Ioannis M. Zacharioudakis

T2 magnetic resonance assay for the rapid diagnosis of candidemia in whole blood: A clinical trial

BACKGROUND Microbiologic cultures, the current gold standard diagnostic method for invasive Candida infections, have low specificity and take up to 2-5 days to grow. We present the results of the first extensive multicenter clinical trial of a new nanodiagnostic approach, T2 magnetic resonance (T2MR), for diagnosis of candidemia. METHODS Blood specimens were collected from 1801 hospitalized patients who had a blood culture ordered for routine standard of care; 250 of them were manually supplemented with concentrations from <1 to 100 colony-forming units (CFUs)/mL for 5 different Candida species. RESULTS T2MR demonstrated an overall specificity per assay of 99.4% (95% confidence interval [CI], 99.1%-99.6%) with a mean time to negative result of 4.2 ± 0.9 hours. Subanalysis yielded a specificity of 98.9% (95% CI, 98.3%-99.4%) for Candida albicans/Candida tropicalis, 99.3% (95% CI, 98.7%-99.6%) for Candida parapsilosis, and 99.9% (95% CI, 99.7%-100.0%) for Candida krusei/Candida glabrata. The overall sensitivity was found to be 91.1% (95% CI, 86.9%-94.2%) with a mean time of 4.4 ± 1.0 hours for detection and species identification. The subgroup analysis showed a sensitivity of 92.3% (95% CI, 85.4%-96.6%) for C. albicans/C. tropicalis, 94.2% (95% CI, 84.1%-98.8%) for C. parapsilosis, and 88.1% (95% CI, 80.2%-93.7%) for C. krusei/C. glabrata. The limit of detection was 1 CFU/mL for C. tropicalis and C. krusei, 2 CFU/mL for C. albicans and C. glabrata, and 3 CFU/mL for C. parapsilosis. The negative predictive value was estimated to range from 99.5% to 99.0% in a study population with 5% and 10% prevalence of candidemia, respectively. CONCLUSIONS T2MR is the first fully automated technology that directly analyzes whole blood specimens to identify species without the need for prior isolation of Candida species, and represents a breakthrough shift into a new era of molecular diagnostics. CLINICAL TRIALS REGISTRATION NCT01752166.

Colonization With Toxinogenic C. difficile Upon Hospital Admission, and Risk of Infection: A Systematic Review and Meta-Analysis

Objectives:It has been suggested that colonization with C. difficile protects from infection. Nevertheless, the association between carriage of toxinogenic strains and ensuing C. difficile infections (CDIs) has not been studied.Methods:We searched PubMed and EMBASE databases up to 20 June 2014, using the term “difficile”. Our primary outcomes of interest included the prevalence of isolation of toxinogenic C. difficile or its toxins from asymptomatic patients on hospital admission through stool or rectal swab testing and the risk of ensuing infection among colonized and noncolonized patients. Data on previous hospitalization, antibiotic, and proton pump inhibitor (PPI) use and prior CDIs among colonized and noncolonized patients were also extracted.Results:Nineteen out of 26,081 studies on 8,725 patients were included. The pooled prevalence of toxinogenic C. difficile colonization was 8.1% (95% confidence interval (CI) 5.7–11.1%), with an increasing trend over time (P=0.003), and 10.0% (95% CI 7.1–13.4%) among North American studies. Patients colonized upon hospital admission had a 5.9 times higher risk of subsequent CDIs compared with noncolonized patients (relative risk (RR) 5.86; 95% CI 4.21–8.16). The risk of CDI for colonized patients was 21.8% (95% CI 7.9–40.1%), which was significantly higher than that of noncolonized patients (3.4%; 95% CI 1.5–6.0%; P=0.03), with an attributable risk of 18.4%. History of hospitalization during the previous 3 months was associated with a higher risk of colonization (RR 1.63; 95% CI 1.13–2.34), as opposed to previous antibiotic (RR 1.07; 95% CI 0.75–1.53) and PPI use (RR 1.44; 95% CI 0.94–2.23), as well as history of CDI (RR 1.45; 95% CI 0.66–3.18) that had no impact.Conclusions:Over 8% of admitted patients are carriers of toxinogenic C. difficile with an almost 6 times higher risk of infection. These findings update current knowledge regarding the contribution of colonization in CDI epidemiology and stress the importance of preventive measures toward colonized patients.

PCR in Diagnosis of Invasive Aspergillosis: a Meta-Analysis of Diagnostic Performance

ABSTRACT Invasive aspergillosis is a difficult-to-diagnose infection with a high mortality rate that affects high-risk groups such as patients with neutropenia and hematologic malignancies. We performed a bivariate meta-analysis of diagnostic data for an Aspergillus sp. PCR assay with blood specimens from high-risk hematology patients. We included all studies involving human subjects that assessed the performance of any PCR assay for invasive aspergillosis in whole blood or serum and that used the European Organization for the treatment of Cancer/Mycoses Study Group criteria as a reference standard. Three investigators independently searched the literature for eligible studies and extracted the data. Out of a total of 37 studies, 25 met strict quality criteria and were included in our evidence synthesis. Twenty-five studies with 2,595 patients were analyzed. The pooled diagnostic performance of whole-blood and serum PCR assays was moderate, with a sensitivity and specificity of 84% (95% confidence interval [CI], 75 to 91%) and 76% (95% CI, 65 to 84%), respectively, suggesting that a positive or negative result is unable, on its own, to confirm or exclude a suspected infection. The performance of a PCR assay of serum was not significantly different from that of whole blood. Notably, at least two positive PCR test results were found to have a specificity of 95% and a sensitivity of 64% for invasive infection, achieving a high positive likelihood ratio of 12.8. Importantly, the European Aspergillus PCR Initiative (EAPCRI) recommendations improved the performance of the PCR even further when at least two positive specimens were used to define PCR positivity. In conclusion, two positive PCR results should be considered highly indicative of an active Aspergillus sp. infection. Use of the EAPCRI recommendations by clinical laboratories can further enhance PCR performance.

MRSA Colonization and Risk of Infection in the Neonatal and Pediatric ICU: A Meta-analysis

BACKGROUND AND OBJECTIVE: Methicillin-resistant Staphylococcus aureus (MRSA) is a significant cause of morbidity and mortality in NICUs and PICUs. Our objective was to assess the burden of MRSA colonization on admission, study the time trends, and examine the significance of MRSA colonization in this population. METHODS: PubMed and Embase databases were consulted. Studies that reported prevalence of MRSA colonization on ICU admission were selected. Two authors independently extracted data on MRSA colonization and infection. RESULTS: We identified 18 suitable articles and found an overall prevalence of MRSA colonization of 1.9% (95% confidence interval [CI] 1.3%–2.6%) on admission to the NICU or PICU, with a stable trend over the past 12 years. Interestingly, 5.8% (95% CI 1.9%–11.4%) of outborn neonates were colonized with MRSA on admission to NICU, compared with just 0.2% (95% CI 0.0%–0.9%) of inborn neonates (P = .01). The pooled acquisition rate of MRSA colonization was 4.1% (95% CI 1.2%–8.6%) during the NICU and PICU stay and was as high as 6.1% (95% CI 2.8%–10.6%) when the NICU population was studied alone. There was a relative risk of 24.2 (95% CI 8.9–66.0) for colonized patients to develop a MRSA infection during hospitalization. CONCLUSIONS: In the NICU and PICU, there are carriers of MRSA on admission, and MRSA colonization in the NICU is almost exclusively associated with outborn neonates. Importantly, despite infection control measures, the acquisition rate is high, and patients colonized with MRSA on admission are more likely to suffer a MRSA infection during hospitalization.

Meta-Analysis of Methicillin-Resistant Staphylococcus aureus Colonization and Risk of Infection in Dialysis Patients

Patients undergoing dialysis are particularly vulnerable to methicillin-resistant Staphylococcus aureus (MRSA) infections. We performed a meta-analysis of published studies to estimate the prevalence of MRSA colonization in dialysis patients, time trends, and long-term risk of subsequent MRSA infections. Our search of the PubMed and Embase databases returned 5743 nonduplicate citations, from which we identified 38 relevant studies that included data on 5596 dialysis patients. The estimated prevalence of MRSA colonization was 6.2% (95% confidence interval [95% CI], 4.2% to 8.5%). The prevalence increased over time but remained stable after 2000. Stratification of patients according to dialysis modality and setting revealed that 7.2% (95% CI, 4.9% to 9.9%) of patients on hemodialysis were colonized with MRSA compared with 1.3% (95% CI, 0.5% to 2.4%) of patients on peritoneal dialysis (P=0.01), and that a statistically significant difference existed in the percentage of colonized inpatients and outpatients (14.2% [95% CI, 8.0% to 21.8%] versus 5.4% [95% CI, 3.5% to 7.7%], respectively; P=0.04). Notably, the risk of developing MRSA infections increased among colonized hemodialysis patients compared with noncolonized patients (relative risk, 11.5 [95% CI, 4.7 to 28.0]). The long-term (6-20 months) probability of developing a MRSA infection was 19% among colonized hemodialysis patients compared with only 2% among noncolonized patients. In summary, 6.2% of dialysis patients are MRSA colonized, and the average prevalence of colonization has remained stable since 2000. Colonization in hemodialysis patients is associated with increased risk of MRSA infection.

Prevalence of Clostridium difficile infection among solid organ transplant recipients: a meta-analysis of published studies.

Several factors including antibiotic use, immunosuppression and frequent hospitalizations make solid organ transplant (SOT) recipients vulnerable to Clostridium difficile infection (CDI). We conducted a meta-analysis of published studies from 1991-2014 to estimate the prevalence of CDI in this patient population. We searched PubMed, EMBASE and Google Scholar databases. Among the 75,940 retrieved citations, we found 30 studies coded from 35 articles that were relevant to our study. Based on these studies, we estimated the prevalence of CDI among 21,683 patients who underwent transplantation of kidney, liver, lungs, heart, pancreas, intestine or more than one organ and stratified each study based on the type of transplanted organ, place of the study conduction, and size of patient population. The overall estimated prevalence in SOT recipients was 7.4% [95%CI, (5.6-9.5%)] and it varied based on the type of organ transplant. The prevalence was 12.7% [95%CI, (6.4%-20.9%)] among patients who underwent transplantation for more than one organ. The prevalence among other SOT recipients was: lung 10.8% [95% CI, (5.5%-17.7%)], liver 9.1 % [95%CI, (5.8%-13.2%)], intestine 8% [95% CI, (2.6%-15.9%)], heart 5.2% [95%CI, (1.8%-10.2%)], kidney 4.7% [95% CI, (2.6%-7.3%)], and pancreas 3.2% [95% CI, (0.5%-7.9%)]. Among the studies that reported relevant data, the estimated prevalence of severe CDI was 5.3% [95% CI (2.3%-9.3%)] and the overall recurrence rate was 19.7% [95% CI, (13.7%-26.6%)]. In summary, CDI is a significant complication after SOT and preventive strategies are important in order to reduce the CDI related morbidity and mortality.

Antimicrobial Lock Solutions as a Method to Prevent Central Line–Associated Bloodstream Infections: A Meta-analysis of Randomized Controlled Trials

BACKGROUND Antimicrobial lock solutions may be an effective strategy to prevent catheter-associated infections. However, there remains concern about their efficacy and safety. METHODS To investigate the efficacy of antimicrobial lock therapy to prevent central line-associated bloodstream infections (CLABSIs), we performed a systematic search of PubMed, Embase, Cochrane Central Register of Controlled Trials, and ClinicalTrials.gov, from the earliest date up to 31 December 2013. Studies were eligible if they were randomized controlled trials comparing antimicrobial lock solutions to heparin and if they provided an appropriate definition of infection. RESULTS The 23 included studies reported data on 2896 patients, who were predominantly adult patients undergoing hemodialysis (16/23 studies), but also adult and pediatric oncology patients, critically ill neonates, and patients receiving total parenteral nutrition. The use of antimicrobial lock solutions led to a 69% reduction in CLABSI rate (relative risk [RR], 0.31; 95% confidence interval [CI], .24-.40) and a 32% reduction in the rate of exit site infections (RR, 0.68; 95% CI, .49-.95) compared with heparin, without significantly affecting catheter failure due to noninfectious complications (RR, 0.83; 95% CI, .65-1.06). All-cause mortality was not different between the groups (RR, 0.84; 95% CI .64-1.12). Neither the type of antimicrobial solution nor the population studied, affected the relative reduction in CLABSIs, which also remained significant among studies reporting baseline infection rates of <1.15 per 1000 catheter-days, and studies providing data for catheter-related bloodstream infections. Publication and selective reporting bias are a concern in our study and should be acknowledged. CONCLUSIONS Antimicrobial lock solutions are effective in reducing risk of CLABSI, and this effect appears to be additive to traditional prevention measures.

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.

Prevalence of and Risk Factors for Methicillin-Resistant Staphylococcus aureus Colonization in HIV Infection: A Meta-Analysis

BACKGROUND Human immunodeficiency virus (HIV)-infected individuals who are colonized with methicillin-resistant Staphylococcus aureus (MRSA) have increased risk for MRSA infection. We conducted a meta-analysis of published studies to estimate the prevalence of MRSA colonization in this population. METHODS We performed a systematic literature review and meta-analysis. The PubMed and Embase databases were searched and studies reporting prevalence of MRSA colonization among HIV-infected individuals were included. RESULTS Among 7940 citations, 32 studies reporting data on 6558 HIV-infected individuals were considered eligible for our meta-analysis. We found that 6.9% (95% confidence interval [CI], 4.8-9.3) of individuals with HIV infection are MRSA carriers, with the corresponding figure across North American studies being 8.8% (95% CI, 6.0-12.2). History of hospitalization during the previous 12 months was associated with a 3.1 times higher risk of MRSA colonization (risk ratio [RR], 3.11 [95% CI, 1.62-5.98]). Previous or current incarceration was also associated with a higher risk for carriage (RR, 1.77 [95% CI, 1.26-2.48]). Current antiretroviral therapy or use of trimethoprim-sulfamethoxazole did not impact the risk of MRSA carriage (RR, 1.02 [95% CI, .64-1.63] and 1.45 [95% CI, .69-3.03], respectively). Extranasal screening increased the detection of MRSA colonization by at least 31.6% (95% CI, 15.8-50.0). The added yield from groin screening was 19.3% (95% CI, 11.5-28.5), from perirectal screening 18.5% (95% CI, 7.4-33.2), and from throat cultures 17.5% (95% CI, 12.0-24). CONCLUSIONS Individuals with HIV infection constitute a highly vulnerable population for MRSA colonization, and prior exposure to hospital or incarceration are significant factors. Nasal screening alone will underestimate the rate of colonization by at least one-third.

Methicillin-resistant Staphylococcus aureus prevention strategies in the ICU: a clinical decision analysis*.

Objectives:ICUs are a major reservoir of methicillin-resistant Staphylococcus aureus. Our aim was to estimate costs and effectiveness of methicillin-resistant Staphylococcus aureus prevention policies. Design and Interventions:We evaluated three up-to-date methicillin-resistant Staphylococcus aureus prevention policies, namely, 1) nasal screening and contact precautions of methicillin-resistant Staphylococcus aureus–positive patients; 2) nasal screening, contact precautions, and decolonization (targeted decolonization) of methicillin-resistant Staphylococcus aureus carriers; and 3) universal decolonization without screening. We implemented a decision-analytic model with deterministic and probabilistic analyses. Methicillin-resistant Staphylococcus aureus infections averted, quality-adjusted life years gained, and incremental cost-effectiveness ratios were calculated. Cost-effectiveness planes and acceptability curves were plotted for various willingness-to-pay thresholds to address uncertainty. Measurements and Main Results:At base-case scenario, universal decolonization was the dominant strategy; it averted 1.31% and 1.59% of methicillin-resistant Staphylococcus aureus infections over targeted decolonization and screening and contact precautions, respectively, and saved