Giulia De Angelis

Rapid screening tests for meticillin-resistant Staphylococcus aureus at hospital admission: systematic review and meta-analysis

Detection and eradication of meticillin-resistant Staphylococcus aureus (MRSA) represents a public health priority worldwide. Our aim was to do a systematic review and meta-analysis of randomised, non-randomised, and observational studies to summarise the available evidence on the effect of MRSA detection by rapid screening tests on hospital-acquired MRSA infections and acquisition rate. Eligible studies were retrieved from Medline, EmBase, Science Citation Index, and the Cochrane database. We judged as eligible those studies that compared hospitals and wards in which active screening for the detection of MRSA carriers was done at hospital admission by use of a rapid molecular test to those in which active screening was done with culture alone or not at all. To account for statistical heterogeneity between studies, random-effects models were used. Ten studies (nine interventional studies and one unblinded, cluster-randomised, crossover trial) were reviewed. Meta-analysis was done for studies reporting data on the same outcome. Primary outcomes included MRSA acquisition rate per 1000 patient-days (four studies); incidence of MRSA bloodstream infections per 1000 patient-days (three studies); and incidence of MRSA surgical-site infections per 100 surgical procedures (five studies). Compared with culture screening, use of rapid screening tests was not associated with a significant decrease in MRSA acquisition rate (risk ratio 0.87, 95% CI 0.61-1.24). Between wards applying rapid screening tests and those not applying screening, we noted a significantly decreased risk for MRSA bloodstream infections (0.54, 95% CI 0.41-0.71), but not for MRSA surgical-site infections (0.69, 95% CI 0.46-1.01). We conclude that active screening for MRSA is more important than the type of test used. Since important and costly decisions, such as mandatory legislation for MRSA universal screening, are under consideration in many countries worldwide, policy makers should be aware of the limits and the heterogeneity of the available evidence.

Antibiotic Usage and Risk of Colonization and Infection with Antibiotic-Resistant Bacteria: a Hospital Population-Based Study

ABSTRACT Accurate assessment of risk factors for nosocomial acquisition of colonization by antibiotic-resistant bacteria (ARB) is often confounded by scarce data on antibiotic use. A 12-month, nested, multicenter cohort study was conducted. Target ARB were methicillin (meticillin)-resistant Staphylococcus aureus (MRSA), vancomycin-resistant enterococci (VRE), and ciprofloxacin-resistant Pseudomonas aeruginosa (CR-PA). Nares and rectal swabs were obtained before and after starting antibiotics. Pulsed-field gel electrophoresis was done to define genetic relatedness of the strains. Primary outcomes were (i) the mean time, in days, for acquisition of target ARB colonization in patients previously not colonized; (ii) the rate of acquisition per 1,000 antibiotic-days according to different classes of antibiotics; (iii) the rate of infection caused by the same bacteria as those previously isolated in screening samples; and (iv) the risk factors for ARB acquisition. In total, 6,245 swabs from 864 inpatients were processed. The rate of acquisition was 3%, 2%, and 1% for MRSA, VRE, and CR-PA, respectively. The rate of acquisition of ARB per 1,000 antibiotic-days was 14 for carbapenems, 9 for glycopeptides, and 6 for broad-spectrum cephalosporins and quinolones. The highest rates of acquisition were observed for carbapenems in dialyzed and diabetic patients. Four risk factors were independently associated with acquisition of target ARB: use of carbapenems, age of >70 years, hospitalization for >16 days, and human immunodeficiency virus infection. During the 30-day follow-up, 4 among 42 patients newly colonized by ARB (9%) suffered from an infection due to the same bacteria as those isolated in a previous screening sample. Colonizing and infecting strains from single patients were genotypically identical. Identifying ARB colonization early during antibiotic therapy could target a high-risk hospitalized population that may benefit from intervention to decrease the risk of subsequent nosocomial infections.

High-Mobility Group Box-1 Protein Promotes Angiogenesis After Peripheral Ischemia in Diabetic Mice Through a VEGF-Dependent Mechanism

OBJECTIVE High-mobility group box-1 (HMGB1) protein is a nuclear DNA-binding protein released from necrotic cells, inducing inflammatory responses and promoting tissue repair and angiogenesis. Diabetic human and mouse tissues contain lower levels of HMGB1 than their normoglycemic counterparts. Deficient angiogenesis after ischemia contributes to worse outcomes of peripheral arterial disease in patients with diabetes. To test the hypothesis that HMGB1 enhances ischemia-induced angiogenesis in diabetes, we administered HMGB1 protein in a mouse hind limb ischemia model using diabetic mice. RESEARCH DESIGN AND METHODS After the induction of diabetes by streptozotocin, we studied ischemia-induced neovascularization in the ischemic hind limb of normoglycemic, diabetic, and HMGB1-treated diabetic mice. RESULTS We found that the perfusion recovery was significantly attenuated in diabetic mice compared with normoglycemic control mice. Interestingly, HMGB1 protein expression was lower in the ischemic tissue of diabetic mice than in normoglycemic mice. Furthermore, we observed that HMGB1 administration restored the blood flow recovery and capillary density in the ischemic muscle of diabetic mice, that this process was associated with the increased expression of vascular endothelial growth factor (VEGF), and that HMGB1-induced angiogenesis was significantly reduced by inhibiting VEGF activity. CONCLUSIONS The results of this study show that endogenous HMGB1 is crucial for ischemia-induced angiogenesis in diabetic mice and that HMGB1 protein administration enhances collateral blood flow in the ischemic hind limbs of diabetic mice through a VEGF-dependent mechanism.

Infection control and prevention measures to reduce the spread of vancomycin-resistant enterococci in hospitalized patients: a systematic review and meta-analysis

OBJECTIVES Vancomycin-resistant enterococci (VRE) represent a major problem in healthcare settings worldwide. It is still unclear which is the most effective infection control and prevention (ICP) measure to reduce the spread of hospital-acquired VRE. METHODS Cochrane databases, MEDLINE, EMBASE and CINAHL were searched until June 2012 to find studies comparing wards/hospitals where ICP measures to prevent VRE transmission were investigated. In the absence of heterogeneity, a fixed-effects model was used to estimate the pooled risk ratio (RR). Study quality was assessed according to Cochrane Effective Practice and Organisation of Care (EPOC) criteria. RESULTS The search strategy retrieved 549 studies and 9 studies (1 randomized clinical trial, 3 controlled clinical trials and 5 interrupted time series) with 30, 949 participants were included. The overall study quality was low. Implementation of hand hygiene was associated with a 47% decrease in the VRE acquisition rate (pooled RR 0.53, 95% CI 0.39-0.73, I(2) 26%) while contact precautions did not significantly reduce the VRE acquisition rate (pooled RR 1.08, 95% CI 0.63-1.83, I(2) 0%). Due to the low number of studies, meta-analysis was not applied for surveillance screening, environmental cleaning and antibiotic formulary interventions. No studies were available on the effectiveness of isolation and cohorting of patients and staff. CONCLUSIONS Available evidence on the ICP measures to reduce VRE spread in adult hospitalized patients is poor. This systematic review suggests a significant role for the implementation of hand hygiene. Further studies with appropriate study design are urgently needed to define ICP measures able to reduce the acquisition of VRE among hospitalized patients.

In Vivo Emergence of Tigecycline Resistance in Multidrug-Resistant Klebsiella pneumoniae and Escherichia coli

ABSTRACT Although resistance to tigecycline has been reported in surveillance studies, very few reports have described the emergence of resistance in vivo. We report two cases of patients with infections due to SHV-12-producing Klebsiella pneumoniae and K. pneumoniae carbapenemase-3 (KPC-3)-producing Escherichia coli, which developed tigecycline resistance in vivo after treatment. The reported limited experience underlines the risk of occurrence of a tigecycline MIC increase under treatment pressure.

Time-dependent study entries and exposures in cohort studies can easily be sources of different and avoidable types of bias

OBJECTIVES To display and discuss the reasons and consequences of length and time-dependent bias. They might occur in presence of a time-dependent study entry or a time-dependent exposure which might change from unexposed to exposed. STUDY DESIGN AND SETTING Recalling the popular study of Oscar nominees and using a real-data example from hospital epidemiology, we give innovative and easy-to-understand graphical presentations of how these biases corrupt the analyses via distorted time-at-risk. Cumulative hazard plots and Cox proportional hazards models were used. We are building bridges to medical disciplines such as critical care medicine, hepatology, pharmaco-epidemiology, transplantation medicine, neurology, gynecology and cardiology. RESULTS In presence of time-dependent bias, the hazard ratio (comparing exposed with unexposed) is artificially underestimated. The length bias leads to an artificial underestimation of the overall hazard. When both biases coexist it can lead to different directions of biased hazard ratios. CONCLUSION Since length and time-dependent bias might occur in several medical disciplines, we conclude that understanding and awareness are the best prevention of survival bias.

Pioglitazone enhances collateral blood flow in ischemic hindlimb of diabetic mice through an Akt-dependent VEGF-mediated mechanism, regardless of PPARγ stimulation

BackgroundType 2 diabetes mellitus (T2DM) is commonly associated with both microvascular and macrovascular complications and a strong correlation exists between glycaemic control and the incidence and progression of vascular complications. Pioglitazone, a Peroxisome proliferator-activated receptor-γ (PPARγ) ligand indicated for therapy of type T2DM, induces vascular effects that seem to occur independently of glucose lowering.MethodsBy using a hindlimb ischemia murine model, in this study we have found that pioglitazone restores the blood flow recovery and capillary density in ischemic muscle of diabetic mice and that this process is associated with increased expression of Vascular Endothelial Growth Factor (VEGF). Importantly, these beneficial effects are abrogated when endogenous Akt is inhibited; furthermore, the direct activation of PPARγ, with its selective agonist GW1929, does not restore blood flow recovery and capillary density. Finally, an important collateral vessel growth is obtained with combined treatment with pioglitazone and selective PPARγ inhibitor GW9662.ConclusionThese data demonstrate that Akt-VEGF pathway is essential for ischemia-induced angiogenic effect of pioglitazone and that pioglitazone exerts this effect via a PPARγ independent manner.

Burden of Bloodstream Infection Caused by Extended-Spectrum β-Lactamase–Producing Enterobacteriaceae Determined Using Multistate Modeling at a Swiss University Hospital and a Nationwide Predictive Model

OBJECTIVE To obtain an unbiased estimate of the excess hospital length of stay (LOS) and cost attributable to extended-spectrum β-lactamase (ESBL) positivity in bloodstream infections (BSIs) due to Enterobacteriaceae. DESIGN Retrospective cohort study. SETTING A 2,200-bed academic medical center in Geneva, Switzerland. PATIENTS Patients admitted during 2009. METHODS We used multistate modeling and Cox proportional hazards models to determine the excess LOS and adjusted end-of-LOS hazard ratio (HR) for ESBL-positive and ESBL-negative BSI. We estimated economic burden as the product of excess LOS and average bed-day cost. Patient-level accounting data provided a complementary analysis of economic burden. A predictive model was fitted to national surveillance data. RESULTS Thirty ESBL-positive and 96 ESBL-negative BSI cases were included. The excess LOS attributable to ESBL-positive and ESBL-negative BSI was 9.4 (95% confidence interval [CI], 0.4-18.4) and 2.6 (95% CI, 0.7-5.9) days, respectively. ESBL positivity was therefore associated with 6.8 excess days and CHF 9,473 per BSI. The adjusted end-of-LOS HRs for ESBL-positive and ESBL-negative BSI were 0.62 (95% CI, 0.43-0.89) and 0.90 (95% CI, 0.74-1.10), respectively. After reimbursement, the average financial loss per acute care episode in ESBL-positive BSI, ESBL-negative BSI, and control cohorts was CHF 48,674, 48,131, and 13,532, respectively. Our predictive model estimated that the nationwide cost of third-generation cephalosporin resistance would increase from CHF 2,084,000 in 2010 to CHF 3,526,000 in 2015. CONCLUSIONS This is the first hospital-wide analysis of excess LOS attributable to ESBL positivity determined using multistate modeling to avoid time-dependent bias. These results may inform health-economic evaluations of interventions targeting ESBL control.

Antifungal Susceptibility Profiles of Bloodstream Yeast Isolates by Sensititre YeastOne over Nine Years at a Large Italian Teaching Hospital

ABSTRACT Sensititre YeastOne (SYO) is an affordable alternative to the Clinical and Laboratory Standards Institute (CLSI) reference method for antifungal susceptibility testing. In this study, the MICs of yeast isolates from 1,214 bloodstream infection episodes, generated by SYO during hospital laboratory activity (January 2005 to December 2013), were reanalyzed using current CLSI clinical breakpoints/epidemiological cutoff values to assign susceptibility (or the wild-type [WT] phenotype) to systemic antifungal agents. Excluding Candida albicans (57.4% of all isolates [n = 1,250]), the most predominant species were Candida parapsilosis complex (20.9%), Candida tropicalis (8.2%), Candida glabrata (6.4%), Candida guilliermondii (1.6%), and Candida krusei (1.3%). Among the non-Candida species (1.9%), 7 were Cryptococcus neoformans and 17 were other species, mainly Rhodotorula species. Over 97% of Candida isolates were susceptible (WT phenotype) to amphotericin B and flucytosine. Rates of susceptibility (WT phenotype) to fluconazole, itraconazole, and voriconazole were 98.7% in C. albicans, 92.3% in the C. parapsilosis complex, 96.1% in C. tropicalis, 92.5% in C. glabrata, 100% in C. guilliermondii, and 100% (excluding fluconazole) in C. krusei. The fluconazole-resistant isolates consisted of 6 C. parapsilosis complex isolates, 3 C. glabrata isolates, 2 C. albicans isolates, 2 C. tropicalis isolates, and 1 Candida lusitaniae isolate. Of the non-Candida isolates, 2 C. neoformans isolates had the non-WT phenotype for susceptibility to fluconazole, whereas Rhodotorula isolates had elevated azole MICs. Overall, 99.7% to 99.8% of Candida isolates were susceptible (WT phenotype) to echinocandins, but 3 isolates were nonsusceptible (either intermediate or resistant) to caspofungin (C. albicans, C. guilliermondii, and C. krusei), anidulafungin (C. albicans and C. guilliermondii), and micafungin (C. albicans). However, when the intrinsically resistant non-Candida isolates were included, the rate of echinocandin nonsusceptibility reached 1.8%. In summary, the SYO method proved to be able to detect yeast species showing antifungal resistance or reduced susceptibility.

Pneumonia due to methicillin-resistant staphylococcus aureus : clinical features, diagnosis and management

Purpose of review The review highlights the clinical findings and the management of community-acquired, health-care associated and nosocomial pneumonia due to methicillin-resistant Staphylococcus aureus (MRSA). Recent findings Although previously considered as a purely nosocomial event, community-acquired MRSA pneumonia is underestimated and is spreading worldwide. A retrospective study showed that almost half of patients with nonnosocomial MRSA pneumonia admitted to a large teaching hospital did not present established criteria for healthcare-associated infections. Recent data show that MRSA ventilator-associated pneumonia is associated with significantly higher mortality than ventilator-associated pneumonia caused by methicillin-susceptible Staphylococcus aureus. Therefore, prompt and appropriate therapy is essential. The optimal therapy for MRSA pneumonia has not been fully elucidated. Although vancomycin has been considered the gold standard for the treatment of MRSA infections, clinical failures have also been reported in the presence of in-vitro susceptibility. Linezolid may provide improved outcomes compared with vancomycin in patients with MRSA pneumonia, but validation in a prospective trial is currently lacking. Recently licensed tigecycline and dalbavancin, a drug in phase III trial, look promising. Animal models showed that immunization against a cytolytic toxin secreted by most Staphylococcus aureus strains protects against lethal pneumonia. Summary Rapid recognition of possible staphylococcal infection in patients with severe pneumonia is essential. The treatment of MRSA pneumonia must be prompt and effective in order to allow a fast microbiological clearance and to successfully manage the infection.