Data-based analysis, modelling and forecasting of the COVID-19 outbreak

Since the first suspected case of coronavirus disease-2019 (COVID-19) on December 1st, 2019, in Wuhan, Hubei Province, China, a total of 40,235 confirmed cases and 909 deaths have been reported in China up to February 10, 2020, evoking fear locally and internationally. Here, based on the publicly available epidemiological data for Hubei, China from January 11 to February 10, 2020, we provide estimates of the main epidemiological parameters. In particular, we provide an estimation of the case fatality and case recovery ratios, along with their 90% confidence intervals as the outbreak evolves. On the basis of a Susceptible-Infectious-Recovered-Dead (SIDR) model, we provide estimations of the basic reproduction number (R0), and the per day infection mortality and recovery rates. By calibrating the parameters of the SIRD model to the reported data, we also attempt to forecast the evolution of the outbreak at the epicenter three weeks ahead, i.e. until February 29. As the number of infected individuals, especially of those with asymptomatic or mild courses, is suspected to be much higher than the official numbers, which can be considered only as a subset of the actual numbers of infected and recovered cases in the total population, we have repeated the calculations under a second scenario that considers twenty times the number of confirmed infected cases and forty times the number of recovered, leaving the number of deaths unchanged. Based on the reported data, the expected value of R0 as computed considering the period from the 11th of January until the 18th of January, using the official counts of confirmed cases was found to be ~4.6, while the one computed under the second scenario was found to be ~3.2. Thus, based on the SIRD simulations, the estimated average value of R0 was found to be ~2.6 based on confirmed cases and ~2 based on the second scenario. Our forecasting flashes a note of caution for the presently unfolding outbreak in China. Based on the official counts for confirmed cases, the simulations suggest that the cumulative number of infected could reach 180,000 (with a lower bound of 45,000) by February 29. Regarding the number of deaths, simulations forecast that on the basis of the up to the 10th of February reported data, the death toll might exceed 2,700 (as a lower bound) by February 29. Our analysis further reveals a significant decline of the case fatality ratio from January 26 to which various factors may have contributed, such as the severe control measures taken in Hubei, China (e.g. quarantine and hospitalization of infected individuals), but mainly because of the fact that the actual cumulative numbers of infected and recovered cases in the population most likely are much higher than the reported ones. Thus, in a scenario where we have taken twenty times the confirmed number of infected and forty times the confirmed number of recovered cases, the case fatality ratio is around ~0.15% in the total population. Importantly, based on this scenario, simulations suggest a slow down of the outbreak in Hubei at the end of February

Occurrence of False Positive Results for the Detection of Carbapenemases in Carbapenemase-Negative Escherichia coli and Klebsiella pneumoniae Isolates

Adequate detection of the production of carbapenemase in Enterobacteriaceae isolates is crucial for infection control measures and the appropriate choice of antimicrobial therapy. In this study, we investigated the frequency of false positive results for the detection of carbapenemases in carbapenemase-negative Escherichia coli and Klebsiella pneumoniae clinical isolates by the modified Hodge test (MHT). Three hundred and one E. coli and K. pneumoniae clinical isolates were investigated. All produced extended spectrum β-lactamases (ESBLs) but were susceptible to carbapenems. Antimicrobial susceptibility testing was performed by the disk diffusion and agar dilution methods. The MHT was performed using the standard inoculum of test organisms recommended by the CLSI. Genes that encoded ESBLs and carbapenemases were identified by PCR and DNA sequencing. Among the 301 clinical isolates, none of the isolates conformed to the criteria for carbapenemase screening recommended by the CLSI. The susceptibility rates for imipenem, meropenem, and ertapenem all were 100.0%, 100.0%, and 100.0%, respectively. Of the 301 E. coli and K. pneumoniae isolates, none produced carbapenemase. The MHT gave a positive result for 3.3% (10/301) of the isolates. False positive results can occur when the MHT is used to detect carbapenemase in ESBL-producing isolates and clinical laboratories must be aware of this fact

Tracing day-zero and forecasting the COVID-19 outbreak in Lombardy, Italy: A compartmental modelling and numerical optimization approach

Introduction Italy became the second epicenter of the novel coronavirus disease 2019 (COVID-19) pandemic after China, surpassing by far China’s death toll. The disease swept through Lombardy, which remained in lockdown for about two months, starting from the 8th of March. As of that day, the isolation measures taken in Lombardy were extended to the entire country. Here, assuming that effectively there was one case “zero” that introduced the virus to the region, we provide estimates for: (a) the day-zero of the outbreak in Lombardy, Italy; (b) the actual number of asymptomatic infected cases in the total population until March 8; (c) the basic (R0)and the effective reproduction number (Re) based on the estimation of the actual number of infected cases. To demonstrate the efficiency of the model and approach, we also provide a tentative forecast two months ahead of time, i.e. until May 4, the date on which relaxation of the measures commenced, on the basis of the COVID-19 Community Mobility Reports released by Google on March 29. Methods To deal with the uncertainty in the number of the actual asymptomatic infected cases in the total population Volpert et al. (2020), we address a modified compartmental Susceptible/ Exposed/ Infectious Asymptomatic/ Infected Symptomatic/ Recovered/ Dead (SEIIRD) model with two compartments of infectious persons: one modelling the cases in the population that are asymptomatic or experience very mild symptoms and another modelling the infected cases with mild to severe symptoms. The parameters of the model corresponding to the recovery period, the time from the onset of symptoms to death and the time from exposure to the time that an individual starts to be infectious, have been set as reported from clinical studies on COVID-19. For the estimation of the day-zero of the outbreak in Lombardy, as well as of the “effective” per-day transmission rate for which no clinical data are available, we have used the proposed SEIIRD simulator to fit the numbers of new daily cases from February 21 to the 8th of March. This was accomplished by solving a mixed-integer optimization problem. Based on the computed parameters, we also provide an estimation of the basic reproduction number R0 and the evolution of the effective reproduction number Re. To examine the efficiency of the model and approach, we ran the simulator to “forecast” the epidemic two months ahead of time, i.e. from March 8 to May 4. For this purpose, we considered the reduction in mobility in Lombardy as released on March 29 by Google COVID-19 Community Mobility Reports, and the effects of social distancing and of the very strict measures taken by the government on March 20 and March 21, 2020. Results Based on the proposed methodological procedure, we estimated that the expected day-zero was January 14 (min-max rage: January 5 to January 23, interquartile range: January 11 to January 18). The actual cumulative number of asymptomatic infected cases in the total population in Lombardy on March 8 was of the order of 15 times the confirmed cumulative number of infected cases, while the expected value of the basic reproduction number R0 was found to be 4.53 (min-max range: 4.40- 4.65). On May 4, the date on which relaxation of the measures commenced the effective reproduction number was found to be 0.987 (interquartiles: 0.857, 1.133). The model approximated adequately two months ahead of time the evolution of reported cases of infected until May 4, the day on which the phase I of the relaxation of measures was implemented over all of Italy. Furthermore the model predicted that until May 4, around 20% of the population in Lombardy has recovered (interquartile range: *10% to *30%)

Carbapenem resistance in Acinetobacter baumannii: the molecular epidemic features of an emerging problem in health care facilities

Acinetobacter baumannii is an opportunistic gram-negative pathogen with increasing relevance in a variety of nosocomial infections especially among intensive-care-unit (ICU) patients. Carbapenems have been widely used to treat serious multidrug-resistant A. baumannii infections; however, incidences of carbapenem-resistant A. baumannii are rising in several parts of the world and large and sustained outbreaks caused by such bacteria have been described. Carbapenem-resistant A. baumannii epidemics are sustained by clusters of highly similar strains that successfully spread among different cities and countries; their resistance phenotype is mainly due to the acquisition of carbapenem-hydrolyzing class D β-lactamase (CHDL) genes flanked by insertion sequence (IS) elements. Multi-facility outbreaks can be also sustained by inter-hospital transfer of colonized patients. Here, we review the global epidemiology of carbapenem-resistant A. baumannii, with the emphasis on the molecular epidemiology and genetic characterization of carbapenem resistance in epidemic strains

Exploring colistin pharmacodynamics against Klebsiella pneumoniae: A need to revise current susceptibility breakpoints

Objectives: Because the pharmacokinetic/pharmacodynamic (PK/PD) characteristics of colistin against Enterobacteriaceae are not well explored, we studied the activity of colistin against K. pneumoniae in an in vitro PK/PD model simulating different dosing regimens. Methods: Three clinical isolates of K. pneumoniae with MICs of 0.5, 1 and 4mg/L were tested in an in vitro PK/PD model following a dose-fractionation design over a period of 24h. A high and low inoculumof 107 and 104 cfu/mL with and without a heteroresistant subpopulation, respectively, were used. PK/PD indices associated with colistin activity were explored and Monte Carlo analysis was performed in order to determine the PTA for achieving a bactericidal effect (2 log kill). Results: The fAUC/MIC (R2"0.64-0.68) followed by fCmax/MIC (R2=0.55-0.63) best described colistin's 24 h log10 cfu/mL reduction for both low and high inocula. Dosing regimens with fCmax/MIC≥6 were always associated with a bactericidal effect (P=0.0025). However, at clinically achievable concentrations, usually below fCmax/MIC=6, an fAUC/MIC ≤25 was more predictive of a bactericidal effect. Using a dosing regimen of 9 MU/ day, the PTA for this pharmacodynamic target was 100%, 5%-70%and 0%, for isolates with MICs of ≤0.5, 1 and ≥2 mg/L, respectively. Dosing regimens that aim for a trough level of 1 mg/L achieve coverage of strains up to 0.5 mg/L (target trough/MIC=2 mg/L). Conclusions: Characterization of the pharmacodynamics of colistin against Enterobacteriaceae in an in vitro model of infection indicates that a revision of current susceptibility breakpoints is needed. Therapeutic drug monitoring of colistin to achieve pharmacodynamic targets in individual patients is highly recommended

Standardization of measles, mumps and rubella assays to enable comparisons of seroprevalence data across 21 European countries and Australia

The aim of the European Sero-Epidemiology Network is to establish comparability of the serological surveillance of vaccine-preventable diseases in Europe. The designated reference laboratory (RL) for measles, mumps, rubella (MMR) prepared and tested a panel of 151 sera by the reference enzyme immunoassay (rEIA). Laboratories in 21 countries tested the panel for antibodies against MMR using their usual assay (a total of 16 different EIAs) and the results were plotted against the reference results in order to obtain equations for the standardization of national serum surveys. The RL also tested the panel by the plaque neutralization test (PNT). Large differences in qualitative results were found compared to the RL. Well-fitting standardization equations with R20·8 were obtained for almost all laboratories through regression of the quantitative results against those of the RL. When compared to PNT, the rEIA had a sensitivity of 95·3%, 92·8% and 100% and a specificity of 100%, 87·1% and 92·8% for measles, mumps and rubella, respectively. The need for standardization was highlighted by substantial inter-country differences. Standardization was successful and the selected standardization equations allowed the conversion of local serological results into common units and enabled direct comparison of seroprevalence data of the participating countrie