Christos Grigoras

Fecal Colonization With Extended-spectrum Beta-lactamase–Producing Enterobacteriaceae and Risk Factors Among Healthy Individuals: A Systematic Review and Metaanalysis

BACKGROUND Gut colonization is a risk factor for infections with extended-spectrum beta-lactamase (ESBL)-producing organisms. We aimed to determine the ESBL class A reservoir among healthy individuals. METHODS We searched PubMed and EMBASE (through 10 July 2015) looking for studies that contained data for fecal colonization with ESBL class A bacteria among healthy individuals for each World Health Organization-defined region. Distribution of isolates among cefotaximase (CTX-M), sulfhydryl variable, and temoneira enzymes and data on previous antibiotic use, international travel, previous hospitalization, and animal contacts were extracted. RESULTS Sixty-six of 17 479 studies on 28 909 healthy individuals were included. The pooled prevalence of ESBL class A colonization was 14% (95% confidence interval [CI], 9, 20), with an increasing trend of 5.38% annually (P = .003). The pooled prevalence was higher in Asia and Africa (ranging from 46%, 95% CI, 29, 63 to 15%, 95% CI, 4, 31) and lower but still significant in central (3%, 95% CI, 1, 5), northern (4%, 95% CI, 2, 6), and southern Europe (6%, 95% CI, 1, 12) and the Americas (2%, 95% CI, 0, 5). CTX-Ms were the prevalent ESBL enzyme (69%). Antibiotic use for the prior 4 or 12 months was associated with a high colonization risk (risk ratio [RR] = 1.63; 95% CI, 1.19, 2.24 and RR = 1.58; 95% CI, 1.16, 2.16, respectively). International travel was also correlated with ESBL colonization [(RR = 4.06, (95% CI, 1.33, 12.41)]. CONCLUSIONS The ESBL colonization rate among healthy individuals is significant worldwide. This should be taken into consideration in infection control and antibiotic management decisions.

Systematic Review and Meta-analysis of Clinical and Economic Outcomes from the Implementation of Hospital-Based Antimicrobial Stewardship Programs

ABSTRACT The implementation of antimicrobial stewardship programs (ASPs) is a promising strategy to help address the problem of antimicrobial resistance. We sought to determine the efficacy of ASPs and their effect on clinical and economic parameters. We searched PubMed, EMBASE, and Google Scholar looking for studies on the efficacy of ASPs in hospitals. Based on 26 studies (extracted from 24,917 citations) with pre- and postimplementation periods from 6 months to 3 years, the pooled percentage change of total antimicrobial consumption after the implementation of ASPs was −19.1% (95% confidence interval [CI] = −30.1 to −7.5), and the use of restricted antimicrobial agents decreased by −26.6% (95% CI = −52.3 to −0.8). Interestingly, in intensive care units, the decrease in antimicrobial consumption was −39.5% (95% CI = −72.5 to −6.4). The use of broad-spectrum antibiotics (−18.5% [95% CI = −32 to −5.0] for carbapenems and −14.7% [95% CI = −27.7 to −1.7] for glycopeptides), the overall antimicrobial cost (−33.9% [95% CI = −42.0 to −25.9]), and the hospital length of stay (−8.9% [95% CI = −12.8 to −5]) decreased. Among hospital pathogens, the implementation of ASPs was associated with a decrease in infections due to methicillin-resistant Staphylococcus aureus (risk difference [RD] = −0.017 [95% CI = −0.029 to −0.005]), imipenem-resistant Pseudomonas aeruginosa (RD = −0.079 [95% CI = −0.114 to −0.040]), and extended-spectrum beta-lactamase Klebsiella spp. (RD = −0.104 [95% CI = −0.153 to −0.055]). Notably, these improvements were not associated with adverse outcomes, since the all-cause, infection-related 30-day mortality and infection rates were not significantly different after implementation of an ASP (RD = −0.001 [95% CI = −0.009 to 0.006], RD = −0.005 [95% CI = −0.016 to 0.007], and RD = −0.045% [95% CI = −0.241 to 0.150], respectively). Hospital ASPs result in significant decreases in antimicrobial consumption and cost, and the benefit is higher in the critical care setting. Infections due to specific antimicrobial-resistant pathogens and the overall hospital length of stay are improved as well. Future studies should focus on the sustainability of these outcomes and evaluate potential beneficial long-term effects of ASPs in mortality and infection rates.

Asymptomatic Carriers of Toxigenic C. difficile in Long-Term Care Facilities: A Meta-Analysis of Prevalence and Risk Factors

Background The impact of Clostridium difficile colonization in C. difficile infection (CDI) is inadequately explored. As a result, asymptomatic carriage is not considered in the development of infection control policies and the burden of carrier state in long-term care facilities (LTCFs) is unknown. Purpose To explore the epidemiology of C. difficile colonization in LTCFs, identify predisposing factors and describe its impact on healthcare management. Data Sources PubMed, Embase and Web of Science (up to June 2014) without language restriction, complemented by reference lists of eligible studies. Study Selection All studies providing extractable data on the prevalence of toxigenic C. difficile colonization among asymptomatic residents in LTCFs. Data Extraction Two authors extracted data independently. Statistical Methods The pooled colonization estimates were calculated using the double arcsine methodology and reported along with their 95% random-effects confidence intervals (CIs), using DerSimonian-Laird weights. We assessed the impact of patient-level covariates on the risk of colonization and effects were reported as odds ratios (OR, 95% CI). We used the colonization estimates to simulate the effective reproduction number R through a Monte Carlo technique. Results Based on data from 9 eligible studies that met the specified criteria and included 1,371 subjects, we found that 14.8% (95%CI 7.6%-24.0%) of LTCF residents are asymptomatic carriers of toxigenic C. difficile. Colonization estimates were significantly higher in facilities with prior CDI outbreak (30.1% vs. 6.5%, p = 0.01). Patient history of CDI (OR 6.07; 95% CI 2.06–17.88; effect derived from 3 studies), prior hospitalization (OR 2.11; 95% CI 1.08–4.13; derived from 3 studies) and antimicrobial use within previous 3 months (OR 3.68; 95% CI 2.04–6.62; derived from 4 studies) were associated with colonization. The predicted colonization rate at admission was 8.9%. Conclusion Asymptomatic carriage of toxigenic C. difficile represents a significant burden in LTCFs and is associated with prior CDI outbreaks in the facility, a history of CDI, prior hospitalization and antimicrobial use. These findings can impact infection control measures at LTCFs.

Modeling the 2014 Ebola Virus Epidemic - Agent-Based Simulations, Temporal Analysis and Future Predictions for Liberia and Sierra Leone.

We developed an agent-based model to investigate the epidemic dynamics of Ebola virus disease (EVD) in Liberia and Sierra Leone from May 27 to December 21, 2014. The dynamics of the agent-based simulator evolve on small-world transmission networks of sizes equal to the population of each country, with adjustable densities to account for the effects of public health intervention policies and individual behavioral responses to the evolving epidemic. Based on time series of the official case counts from the World Health Organization (WHO), we provide estimates for key epidemiological variables by employing the so-called Equation-Free approach. The underlying transmission networks were characterized by rather random structures in the two countries with densities decreasing by ~19% from the early (May 27-early August) to the last period (mid October-December 21). Our estimates for the values of key epidemiological variables, such as the mean time to death, recovery and the case fatality rate, are very close to the ones reported by the WHO Ebola response team during the early period of the epidemic (until September 14) that were calculated based on clinical data. Specifically, regarding the effective reproductive number Re, our analysis suggests that until mid October, Re was above 2.3 in both countries; from mid October to December 21, Re dropped well below unity in Liberia, indicating a saturation of the epidemic, while in Sierra Leone it was around 1.9, indicating an ongoing epidemic. Accordingly, a ten-week projection from December 21 estimated that the epidemic will fade out in Liberia in early March; in contrast, our results flashed a note of caution for Sierra Leone since the cumulative number of cases could reach as high as 18,000, and the number of deaths might exceed 5,000, by early March 2015. However, by processing the reported data of the very last period (December 21, 2014-January 18, 2015), we obtained more optimistic estimates indicative of a remission of the epidemic in Sierra Leone, as reflected by the derived Re (~0.82, 95% CI: 0.81-0.83).

Prevalence and Clinical Outcomes of Clostridium difficile Infection in the Intensive Care Unit: A Systematic Review and Meta-Analysis.

We found that ICU setting is associated with higher Clostridium difficile infection (CDI) prevalence than general hospital population and 25% among CDI cases in ICU develop pseudomembranous colitis. CDI also affects adversely overall hospital mortality, ICU and overall hospital stay.

Isolation of C. difficile Carriers Alone and as Part of a Bundle Approach for the Prevention of Clostridium difficile Infection (CDI): A Mathematical Model Based on Clinical Study Data

Clostridium difficile infection is the most common hospital-acquired infection. Besides infected patients, carriers have emerged as a key player in C. difficile epidemiology. In this study, we evaluated the impact of identifying and isolating carriers upon hospital admission on the incidence of CDI incidence and hospital-acquired C. difficile colonization, as a single policy and as part of bundle approaches. We simulated C. difficile transmission using a stochastic mathematical approach, considering the contribution of carriers based on published literature. In the baseline scenario, CDI incidence was 6.18/1,000 admissions (95% CI, 5.72–6.65), simulating reported estimates from U.S. hospital discharges. The acquisition rate of C. difficile carriage was 9.72/1,000 admissions (95% CI, 9.15–10.31). Screening and isolation of colonized patients on admission to the hospital decreased CDI incidence to 4.99/1,000 admissions (95% CI, 4.59–5.42; relative reduction (RR) = 19.1%) and led to 36.2% reduction in the rate of hospital-acquired colonization. Simulating an antimicrobial stewardship program reduced CDI rate to 2.35/1,000 admissions (95% CI, 2.07–2.65). In sensitivity analysis, CDI incidence was less than 2.32/1,000 admissions (RR = 62.4%) in 95% of 1,000 simulations. The combined bundle, focusing on reducing C. difficile transmission from colonized patients and the individual risk of these patients to develop CDI, decreased significantly the incidence of both CDI and hospital-acquired colonization. Implementation of this bundle to current practice is expected to have an important impact in containing CDI.

ATG16L1 and IL23R variants and genetic susceptibility to crohn's disease: mode of inheritance based on meta-analysis of genetic association studies.

Background:Autophagy and regulation of IL-23 signaling pathways have been implicated in the pathogenesis of Crohns disease (CD). We studied the mode of inheritance and reviewed the association of 2 polymorphic variants of ATG16L1 and IL23R with CD. Methods:We searched the PubMed and ISI Web of Science databases (up to May 2014) for pertinent articles. We included all studies that had a case–control design, with cases having CD and controls being healthy and reported full genotype frequencies for the ATG16L1 and/or IL23R variant of interest. We quantified the relative genetic risk using the model-free approach of the generalized odds ratio metric (ORG) and reported 95% precision estimates. Also, we explored the mode of inheritance using the degree of dominance h-index. Results:Fifty-one studies fulfilled these requirements and were included in the analysis. These studies involved 12,762 patients and 16,735 controls evaluating the association of ATG16L1 (rs2241880 p.Thr300Ala) and 8110 patients and 11,900 controls evaluating the association of IL23R (rs11209026 p.Arg381Gln) with CD. The ATG16L1 variant rs2241880 was associated with increased susceptibility to CD (combined ORG = 1.38; 95% confidence interval, 1.29–1.48) and a nondominant mode of inheritance (suggesting that the effect of heterozygosity lies exactly in the middle of extreme homozygotes, h = 0). The IL23R variant rs11209026 was associated with significant protection (ORG = 0.46; 95% confidence interval, 0.41–0.53) and a recessive mode of inheritance, indicating that the effect of a heterozygous genotype would lie close to the wild-type homozygous genotype. In subgroup analysis, the significant effects persisted across Caucasian ancestry studies and pediatric populations but were lacking across studies in Asian populations. Conclusions:The ATG16L1 variant rs2241880 was associated with 38% increase in the risk for CD for higher mutational load, whereas IL23R variant rs11209026 decreased the risk by 54% for higher mutational load. The mode of inheritance for ATG16L1 variant demonstrated perfect additivity for genetic risk, whereas it showed recessiveness for the IL23R variant. This analysis permits risk stratification for CD based on the mutational status and highlight the need for additional studies in certain populations.

Forecasting and control policy assessment for the Ebola virus disease (EVD) epidemic in Sierra Leone using small-world networked model simulations

Objectives As the Ebola virus disease is still sustained in Sierra Leone, we analysed the epidemic for a recent period (21 December 2014 to 17 April 2015) using a small-world networked model and forecasted its evolution. Policy-control scenarios for the containment of the epidemic were also examined. Methods We developed an agent-based model with 6 million individuals (the population of Sierra Leone) interacting through a small-world social network. The model incorporates the main epidemiological factors, including the effect of burial practices to virus transmission. The effective reproductive number (Re) was evaluated directly from the agent-based simulations. Estimates of the epidemiological variables were computed on the basis of the official cases as reported by the Centers for Disease Control and Prevention (CDC). Results From 21 December 2014 to 18 February 2015 the epidemic was in recession compared with previous months, as indicated by the estimated Re of ∼0.77 (95% CI 0.72 to 0.82). From 18 February to 17 April 2015, the Re rose above criticality (∼1.98, 95% CI 1.33 to 2.22), flashing a note of caution for the situation. By projecting in time, we predicted that the epidemic would continue through July 2015. Our predictions were close to the cases reported by CDC by the end of June, verifying the criticality of the situation. In light of these developments, while revising our manuscript, we expanded our analysis to include the most recent data (until 15 August 2015). By mid-August, Re had fallen below criticality and the epidemic was expected to fade out by early December 2015. Conclusions Our results call for the continuation of drastic control measures, which in the absence of an effective vaccine or therapy at present can only translate to isolation of the infected section of the population, to contain the epidemic.

The Attributable Burden of Clostridium difficile Infection to Long-Term Care Facilities Stay: A Clinical Study

Advanced age, history of hospitalization, and antibiotic consumption are associated with the pathogenesis of Clostridium difficile infection (CDI). Long‐term care facilities (LTCFs) represent a setting where CDI has been increasingly reported. We aimed to estimate the actual attributable burden of CDI to LTCF stay and determine the characteristics of the disease epidemiology in this setting.

Colonization With Methicillin-resistant Staphylococcus aureus and Risk for Infection Among Asymptomatic Athletes: A Systematic Review and Metaanalysis

BACKGROUND Athletes are a vulnerable population for methicillin-resistant Staphylococcus aureus (MRSA) infection. Our aim was to determine MRSA colonization in asymptomatic athletes and estimate the risk for subsequent MRSA infection. METHODS We searched the PubMed and EMBASE (through 29 October 2015) for studies on MRSA colonization among asymptomatic athletes. RESULTS The pooled prevalence of MRSA colonization among athletes was 6% (95% confidence interval [CI], 1,13), and it was higher in the United States (8%; 95% CI, 2,17). USA300 was the most common strain detected (22%), and 62% and 36% of isolates were resistant to clindamycin and trimethoprim/sulfamethoxazole, respectively. The prevalence of MRSA colonization among collegiate athletes reached 13% (95% CI, 4,25). Sports with the highest prevalence among collegiate athletes were wrestling (22%; 95% CI, 0,85), football (8%; 95% CI, 3,15) and basketball (8%; 95% CI, 0,28). The risk for MRSA skin and soft tissue infection within 3 months after documented colonization among MRSA-colonized athletes was significantly higher than for noncolonized athletes (relative risk = 7.37, 95% CI, [2.47,21.94]). Decolonization treatment among colonized athletes decreased significantly the risk for infection (relative risk reduction = 0.33; 95% CI, .03,4.28). CONCLUSIONS The prevalence of MRSA colonization among asymptomatic athletes is comparable to that among individuals with chronic illness, it is higher among collegiate athletes and can be twice that for patients in intensive care units. Importantly, colonization is associated with a >7-fold increase in the incidence of subsequent MRSA infection. Infection control and decontamination protocols for this population need to be studied and implemented with urgency.