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BackgroundAntimicrobial surveillance and antimicrobial stewardship (AMS) are essential pillars in the fight against antimicrobial resistance (AMR), but practical guidance on how surveillance data should be linked to AMS activities is lacking. This issue is particularly complex in the hospital setting due to structural heterogeneity of hospital facilities and services. The JPIAMR ARCH and COMBACTE-MAGNET EPI-Net networks have joined efforts to formulate a set of target actions for linking surveillance data with AMS activities.MethodsA scoping review of the literature was carried out addressing research questions on three areas: (i) AMS leadership and accountability; (ii) antimicrobial usage and AMS; (iii) AMR and AMS. Consensus on the target actions was reached through a RAND-modified Delphi process involving over 40 experts in different fields from 18 countries.ResultsEvidence was retrieved from 51 documents. Initially 38 targets were proposed, differentiated as essential or desirable according to clinical relevance, feasibility and applicability to settings and resources. In the first consultation round, preliminary agreement was reached for 32 targets. Following a second consultation, 27 targets were approved, 11 were deleted and 4 were suggested for rephrasing, leading to a final approved list of 34 target actions in the form of a practical checklist.ConclusionsThis White Paper provides a pragmatic and flexible tool to guide the development of calibrated hospital-surveillance-based AMS interventions. The strength of this tool is that it is a comprehensive perspective that takes into account the hospital patient case-mix and the related epidemiology, which ultimately drives antimicrobial usage, and the feasibility in low-resource settings.

ObjectivesTo analyse the rectal carriage rate and the molecular epidemiology of vancomycin-resistant Enterococcus faecium (VREfm) recovered from patients upon hospital admission.MethodsAdult patients were screened at six German university hospitals from five different federal states upon hospital admission for rectal colonization with VREfm between 2014 and 2018. Molecular characterization of VREfm was performed by WGS followed by MLST and core-genome MLST analysis.ResultsOf 16350 patients recruited, 263 were colonized with VREfm, with increasing prevalence rates during the 5 year study period (from 0.8% to 2.6%). In total, 78.5% of the VREfm were vanB positive and 20.2% vanA positive, while 1.2% harboured both vanA and vanB. The predominant ST was ST117 (56.7%) followed by ST80 (15%), ST203 (10.9%), ST78 (5.7%) and ST17 (3.2%). ST117/vanB VREfm isolates formed a large cluster of 96 closely related isolates extending across all six study centres and four smaller clusters comprising 13, 5, 4 and 3 isolates each. In contrast, among the other STs inter-regional clonal relatedness was rarely observed.ConclusionsTo our knowledge, this is the largest admission prevalence and molecular epidemiology study of VREfm. These data provide insight into the epidemiology of VREfm at six German university hospitals and demonstrate the remarkable inter-regional clonal expansion of the ST117/vanB VREfm clone.

Background. There is little information about the efficacy of active alternative drugs to carbapenems except beta-lactam/beta-lactamase inhibitors for the treatment of bloodstream infections (BSIs) due to extended-spectrum beta-lactamase-producing Enterobacteriaceae (ESBL-E). The objective of this study was to assess the outcomes of patients with BSI due to ESBL-E who received empiric therapy with such drugs (other active drugs [OADs]) or carbapenems. Methods. A multinational retrospective cohort study of patients with BSI due to ESBL-E who received empiric treatment with OADs or carbapenems was performed. Cox regression including a propensity score for receiving OADs was performed to analyze 30-day all-cause mortality as main outcome. Clinical failure and length of stay were also analyzed. Results. Overall, 335 patients were included; 249 received empiric carbapenems and 86 OADs. The most frequent OADs were aminoglycosides (43 patients) and fluoroquinolones (20 patients). Empiric therapy with OADs was not associated with mortality (hazard ratio [HR], 0.75; 95% confidence interval [CI],.38-1.48) in the Cox regression analysis. Propensity score-matched pairs, subgroups, and sensitivity analyses did not show different trends; specifically, the adjusted HR for aminoglycosides was 1.05 (95% CI,.51-2.16). OADs were neither associated with 14-day clinical failure (adjusted odds ratio, 0.62; 95% CI,.29-1.36) nor length of hospital stay. Conclusions. We were unable to show that empiric treatment with OAD was associated with a worse outcome compared with carbapenems. This information allows more options to be considered for empiric therapy, at least for some patients, depending on local susceptibility patterns of ESBL-E.

Antibiotic resistance (ABR) is a global public health threat. Despite the emergence of highly resistant organisms and the huge medical need for new drugs, the development of antibacterials has slowed to an unacceptable level worldwide. Numerous government and non-government agencies have called for public-private partnerships and innovative funding mechanisms to address this problem. To respond to this public health crisis, the Innovative Medicines Initiative Joint Undertaking programme has invested more than a,not sign660 million, with a goal of matched contributions from the European Commission and the European Federation of Pharmaceutical Industries and Associations, in the development of new antibacterial strategies. The New Drugs for Bad Bugs (ND4BB) programme, an Innovative Medicines Initiative, has the ultimate goal to boost the fight against ABR at every level from basic science and drug discovery, through clinical development to new business models and responsible use of antibiotics. Seven projects have been launched within the ND4BB programme to achieve this goal. Four of them will include clinical trials of new anti-infective compounds, as well as epidemiological studies on an unprecedented scale, which will increase our knowledge of ABR and specific pathogens, and improve the designs of the clinical trials with new investigational drugs. The need for rapid concerted action has driven the funding of seven topics, each of which should add significantly to progress in the fight against ABR. ND4BB unites expertise and provides a platform where the commitment and resources required by all parties are streamlined into a joint public-private partnership initiative of unprecedented scale.

Background Puumala virus (PUUV) is the most common species of hantavirus in Central Europe. Nephropathia epidemica (NE), caused by PUUV, is characterized by acute kidney injury (AKI) and thrombocytopenia. The major goals of this study were to provide a clear clinical phenotyping of AKI in patients with NE and to develop an easy prediction rule to identify patients, who are at lower risk to develop severe AKI. Methods A cross-sectional prospective survey of 456 adult patients with serologically confirmed NE was performed. Data were collected from medical records and prospectively at follow-up visit. Severe AKI was defined by standard criteria according to the RIFLE (Risk, Injury, Failure, Loss, End-stage kidney disease) classification. Fuller statistical models were developed and validated to estimate the probability for severe AKI. Results During acute NE, 88% of the patients had AKI according to the RILFE criteria during acute NE. A risk index score for severe AKI was derived by using three independent risk factors in patients with normal kidney function at time of diagnosis: thrombocytopenia [two points; odds ratios (OR): 3.77; 95% confidence intervals (CI): 1.82, 8.03], elevated C-reactive protein levels (one point; OR: 3.02; 95% CI: 1.42, 6.58) and proteinuria (one point; OR: 3.92; 95% CI: 1.33, 13.35). On the basis of a point score of one or two, the probability of severe AKI was 0.18 and 0.28 with an area under the curve of 0.71. Conclusion This clinical prediction rule provides a novel and diagnostically accurate strategy for the potential prevention and improved management of kidney complications in patients with NE and, ultimately, for a possible decrease in unnecessary hospitalization in a high number of patients.

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.

OBJECTIVES To assess risk factors for acquiring extended-spectrum β-lactamase-producing Gram-negative bacteria (ESBL+ GN) causing urinary tract infections (UTIs) in long-term care facilities (LTCFs). METHODS A prospective case-case-control study was carried out. In the first study, cases were defined as patients harbouring ESBL+ GN, while, in the second study, cases were defined as patients harbouring ESBL-negative (ESBL-) GN. Controls were selected by simple random sampling from patients without GN infection. ESBL determinants were characterized by hybridization, and confirmed by PCR and sequencing. RESULTS The study involved 297 LTCF patients (99 with ESBL+ GN UTI, 99 with ESBL- GN UTI and 99 without GN infection). ESBL+ GN UTIs were due to Escherichia coli (64%), Proteus mirabilis (25%) and Klebsiella pneumoniae (11%). The CTX-M-type enzymes were the most prevalent (73% of isolates), whereas TEM- and SHV-type ESBLs and AmpC-type enzymes were less prevalent (10%, 2% and 15% of isolates, respectively). Patients with ESBL+ GN UTI were more likely to have a permanent urinary catheter (OR 15, 95% CI 6.9-30.5) and to have received antimicrobial therapy in the previous 30 days (OR 4, 95% CI 1.2-10.9). After adjusting for type, dosage and duration of antibiotic, exposure to ≥7 days of quinolones and third-generation cephalosporins was associated with the highest risk of ESBL+ GN UTI development (OR 7, 95% CI 1.2-40). Independent risk factors for acquiring ESBL- GN UTIs were previous surgical procedures (OR 2, 95% CI 1.1-4) and the presence of a urinary catheter (OR 8, 95% CI 4-16). No specific antibiotics remained a significant risk for ESBL- GN UTI after adjusting for demographic and clinical risk factors. CONCLUSIONS Exposure to ≥7 days of quinolones and third-generation cephalosporins significantly increases the risk of ESBL+ GN UTI. Interventions aimed at improving compliance with antimicrobial stewardship principles should be further developed and implemented in LTCFs.

Translation research strategy in infectious diseases, combining the results from basic research with patient-orientated research, aims to bridge the gap between laboratory findings and clinical infectious disease practice to improve disease management. In an era of increasing antimicrobial resistance, there are four main areas of clinical and scientific uncertainty that need to be urgently addressed by translational research: (i) early diagnosis of antibiotic-resistant infections and the appropriateness of empirical antibiotic therapy; (ii) the identification of reservoirs of antibiotic-resistant pathogens; (iii) the development of new antibiotics with lower propensities to evoke resistance; and (iv) the development of new non-antibiotic drugs to be used in the prevention of the spread of resistant bacterial strains. Strict European collaboration among major stakeholders is therefore essential. Appropriate educational tools to train a new generation of scientists with regard to a multifaceted approach to antimicrobial resistance research should be developed. Key areas include the support and implementation of European networks focused on translational research and related education activities, making potential therapeutics more attractive to investors and helping academic investigators to determine whether new molecules can be developed with clinical applicability.

Current evidence does not provide a clear definition of the association between methicillin-resistant Staphylococcus aureus (MRSA) isolation and previous antibiotic use. A systematic review was performed to determine whether antibiotic exposure is a risk factor for the isolation of MRSA.MEDLINE and EMBASE databases were searched to identify studies published between 1976 and 2007 on the role of antibiotics as a risk factor for MRSA isolation in adult patients. The outcome of interest was MRSA isolation. Summary statistics were risk ratios (RR) comparing MRSA-positive patients to those without S. aureus isolation or with methicillin-susceptible S. aureus isolation.Seventy-six studies, including a total of 24 230 patients, met the inclusion criteria. Antibiotic exposure was determined in the 126 +/- 184 (mean +/- SD) days preceding MRSA isolation. The risk of acquiring MRSA was increased by 1.8-fold [95% confidence interval (CI), 1.7-1.9; P0.001] in patients who had taken antibiotics. The RR for single classes of antibiotics was 3 (95% CI, 2.5-3.5) for quinolones, 2.9 (95% CI, 2.4-3.5) for glycopeptides, 2.2 (95% CI, 1.7-2.9) for cephalosporins and 1.9 (95% CI, 1.7-2.2) for other beta-lactams. Significant heterogeneity was detected among studies. A regression analysis revealed that the heterogeneity was linked to the length of time in which antibiotic exposure was detected before MRSA isolation (more or less than 180 days).This meta-analysis shows a clear association between exposure to antibiotics and MRSA isolation. This information may be useful for researchers in designing future studies and for policy decision-making on the appropriate management of antibiotic therapies.

BACKGROUND Methicillin-resistant Staphylococcus aureus (MRSA) infections diagnosed at hospital admission are often referred to as community-acquired. This designation may include MRSA strains previously acquired in a healthcare setting (healthcare-associated) as well as those that have emerged from community-based S. aureus strains. METHODS To understand further the epidemiology of MRSA from the community, a case-control study was performed. During 1997-2002, 254 patients with and without MRSA bacteraemia at hospital admission were studied. RESULTS All patients with MRSA bacteraemia in the first 24 h of hospital admission had a recent exposure to a healthcare setting: true community-acquired MRSA was not detected. Independent risk factors for healthcare-associated MRSA bacteraemia, defined as MRSA bacteraemia in the first 24 h of hospital admission among patients with a recent exposure to a healthcare setting or intervention, included previous MRSA infection or colonization (OR = 17, P < 0.001), cellulitis (OR = 4, P = 0.006), presence of a central venous catheter (OR = 3, P < 0.001) and skin ulcers (OR = 3, P = 0.007). CONCLUSIONS In this study, MRSA bacteraemia diagnosed in the first 24 h of hospital admission represented healthcare-associated MRSA strains and not true community-acquired strains. The clinical characteristics associated with healthcare-associated MRSA bacteraemia can assist clinicians in targeting measures to prevent cross-transmission and may help to streamline empirical vancomycin therapy.

A systematic review of the English-language literature was performed to determine the overall benefit of mupirocin therapy in reducing the rate of Staphylococcus aureus infection among patients undergoing hemodialysis (HD) or peritoneal dialysis (PD). Included studies met the following criteria: they were randomized clinical trials or cohort studies; cohorts consisted of adults (age, > or =18 years) requiring HD or PD; mupirocin therapy was administered to the treatment group, and placebo or no therapy was administered to the control group; and the primary outcome of interest was the difference in the number of S. aureus infections among mupirocin-treated and -untreated patients. Ten studies described in 9 articles were analyzed. A total of 2445 patients were included in the analysis. Use of mupirocin reduced the rate of S. aureus infections by 68% (95% confidence interval [CI], 57%-76%) among all patients undergoing dialysis; risk reductions were 80% (95% CI, 65%-89%) among patients undergoing HD and 63% (95% CI, 50%-73%) among patients undergoing PD. When data were stratified by type of infection, S. aureus bacteremia was found to be reduced by 78% among patients undergoing HD, and peritonitis and exit-site infections were found to be reduced by 66% and 62%, respectively, among patients undergoing PD. Mupirocin prophylaxis substantially reduces the rate of S. aureus infection in the dialysis population. Optimal regimens that minimize the emergence of mupirocin resistance need to be explored.

OBJECTIVES To define the incidence, risk factors and short-term predictors of mortality of methicillin-resistant Staphylococcus aureus (MRSA) bacteraemia in HIV-infected patients. PATIENTS AND METHODS All HIV-infected subjects with S. aureus bacteraemia were consecutively enrolled in a case-control study between January 1, 1991 and December 31, 2000 and prospectively followed up. RESULTS In the study period, 129 of 419 (31%) HIV-infected patients with bacteraemia had a diagnosis of S. aureus bacteraemia. The comparative analysis of incidence of S. aureus bacteraemia in the period 1991-96 and 1997-2000 showed a significant decrease (P < 0.001). The same trend was observed for MRSA bacteraemia (P = 0.002). The analysis of antimicrobial resistance showed that among 129 S. aureus strains, 88 (68%) were methicillin susceptible and 41 (32%) were methicillin resistant. The majority of MRSA bacteraemia was hospital acquired (78%). Previous administration of beta-lactams (P < 0.001), multiple previous hospital admissions (P < 0.001) and low numbers of CD4+ peripheral cells (P < 0.001) were found to be independent risk factors of methicillin resistance at multivariate analysis. The mortality rate was 34% in the cases and 11% in the controls (P = 0.002). Multivariate analysis indicated that a high Acute Physiology and Chronic Health Evaluation (APACHE) III score (P < 0.001) and high HIV viraemia (P = 0.02), but not methicillin resistance, predicted an increased risk of death in patients with S. aureus bacteraemia. CONCLUSION Individual exposure to beta-lactams, in association with a history of multiple hospitalizations and low CD4+ cell number, plays a pivotal role as a risk factor for the development of methicillin resistance in HIV-infected patients. Methicillin resistance does not influence the outcome of S. aureus bacteraemia when included in a multivariate analysis.

Highly active antiretroviral therapies (HAARTs) that contain human immunodeficiency virus (HIV) protease inhibitors (PIs) or nonnucleoside reverse-transcriptase inhibitors (NNRTIs) were compared for their effect on secretory aspartyl proteinase (Sap), a virulence trait for mucosal candidiasis. In therapy-naive HIV-positive subjects, oral Sap was detected in 11, 6, 3, 0, and 0 of 15 subjects treated with PI-HAART and in 7, 7, 9, 6, and 5 of 15 subjects treated with NNRTI-HAART, on days 0, 14, 30, 90, and 180 of treatment, respectively. In another 30 subjects, Sap was detected in 0 and 7 of 15 subjects after 1 year of treatment with PI-HAART or NNRTI-HAART, respectively. The anti-Sap effect of PI-HAART was associated with clinical resolution of oral candidiasis but not with late and inconstant recovery of anticandidal cellular immunity. In all subjects, the 2 therapeutic regimens compared well in increasing CD4(+) cell count and abating viremia. Thus, PIs exert an early, immune reconstitution-independent effect on Candida virulence in the oral cavities of HIV-positive subjects.

A 1-year prospective case-control study (ratio of control patients to case patients, 3:1) was performed to assess the incidence, risk factors, and genotypic patterns of bacteremia caused by glycopeptide-resistant coagulase-negative staphylococci (CoNS) and their correlation with hospital glycopeptide use. Among 535 subjects with CoNS bacteremia, 20 subjects had a glycopeptide-resistant strain (19 strains were resistant to teicoplanin and 1 was resistant to both teicoplanin and vancomycin). The percentage of resistant isolates recovered in 1 year was 8% in intensive care units and 3% and 2% in medical and surgical wards, respectively. Genotypic analysis of resistant strains showed different patterns with a high degree of polymorphism. Use of glycopeptides in individual wards was not statistically associated with the percentage of resistance. Previous exposure to beta-lactams and glycopeptides, multiple hospitalization in the previous year, and concomitant pneumonia were significantly associated with the onset of glycopeptide-resistant CoNS bacteremia. Mortality rates were 25% among case patients and 18% among control patients, and they were significantly higher among patients who presented with concomitant pneumonia and a high Acute Physiology and Chronic Health Evaluation III score.

The objective of this case-control study, conducted in a large Italian university hospital over a 12-month period, was to evaluate the risk factors associated with the emergence of azole resistant oral candidosis in 64 Human Immunodeficiency Virus (HIV) infected patients. A swab was obtained from each patient by brushing candidal lesions. Candida albicans was isolated in 41 patients (64%), Candida glabrata in ten (16%), Candida krusei in five (8%), Candida kefyr in two (3%), Candida tropicalis in two (3%), and Candida lipolytica and Candida guilliermondii in one case, respectively. Two patients suffered a double infection i.e. C. albicans + C. krusei and C. albicans + C. glabrata, respectively. Candida species were tested in vitro for their susceptibility to ketoconazole, fluconazole, itraconazole and amphotericin B. MICs of the four antifungal drugs were obtained for each yeast using a microdilution broth method developed in our laboratory. Twenty four (37%) of the isolated strains were resistant both to itraconazole and fluconazole, five (8%) to fluconazole alone, and two (3%) to ketoconazole alone, while none of the isolated strains was resistant to amphotericin B. Patients with oral candidosis caused by a strain resistant to one or more azole drug were compared to control patients with azole-susceptible oral candidosis. On univariate analysis, more than five episodes of oral candidosis in the last year (P = 0.01), previous use of azole therapy (P = 0.001), C2-3 category of HIV infection (P = 0.01) and low number of circulating CD4+ T-cells (P = 0.03) were significantly associated with an increased risk for the development of azole resistance. However, previous use of azole therapy was the only factor selected by a stepwise logistic regression analysis which was independently associated with the isolation of azole resistant strains (P = 0.003). Our findings indicate that, in view of the potential risk for the emergence and selection of azole resistant strains of Candida in patients with AIDS, it is important to carefully choose the antifungal drug for the therapy of mild fungal infections after evaluation of the in-vitro susceptibility of the isolated strains.