectives: To identify risk factors for S aureus colonization and infections in hospitalized newborns and to investigate S aureus transmission and its dynamics in a nonoutbreak setting. Design, Setting, and Participants: This monocentric cohort study in a tertiary NICU in Heidelberg, Germany, enrolled all hospitalized neonates (n = 590) with at least 1 nasal screening swab positive for S aureus. Data were collected from January 1, 2018, to December 31, 2019. Exposures: Weekly screening for S aureus colonization was performed for all newborns until discharge. Main Outcomes and Measures: The primary end point was any S aureus infection until hospital discharge. Transmission of S aureus and performance of routine typing to detect transmissions were defined as the secondary outcomes of the study. Results: In total, 590 newborns were enrolled (276 [46.8%] female and 314 [53.2%] male; 220 [37.3%] with birthweight <1500 g; 477 [80.8%] preterm; 449 [76.1%] singletons; 419 [71.5%] delivered via cesarean section). The median length of stay was 26 (range, 10-62) days. Overall, 135 infants (22.9%) were colonized by S aureus at some time during their hospital stay. The median time to first detection was 17 (interquartile range, 11-37) days. The overall incidence of S aureus infection was 1.7% (10 of 590). Low birth weight (<1500 g [odds ratio, 9.3; 95% CI, 5.9-14.6; P < .001]) and longer hospital stay (odds ratio, 2.3; 95% CI, 1.9-2.7; P < .001) were associated with colonization. Nasal carriage was significantly associated with S aureus infection (odds ratio, 8.2; 95% CI, 2.1-32.3; P = .002). A total of 123 of 135 colonization isolates were sequenced. All recoverable infection isolates (4 of 7) of newborns with colonization were genetically identical to the colonizing isolate. Whole-genome sequencing indicated 23 potential transmission clusters. Conclusions and Relevance: The findings of this cohort study suggest that nasal colonization is a relevant risk factor for S aureus infection in a nonoutbreak NICU setting. In colonized newborns, infection and colonization isolates were genetically identical, suggesting that eradication of colonization may be a useful measure to prevent infection. Further investigations are necessary to validate and assess the generalizability of our findings.

Differences in infection control and diagnostic measures for multidrug-resistant organisms in the tristate area of France, Germany and Switzerland in 2019 - survey results from the RH(E)IN-CARE network.

BACKGROUND: Multidrug-resistant organisms (MDROs) are a public health threat. Single-centre interventions, however, are likely to fail in the long term, as patients are commonly transferred between institutions given the economic integration across borders. A transnational approach targeting larger regions is needed to plan overarching sets of interventions. Here, we aim to describe differences in diagnostic and infection prevention and control (IPC) measures in the fight against MDROs. METHODS: In 2019, we systematically assessed diagnostic algorithms and IPC measures implemented for detection and control of MDROs at three tertiary academic care centres (Freiburg; Strasbourg; Basel). Data were collected using a standardised data collection sheet to be filled in by every centre. Uncertainties were clarified by direct contact via telephone or email with the data supplier. Internal validity was checked by at least two researchers independently filling in the survey. RESULTS: All centres have established a primarily culture-based, rather than a nucleic acid amplification-based approach for detection of MDROs (i.e., vancomycin-resistant Enterococci [VRE], methicillin-resistant Staphylococcus aureus [MRSA], extended-spectrum beta-lactamase-producing Enterobacteriaceae [ESBL], carbapenemase-producing and carbapenem-resistant Gram-negatives [CPGN/CRGN]). IPC measures differed greatly across all centres. High-risk patients are screened for most MDROs on intensive care unit (ICU) admission in all centres; only the French centre is screening all patients admitted to the ICU for VRE, MRSA and ESBL. Patients colonised/infected by MRSA, quinolone-resistant ESBL Klebsiella spp. and CPGN/CRGN are isolated everywhere, whereas patients colonised/infected by VRE and ESBL are usually not isolated in the German centre. CONCLUSIONS: In contrast to the French and Swiss centres, the German centre no longer uses isolation measures to control VRE and quinolone-susceptible ESBL. Overall, the French centre is more focused on intercepting MDRO transmission from outside, whereas the German and Swiss centres are more focused on intercepting endemic MDRO transmission. These findings point to important challenges regarding future attempts to standardise IPC measures across borders.    .

Genomic Investigation and Successful Containment of an Intermittent Common Source Outbreak of OXA-48-Producing Enterobacter cloacae Related to Hospital Shower Drains.

The hospital environment has been reported as a source of transmission events and outbreaks of carbapenemase-producing Enterobacterales. Interconnected plumbing systems and the microbial diversity in these reservoirs pose a challenge for outbreak investigation and control. A total of 133 clinical and environmental OXA-48-producing Enterobacter cloacae isolates collected between 2015 and 2021 were characterized by whole-genome sequencing (WGS) to investigate a prolonged intermittent outbreak involving 41 patients in the hematological unit. A mock-shower experiment was performed to investigate the possible acquisition route. WGS indicated the hospital water environmental reservoir as the most likely source of the outbreak. The lack of diversity of the blaOXA-48-like harbouring plasmids was a challenge for data interpretation. The detection of blaOXA-48-like-harboring E. cloacae strains in the shower area after the mock-shower experiment provided strong evidence that showering is the most likely route of acquisition. Initially, in 20 out of 38 patient rooms, wastewater traps and drains were contaminated with OXA-48-positive E. cloacae. Continuous decontamination using 25% acetic acid three times weekly was effective in reducing the trap/drain positivity in monthly environmental screening but not in reducing new acquisitions. However, the installation of removable custom-made shower tubs did prevent new acquisitions over a subsequent 12-month observation period. In the present study, continuous decontamination was effective in reducing the bacterial burden in the nosocomial reservoirs but was not sufficient to prevent environment-to-patient transmission in the long term. Construction interventions may be necessary for successful infection prevention and control. IMPORTANCE The hospital water environment can be a reservoir for a multiward outbreak, leading to acquisitions or transmissions of multidrug-resistant organisms in a hospital setting. The majority of Gram-negative bacteria are able to build biofilms and persist in the hospital plumbing system over a long period of time. The elimination of the reservoir is essential to prevent further transmission and spread, but proposed decontamination regimens, e.g., using acetic acid, can only suppress but not fully eliminate the environmental reservoir. In this study, we demonstrated that colonization with multidrug-resistant organisms can be acquired by showering in showers with contaminated water traps and drains. A construction intervention by installing removable and autoclavable shower inserts to avoid sink contact during showering was effective in containing this outbreak and may be a viable alternative infection prevention and control measure in outbreak situations involving contaminated shower drains and water traps.