Search

A prospective multicentre study was carried out between 2017 and 2021 to assess (1) the appropriateness of the empirical treatment to the local guidelines of urinary source Escherichia coli bacteraemia, (2) the appropriateness of empirical treatment to antibiotic sensitivity results and (3) the degree of error in the local guidelines regarding the antibiotic sensitivity reported in acute care hospitals enrolled in the vigilància de les infeccions relacionades amb l'atenció sanitària de Catalunya program. During the study period, 79.0% of the empirical treatments analysed complied with the guidelines and 88.1% were appropriate in view of the in vitro activity of the isolated strain. The rate of appropriateness rose from 73.8% in 2017 to 81.0% in 2021 (P < 0.001). The degree of error in the recommendations regarding the in vitro activity of the isolated strains was 5.9% and remained stable during the study period. Antibiotic families correctly prescribed according to the guidelines were third-generation cephalosporins (54.9%), carbapenems (16.8%) and combinations of penicillins and beta-lactamase inhibitors (16.4%). Of the 8009 E. coli strains, 19.0% were extended-spectrum beta-lactamases producers, 36.8% were resistant to quinolones and 0.5% were resistant to carbapenems. The broad implementation of an antimicrobial stewardship program with quality indicators of antibiotic use improved compliance to local guidelines in the empiric treatment of urinary tract E. coli bacteraemia. The degree of error in local guidelines was low but higher in more complex hospitals and in healthcare-associated infections. Guidelines need to be constantly updated with the use of epidemiological data, rapid diagnostic tests and the analysis of patient risk factors specific to each geographical area., (Copyright © 2024 Elsevier Ltd and International Society of Antimicrobial Chemotherapy. All rights reserved.)

Background: Complicated urinary tract infections (cUTIs) are responsible for a major share of all antibiotic consumption in hospitals. We aim to describe risk factors for treatment failure and mortality among patients with cUTIs., Methods: A multinational, multicentre retrospective cohort study, conducted in 20 countries in Europe and the Middle East. Data were collected from patients' files on hospitalised patients with a diagnosis of cUTI during 2013-2014. Primary outcome was treatment failure, secondary outcomes included 30 days all-cause mortality,among other outcomes. Multivariable analysis using a logistic model and the hospital as a random variable was performed to identify independent predictors for these outcomes., Results: A total of 981 patients with cUTI were included. Treatment failure was observed in 26.6% (261/981), all cause 30-day mortality rate was 8.7% (85/976), most of these in patients with catheter related UTI (CaUTI). Risk factors for treatment failure in multivariable analysis were ICU admission (OR 5.07, 95% CI 3.18-8.07), septic shock (OR 1.92, 95% CI 0.93-3.98), corticosteroid treatment (OR 1.92, 95% CI 1.12-3.54), bedridden (OR 2.11, 95%CI 1.4-3.18), older age (OR 1.02, 95% CI 1.0071.03-), metastatic cancer (OR 2.89, 95% CI 1.46-5.73) and CaUTI (OR 1.48, 95% CI 1.04-2.11). Management variables, such as inappropriate empirical antibiotic treatment or days to starting antibiotics were not associated with treatment failure or 30-day mortality. More patients with pyelonephritis were given appropriate empirical antibiotic therapy than other CaUTI [110/171; 64.3% vs. 116/270; 43%, p <0.005], nevertheless, this afforded no advantage in treatment failure rates nor mortality in these patients., Conclusions: In patients with cUTI we found no benefit of early appropriate empirical treatment on survival rates or other outcomes. Physicians might consider supportive treatment and watchful waiting in stable patients until the causative pathogen is defined.

The purpose of this study was to describe the presence of the novel optrA gene among clinical isolates of enterococci in a Spanish teaching hospital (May 2016-April 2017). optrA and cfr genes were screened by PCR in all isolates showing linezolid minimal inhibitory concentration (MIC) ≥4 mg/L. The genetic relatedness of the isolates, the presence of resistance and virulence genes, and the genetic environment of optrA were assessed by whole-genome sequencing (WGS). Six of 1,640 enterococci had linezolid MIC ≥4 mg/L. Among them, the optrA gene was detected in five Enterococcus faecalis isolated from unrelated patients. Although none of them had received linezolid or chloramphenicol, all had antecedents of recent quinolone consumption. WGS analysis revealed the existence of two different genotypes: ST585 and ST474. cfr was not detected in any of the isolates. No mutations were detected among the 23S ribosomal RNA and the ribosomal proteins L3, L4, and L22. Both genotypes also carried genes related to aminoglycoside, lincosamide, macrolide, phenicol, and tetracycline resistance. Detection of optrA in a setting with low linezolid consumption and among patients without antecedents of oxazolidinone therapy is of concern.

Background: Healthcare-associated infections caused by Pseudomonas aeruginosa are associated with poor outcomes. However, the role of P. aeruginosa in surgical site infections after colorectal surgery has not been evaluated. The aim of this study was to determine the predictive factors and outcomes of surgical site infections caused by P. aeruginosa after colorectal surgery, with special emphasis on the role of preoperative oral antibiotic prophylaxis., Methods: We conducted an observational, multicenter, prospective cohort study of all patients undergoing elective colorectal surgery at 10 Spanish hospitals (2011-2014). A logistic regression model was used to identify predictive factors for P. aeruginosa surgical site infections., Results: Out of 3701 patients, 669 (18.1%) developed surgical site infections, and 62 (9.3%) of these were due to P. aeruginosa. The following factors were found to differentiate between P. aeruginosa surgical site infections and those caused by other microorganisms: American Society of Anesthesiologists' score III-IV (67.7% vs 45.5%, p = 0.001, odds ratio (OR) 2.5, 95% confidence interval (95% CI) 1.44-4.39), National Nosocomial Infections Surveillance risk index 1-2 (74.2% vs 44.2%, p < 0.001, OR 3.6, 95% CI 2.01-6.56), duration of surgery ≥75thpercentile (61.3% vs 41.4%, p = 0.003, OR 2.2, 95% CI 1.31-3.83) and oral antibiotic prophylaxis (17.7% vs 33.6%, p = 0.01, OR 0.4, 95% CI 0.21-0.83). Patients with P. aeruginosa surgical site infections were administered antibiotic treatment for a longer duration (median 17 days [interquartile range (IQR) 10-24] vs 13d [IQR 8-20], p = 0.015, OR 1.1, 95% CI 1.00-1.12), had a higher treatment failure rate (30.6% vs 20.8%, p = 0.07, OR 1.7, 95% CI 0.96-2.99), and longer hospitalization (median 22 days [IQR 15-42] vs 19d [IQR 12-28], p = 0.02, OR 1.1, 95% CI 1.00-1.17) than those with surgical site infections due to other microorganisms. Independent predictive factors associated with P. aeruginosa surgical site infections were the National Nosocomial Infections Surveillance risk index 1-2 (OR 2.3, 95% CI 1.03-5.40) and the use of oral antibiotic prophylaxis (OR 0.4, 95% CI 0.23-0.90)., Conclusions: We observed that surgical site infections due to P. aeruginosa are associated with a higher National Nosocomial Infections Surveillance risk index, poor outcomes, and lack of preoperative oral antibiotic prophylaxis. These findings can aid in establishing specific preventive measures and appropriate empirical antibiotic treatment.

Background: Patients with complicated urinary tract infections (cUTIs) frequently receive broad-spectrum antibiotics. We aimed to determine the prevalence and predictive factors of multidrug-resistant gram-negative bacteria in patients with cUTI., Methods: This is a multicenter, retrospective cohort study in south and eastern Europe, Turkey and Israel including consecutive patients with cUTIs hospitalised between January 2013 and December 2014. Multidrug-resistance was defined as non-susceptibility to at least one agent in three or more antimicrobial categories. A mixed-effects logistic regression model was used to determine predictive factors of multidrug-resistant gram-negative bacteria cUTI., Results: From 948 patients and 1074 microbiological isolates, Escherichia coli was the most frequent microorganism (559/1074), showing a 14.5% multidrug-resistance rate. Klebsiella pneumoniae was second (168/1074) and exhibited the highest multidrug-resistance rate (54.2%), followed by Pseudomonas aeruginosa (97/1074) with a 38.1% multidrug-resistance rate. Predictors of multidrug-resistant gram-negative bacteria were male gender (odds ratio [OR], 1.66; 95% confidence interval [CI], 1.20-2.29), acquisition of cUTI in a medical care facility (OR, 2.59; 95%CI, 1.80-3.71), presence of indwelling urinary catheter (OR, 1.44; 95%CI, 0.99-2.10), having had urinary tract infection within the previous year (OR, 1.89; 95%CI, 1.28-2.79) and antibiotic treatment within the previous 30 days (OR, 1.68; 95%CI, 1.13-2.50)., Conclusions: The current high rate of multidrug-resistant gram-negative bacteria infections among hospitalised patients with cUTIs in the studied area is alarming. Our predictive model could be useful to avoid inappropriate antibiotic treatment and implement antibiotic stewardship policies that enhance the use of carbapenem-sparing regimens in patients at low risk of multidrug-resistance., Competing Interests: This study was approved by the local research ethics committee of each site. The processing of patients’ personal data was anonymised and complied with local data protection legislations and with the European Union Data Protection Directive (95/46/EC). As no individual data is published as well as no intervention was performed to patients, patient consent was waived by the Ethics Committee.No applicable.Authors IA, CV, IW, and CV belong to EFPIA (European Federation of Pharmaceutical Industries and Association) member companies in the IMI JU and costs related to their part in the research were carried by the respective company as in kind contribution under the IMI JU scheme. Other authors declare no potential conflicts.Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

We investigated whether the addition of fosfomycin or cloxacillin to daptomycin provides better outcomes in the treatment of methicillin-resistant Staphylococcus aureus (MRSA) experimental aortic endocarditis in rabbits. Five MRSA strains were used to perform in vitro time-kill studies using standard (10 6 ) and high (10 8 ) inocula. Combined therapy was compared to daptomycin monotherapy treatment in the MRSA experimental endocarditis model. A human-like pharmacokinetics model was applied, and the equivalents of cloxacillin at 2 g/4 h, fosfomycin at 2 g/6 h, and daptomycin at 6 to 10 mg/kg/day were administered intravenously. A combination of daptomycin and either fosfomycin or cloxacillin was synergistic in the five strains tested at both inocula. A bactericidal effect was detected in four of five strains tested with both combinations. The MRSA-277 strain (vancomycin MIC, 2 μg/ml) was used for the experimental endocarditis model. Daptomycin plus fosfomycin significantly improved the efficacy of daptomycin monotherapy at 6 mg/kg/day in terms of both the proportion of sterile vegetations (100% versus 72%, P = 0.046) and the decrease in the density of bacteria within the vegetations ( P = 0.025). Daptomycin plus fosfomycin was as effective as daptomycin monotherapy at 10 mg/kg/day (100% versus 93%, P = 1.00) and had activity similar to that of daptomycin plus cloxacillin when daptomycin was administered at 6 mg/kg/day (100% versus 88%, P = 0.48). Daptomycin nonsusceptibility was not detected in any of the isolates recovered from vegetations. In conclusion, for the treatment of MRSA experimental endocarditis, the combination of daptomycin plus fosfomycin showed synergistic and bactericidal activity., (Copyright © 2018 American Society for Microbiology.)

Introduction: Case-fatality rates for Staphylococcus aureus bacteremia (SAB) remain unacceptably high and have improved only modestly in recent decades. Treatment of SAB is still a clinical challenge, especially if methicillin-resistant strains are involved. New drugs with anti-staphylococcal activity are currently available, and their role as alternatives to standard therapies is being investigated. Areas covered: In this review, we give an update of the current available antibiotics for the treatment of SAB. We provide information regarding the pharmacological characteristics, the accepted indications, and the most important adverse events of the old and new anti-staphylococcal agents, as well as the existing evidence on their use for the treatment of SAB. Expert opinion: The management of patients with SAB is very complex and needs a multidisciplinary approach. There are currently new available options for the treatment of methicillin-resistant SAB. However, more data from clinical trials are needed to assign specific roles to each antibiotic and to include them in the new antibacterial armamentarium. The role of combination therapy for the treatment of increasingly complex patients with SAB deserves thorough investigation.

Background: It has been suggested that there is an increased risk of treatment failure in episodes of MRSA bloodstream infection (BSI) caused by strains with high vancomycin MICs. However, it is unknown if this phenomenon may also act as a risk factor for the development of infective endocarditis (IE)., Methods: We analysed 207 episodes of catheter-related (CR)-BSI recruited from June 2008 to December 2009 within a prospective study on MRSA BSI in 21 Spanish hospitals. Vancomycin susceptibility was centrally tested. The impact of high vancomycin MIC values (≥1.5 mg/L by Etest) on the subsequent development of IE was investigated by Cox regression., Results: High vancomycin MIC values were observed in 46.9% of the isolates. Initial therapy consisted of vancomycin [99 episodes (44.7%)], daptomycin [25 (12.1%)], linezolid [18 (8.7%)] and other antistaphylococcal agents [16 (7.7%)]. Haematogenous complications occurred in 41 patients (19.8%), including 10 episodes complicated by IE. Early (48 h) and late (30 day) all-cause mortality were 3.4% and 25.1%, respectively. High vancomycin MIC isolates were more common among patients that developed IE compared with those free from this complication [90.9% (9/10) versus 44.7% (88/197); P  = 0.007]. This association remained significant after adjusting for multiple confounders (including initial antibiotic therapy and catheter removal) in different models (minimum hazard ratio: 9.18; 95% CI: 1.16-72.78; P  = 0.036). There were no differences in mortality according to vancomycin MIC values., Conclusions: Decreased susceptibility to vancomycin acted as a predictor of the development of IE complicating MRSA CR-BSI., (© The Author 2017. Published by Oxford University Press on behalf of the British Society for Antimicrobial Chemotherapy. All rights reserved. For Permissions, please email: journals.permissions@oup.com.)

Surgical site infections (SSIs) are among the most common healthcare-associated infections, and contribute significantly to patient morbidity and healthcare costs. Staphylococcus aureus is the most common microbial cause. The epidemiology of S. aureus is changing with the dissemination of newer clones and the emergence of mupirocin resistance. The prevention and control of SSIs is multi-modal, and this article reviews the evidence on the value of screening for nasal carriage of S. aureus and subsequent decolonization of positive patients pre-operatively. Pre-operative screening, using culture- or molecular-based methods, and subsequent decolonization of patients who are positive for meticillin-susceptible S. aureus and meticillin-resistant S. aureus (MRSA) reduces SSIs and hospital stay. This applies especially to major clean surgery, such as cardiothoracic and orthopaedic, involving the insertion of implanted devices. However, it requires a multi-disciplinary approach coupled with patient education. Universal decolonization pre-operatively without screening for S. aureus may compromise the capacity to monitor for the emergence of new clones of S. aureus, contribute to mupirocin resistance, and prevent the adjustment of surgical prophylaxis for MRSA (i.e. replacement of a beta-lactam agent with a glycopeptide or alternative)., (Copyright © 2016 The Healthcare Infection Society. Published by Elsevier Ltd. All rights reserved.)

Introduction: The emergence of multidrug resistant (MDR) Gram-negative bacteria (GNB), including carbapenemase-producing strains, has become a major therapeutic challenge. These MDR isolates are often involved in complicated urinary tract infection (cUTI), and are associated with poor clinical outcomes. The study has been designed to gain insight into the epidemiology, clinical management, outcome and healthcare cost of patients with cUTI, especially in countries with high prevalence of MDR GNB., Methods and Analysis: This multinational and multicentre observational, retrospective study will identify cases from 1 January 2013 to 31 December 2014 in order to collect data on patients with cUTI as a cause of hospital admission, and patients who develop cUTI during their hospital stay. The primary end point will be treatment failure defined as the presence of any of the following criteria: (1) signs or symptoms of cUTI present at diagnosis that have not improved by days 5-7 with appropriate antibiotic therapy, (2) new cUTI-related symptoms that have developed within 30 days of diagnosis, (3) urine culture taken within 30 days of diagnosis, either during or after completion of therapy, that grows ≥10(4) colony-forming unit/mL of the original pathogen and (4) death irrespective of cause within 30 days of the cUTI diagnosis., Sample Size: 1000 patients afford a power of 0.83 (α=0.05) to detect an absolute difference of 10% in the treatment failure rate between MDR bacteria and other pathogens. This should allow for the introduction of about 20 independent risk factors (or their interaction) in a logistic regression model looking at risk factors for failure., Ethics and Dissemination: Approval will be sought from all relevant Research Ethics Committees. Publication of this study will be considered as a joint publication by the participating investigator leads, and will follow the recommendations of the International Committee of Medical Journal Editors (ICMJE)., Trial Registration Number: NCT02641015; Pre-results., (Published by the BMJ Publishing Group Limited. For permission to use (where not already granted under a licence) please go to http://www.bmj.com/company/products-services/rights-and-licensing/)

We investigated the prognostic role of high MICs for antistaphylococcal agents in patients with methicillin-sensitive Staphylococcus aureus catheter-related bloodstream infection (MSSA CRBSI). We prospectively reviewed 83 episodes from 5 centers in Spain during April 2011-June 2014 that had optimized clinical management and analyzed the relationship between E-test MICs for vancomycin, daptomycin, oxacillin, and linezolid and development of complicated bacteremia by using multivariate analysis. Complicated MSSA CRBSI occurred in 26 (31.3%) patients; MICs for vancomycin and daptomycin were higher in these patients (optimal cutoff values for predictive accuracy = 1.5 μg/mL and 0.5 μg/mL). High MICs for vancomycin (hazard ratio 2.4, 95% CI 1.2-5.5) and daptomycin (hazard ratio 2.4, 95% CI 1.1-5.9) were independent risk factors for development of complicated MSSA CRBSI. Our data suggest that patients with MSSA CRBSI caused by strains that have high MICs for vancomycin or daptomycin are at increased risk for complications.

Resistance to all known antibiotics is a growing concern worldwide, and has renewed the interest in antimicrobial peptides, a structurally diverse class of amphipathic molecules that essentially act on the bacterial membrane. Propelled by the antimicrobial potential of this compound class, we have designed three new lipopeptides derived from polymyxin B, sp-34, sp-96 and sp-100, with potent antimicrobial activity against both Gram positive and Gram negative bacteria. The three peptides bind with high affinity to lipopolysaccharide as demonstrated by monolayer penetration and dansyl-displacement. The interaction with the cytoplasmic membrane has been elucidated by biophysical experiments with model membranes of POPG or POPE/POPG (6:4), mimicking the Gram positive and Gram negative bacterial membrane. Trp-based fluorescence experiments including steady-state, quenching, anisotropy and FRET, reveal selectivity for anionic phospholipids and deep insertion into the membrane. All three lipopeptides induce membrane fusion and leakage from anionic vesicles, a process that is favored by the presence of POPE. The molecules bind to zwitterionic POPC vesicles, a model of the eukaryotic membrane, but in a different way, with lower affinity, less penetration into the bilayer and no fusion or permeabilization of the membrane. Results in model membranes are consistent with flow cytometry experiments in Escherichia coli and Staphylococcus aureus using a membrane potential sensitive dye (bis-oxonol) and a nucleic acid dye (propidium iodide), suggesting that the mechanism of action is based on membrane binding and collapse of membrane integrity by depolarization and permeabilization., (Copyright © 2015 Elsevier B.V. All rights reserved.)

Background: In this study we describe the clinical and molecular characteristics of an outbreak due to carbapenem-resistant Klebsiella pneumoniae (CR-KP) producing CTX-M-15 and OXA-48 carbapenemase. Isogenic strains, carbapenem-susceptible K. pneumoniae (CS-KP) producing CTX-M-15, were also involved in the outbreak., Results: From October 2010 to December 2012 a total of 62 CR-KP and 23 CS-KP were isolated from clinical samples of 42 patients (22 had resistant isolates, 14 had susceptible isolates, and 6 had both CR and CS isolates). All patients had underlying diseases and 17 of them (14 patients with CR-KP and 3 with CS-KP) had received carbapenems previously. The range of carbapenem MICs for total isolates were: imipenem: 2 to >32 μg/ml vs. <2 μg/ml; meropenem: 4 to >32 μg/ml vs. <2 μg/ml; and ertapenem: 8 to >32 μg/ml vs. <2 μg/ml. All the isolates were also resistant to gentamicin, ciprofloxacin, and cotrimoxazole. Both types of isolates shared a common PFGE pattern associated with the multilocus sequence type 101 (ST101). The bla CTX-M-15 gene was detected in all the isolates, whereas the bla OXA-48 gene was only detected in CR-KP isolates on a 70 kb plasmid., Conclusions: The clonal spread of K. pneumoniae ST101 expressing the OXA-48 and CTX-M-15 beta-lactamases was the cause of an outbreak of CR-KP infections. CTX-M-15-producing isolates lacking the bla OXA-48 gene coexisted during the outbreak.

Introduction: Despite the availability of new antibiotics such as daptomycin, methicillin-resistant Staphylococcus aureus (MRSA) bacteraemia continues to be associated with high clinical failure rates. Combination therapy has been proposed as an alternative to improve outcomes but there is a lack of clinical studies. The study aims to demonstrate that combination of daptomycin plus fosfomycin achieves higher clinical success rates in the treatment of MRSA bacteraemia than daptomycin alone., Methods and Analysis: A multicentre open-label, randomised phase III study. Adult patients hospitalised with MRSA bacteraemia will be randomly assigned (1:1) to group 1: daptomycin 10 mg/kg/24 h intravenous; or group 2: daptomycin 10 mg/kg/24 h intravenous plus fosfomycin 2 gr/6 g intravenous. The main outcome will be treatment response at week 6 after stopping therapy (test-of-cure (TOC) visit). This is a composite variable with two values: Treatment success: resolution of clinical signs and symptoms (clinical success) and negative blood cultures (microbiological success) at the TOC visit. Treatment failure: if any of the following conditions apply: (1) lack of clinical improvement at 72 h or more after starting therapy; (2) persistent bacteraemia (positive blood cultures on day 7); (3) therapy is discontinued early due to adverse effects or for some other reason based on clinical judgement; (4) relapse of MRSA bacteraemia before the TOC visit; (5) death for any reason before the TOC visit. Assuming a 60% cure rate with daptomycin and a 20% difference in cure rates between the two groups, 103 patients will be needed for each group (α:0.05, ß: 0.2). Statistical analysis will be based on intention to treat, as well as per protocol and safety analysis., Ethics and Dissemination: The protocol was approved by the Spanish Medicines and Healthcare Products Regulatory Agency (AEMPS). The sponsor commits itself to publishing the data in first quartile peer-review journals within 12 months of the completion of the study., Trial Registration Number: NCT01898338., (Published by the BMJ Publishing Group Limited. For permission to use (where not already granted under a licence) please go to http://group.bmj.com/group/rights-licensing/permissions.)

In Spain, the inclusion of new antibiotics in hospital formularies is performed by the Infection Policy Committee or the Pharmacy and Therapeutic Committee, although now the decision is moving to a regional level. Criteria for the evaluation of new drugs include efficacy, safety and cost. For antimicrobial drugs evaluation it is necessary to consider local sensibility and impact in bacterial resistance to determinate the therapeutic positioning. There is compelling evidence that the use of antibiotics is associated with increasing bacterial resistance, and a great number of antibiotics are used incorrectly. In order to decrease the inappropriate use of antibiotics, several approaches have been proposed. Limiting the use of antimicrobials through formulary restrictions, often aimed at drugs with a specific resistance profile, shows benefits in improving antimicrobial susceptibilities and decreasing colonization by drug-resistant organisms. However, the restriction of one agent may result in the increased utilization of other agents. By using antibiotic cycling, the amount of antibiotics is maintained below the threshold where bacterial resistance develops, thus preserving highly efficient antibiotics. Unfortunately, cumulative evidence to date suggests that antibiotic cycling has limited efficacy in preventing antibiotic resistance. Finally, although there is still little clinical evidence available on antibiotic heterogeneity, the use of most of the existing antimicrobial classes could limit the emergence of resistance. This review summarizes information regarding antibiotic evaluation and available restrictive strategies to limit the use of antibiotics at hospitals with the aim of curtailing increasing antibiotic resistance., (Copyright © 2013 Elsevier España, S.L. All rights reserved.)

The prevalence of multidrug-resistant (MDR) Pseudomonas aeruginosa has increased over the past decade and a significant rise in these isolates in ventilator-associated pneumonia (VAP) has been observed. However, the impact of MDR on VAP outcome has not been analysed in depth. We investigated the risk factors for early and crude mortality in a retrospective study of microbiologically and clinically documented VAP. Ninety-one VAP episodes in 83 patients were included, 31 caused by susceptible P. aeruginosa and 60 by MDR strains, of which 42 (70 %) were extensively drug-resistant (XDR) P. aeruginosa. Thirteen episodes concomitantly presented P. aeruginosa bacteraemia, in seven of which the origin was the respiratory tract. Whereas susceptible P. aeruginosa episodes were more likely than MDR episodes to receive adequate empirical (68 % vs. 30 %; p < 0.001) and definitive antimicrobial therapy (96 % vs. 50 %; p < 0.001), susceptible P. aeruginosa VAP presented a trend towards early mortality (29 % vs. 15 %; p = 0.06). A logistic regression model with early mortality as the dependent variable identified multiorgan dysfunction syndrome (MODS) [odds ratio (OR) 10.4; 95 % confidence interval (CI) 1.7-63.5; p = 0.01] and inadequate antibiotic therapy (OR 4.27; 95 % CI 0.98-18.4; p = 0.052) as independent risk factors for early mortality. A similar analysis identified MODS (OR 4.31; 95 % CI 1.14-16.2; p = 0.03) as the only independent predictor of crude mortality. The severity of acute illness clinical presentation was the main predictor of mortality. Despite adequate antibiotic therapy, susceptible P. aeruginosa seems to cause major early mortality. Although adequate therapy is essential to treat VAP, the severity of acute illness is a more important factor than drug resistance.

Linezolid is an effective antimicrobial agent to treat methicillin-resistant Staphylococcus aureus (MRSA). Resistance to linezolid due to the cfr gene is described worldwide. The present study aimed to analyze the prevalence of the cfr-mediated linezolid resistance among MRSA clinical isolates in our area. A very low prevalence of cfr mediated linezolid resistance was found: only one bacteremic isolate out of 2 215 screened isolates. The only linezolid resistant isolate arose in a patient, previously colonized by MRSA, following linezolid therapy. Despite the low rate of resistance in our area, ongoing surveillance is advisable to avoid the spread of linezolid resistance.

The antimicrobial agents are unique drugs for several reasons. First, their efficacy is higher than other drugs in terms of reduction of morbidity and mortality. Also, antibiotics are the only group of drugs associated with ecological effects, because their administration may contribute to the emergence and spread of microbial resistance. Finally, they are used by almost all medical specialties. Appropriate use of antimicrobials is very complex because of the important advances in the management of infectious diseases and the spread of antibiotic resistance. Thus, the implementation of programs for optimizing the use of antibiotics in hospitals (called PROA in this document) is necessary. This consensus document defines the objectives of the PROA (namely, to improve the clinical results of patients with infections, to minimise the adverse events associated to the use of antimicrobials including the emergence and spread of antibiotic resistance, and to ensure the use of the most cost-efficacious treatments), and provides recommendations for the implementation of these programs in Spanish hospitals. The key aspects of the recommendations are as follows. Multidisciplinary antibiotic teams should be formed, under the auspices of the Infection Committees. The PROA need to be considered as part of institutional programs and the strategic objectives of the hospital. The PROA should include specific objectives based on measurable indicators, and activities aimed at improving the use of antimicrobials, mainly through educational activities and interventions based more on training activities directed to prescribers than just on restrictive measures., (Copyright © 2011 Elsevier España, S.L. All rights reserved.)

Objective: We aimed to study the influence of carbapenem resistance on attributable mortality in a cohort of patients with Pseudomonas aeruginosa bacteremia., Methods: Data on 121 episodes of P. aeruginosa bacteremia occurring between January and December 2005 were retrospectively analyzed., Results: Thirty-three episodes were caused by carbapenem-resistant P. aeruginosa (CRPA) strains and 88 by carbapenem-susceptible P. aeruginosa (CSPA) strains. There was no significant difference in mortality between the groups (33% in CRPA vs. 30% in CSPA; p = 0.69). However, a Kaplan-Meier survival analysis showed that in the first 48h after the onset of bacteremia, there was a lower cumulative mortality proportion in the CRPA group than in the CSPA group (13% vs. 50%; p = 0.026). The independent risk factors associated with death in P. aeruginosa bacteremia were clinical presentation with severe sepsis (odds ratio (OR) 38, 95% confidence interval (CI) 10.2-142.2) and bacteremia of high-risk origin (OR 6.6, 95% CI 1.6-26.9)., Conclusions: According to our data, carbapenem resistance was not associated with higher mortality in patients with P. aeruginosa bacteremia. The slower initial mortality in the CRPA group might have implications in the design of the optimal antibiotic policy strategy., (Copyright © 2010 International Society for Infectious Diseases. Published by Elsevier Ltd. All rights reserved.)

Cefepime (FEP) and ceftazidime (CAZ) are broad-spectrum cephalosporins that display similar MICs for wild-type Pseudomonas aeruginosa strains. Recently, P. aeruginosa isolates showing a discordance in susceptibility to CAZ and FEP have been noted at the Hospital de Bellvitge in Barcelona, Spain, and a clustering was suspected. During the study period (March to December 2007), 51 patients, particularly those in an intensive care units (ICUs) (n = 29 [57%]), infected or colonized with at least one P. aeruginosa non-FEP-susceptible and CAZ-susceptible (Fep(ns) Caz(s)) phenotype strain were detected. Twenty-three (45%) patients were infected, and the respiratory tract was the most frequent site of infection. Changes in the consumption of antimicrobials in the ICUs were observed over time: a progressive reduction in the levels of consumption of carbapenems (247 defined daily doses [DDD]/1,000 patient days to 66 DDD/1,000 patient days; P = 0.008), after restriction of its use in 2006, and an expected increase in the rate of piperacillin-tazobactam use (42 DDD/1,000 patient days in 2004 to 200 DDD/1,000 patient days in 2007; P < 0.001). Throughout the whole study period, only a single clone of a P. aeruginosa Fep(ns) Caz(s) phenotype strain was identified by pulsed-field gel electrophoresis analysis to be associated with the hyperexpression of MexXY-OprM and the production of an integron-borne PSE-1 ss-lactamase. In conclusion, we identified an epidemic P. aeruginosa clone of an Fep(ns) Caz(s) phenotype strain involving 51 patients, in particular, ICU patients. The combination of the overexpression of an efflux pump and PSE-1 ss-lactamase production is associated with the multidrug-resistant phenotype. The dominant use of a single class of antibiotics could have provided the selective pressure required for the emergence and spread of this P. aeruginosa strain.

A cohort study was carried out on hospitalized adult non-critically ill patients (January 2003-December 2004) to identify factors associated with the acquisition of multidrug-resistant Pseudomonas aeruginosa (MDR-PA). A total of 246 non-critically patients were included, 162 (66%) who revealed MDR-PA in the first isolate and 84 (34%) who had carbapenem-resistant P. aeruginosa (CR-PA) isolates. Multivariate analysis identified nosocomial acquisition (odds ratio [OR] 2.7, 95% confidence interval [CI] 1.1-6.3), urinary catheter (OR 2.1, 95%CI 1.1-4.3), and the prior use of fluoroquinolones (OR 2.6, 95%CI 1.0-6.7) as independent risk factors associated with MDR-PA acquisition. Our results show that antibiotics, most notably, fluoroquinolones, may play a major role in the emergence of MDR-PA.

Objectives: We investigated the influence of empirical therapy on the mortality of patients with health care-associated (HCA) sepsis caused by methicillin-resistant Staphylococcus aureus (MRSA) infections in a multicenter cohort, and the variables associated with inappropriate empirical therapy., Methods: All new cases of infection caused by HCA-MRSA presenting with sepsis syndrome in 59 Spanish hospitals during June 2003 were prospectively followed. The main outcome variable was mortality at day 30. Predictors of mortality and of inappropriate empirical therapy were studied using multivariate logistic regression., Results: We included 209 cases. Crude mortality was 23%. After controlling for severity of the underlying condition, ICU stay, presentation with severe sepsis or shock, and site of infection, inappropriate empirical therapy was associated with an increased odds of mortality (OR=3.0; 95% CI: 1.01-9.0; p=0.04). Only 21.1% of the patients received appropriate empirical therapy. Variables independently associated with appropriate therapy were recent surgery, central venous catheter and certain sites of infection (primary bacteraemia, intraabdominal infections, and respiratory tract infections). Cancer patients were at an increased risk of receiving inappropriate therapy., Conclusions: Inappropriate empirical therapy was independently associated with increased mortality in this multicenter cohort. Clinicians should be aware of the need to consider coverage against MRSA more frequently.

Bacteremia and endocarditis due to methicillin-resistant Staphylococcus aureus (MRSA) are prevalent and clinically important. The rise in MRSA bacteremia and endocarditis is related with the increasing use of venous catheters and other vascular procedures. Glycopeptides have been the reference drugs for treating these infections. Unfortunately their activity is not completely satisfactory, particularly against MRSA strains with MICs > 1 microg/mL. The development of new antibiotics, such as linezolid and daptomycin, and the promise of future compounds (dalvabancin, ceftobiprole and telavancin) may change the expectatives in this field.The principal aim of this consensus document was to formulate several recommendations to improve the outcome of MRSA bacteremia and endocarditis, based on the latest reported scientific evidence. This document specifically analyzes the approach for three clinical situations: venous catheter-related bacteremia, persistent bacteremia, and infective endocarditis due to MRSA.

We performed a retrospective matched-cohort study to determine the risk factors for mortality among patients with Escherichia coli infections. From January 1996 to December 2003, 100 hospitalised patients with extended-spectrum beta-lactamase (ESBL)-producing E. coli infections were compared with patients not infected with ESBL-producing E. coli. These patients were selected according to the same site of infection and the closest date of admission. Comparison of the two groups showed that empirical antibiotic therapy was more often inadequate in patients infected with ESBL-producing E. coli (44% vs 15%; P<0.01), and that early mortality (16% vs 6%; P=0.02) and overall mortality (25% vs 11%; P=0.01) were also significantly higher in patients with ESBL-producing E. coli infections. A multivariate model identified the urinary tract focus as the only independent risk factor influencing early mortality for E. coli infections [odds ratio (OR): 0.1; 95% confidence interval (CI): 0.03-0.7; P=0.01]. All 12 patients with ESBL-producing E. coli urinary tract infections treated initially with an oxyimino-beta-lactam survived. Subsequent analysis of the factors influencing early mortality in the cohort of 130 patients with a non-urinary E. coli infection found inadequate empirical antibiotic therapy as an independent risk factor for mortality only for non-urinary E. coli infections (adjusted OR: 3.0; 95% CI: 1.0-8.6; P=0.03). The study showed that hospitalised patients with ESBL-producing E. coli infections more often receive inadequate empiric antibiotic therapy and have a higher mortality rate than those infected with non-ESBL-producing strains. The site of infection strongly influences mortality. The administration of inadequate empirical antibiotic therapy is independently associated with higher mortality only among patients with non-urinary tract infections.

Background: In the setting of a large endemic of Acinetobacter baumannii infections, treatment of those due to carbapenem-resistant strains, susceptible only to colistin, has become a major problem in our hospital during the past years. Successful results have been reported using colistin, but clinical experience with this antibiotic is limited. In our experimental studies using these strains in a mouse pneumonia model, the best results were observed with a combination of rifampicin and imipenem., Methods: From July 2000 to September 2001, we performed a pilot study with patients suffering from serious infections due to carbapenem-resistant A. baumannii. Patients were treated with a rifampicin/imipenem combination and followed up prospectively. Cultures were repeated during and after treatment, and in vitro activity of rifampicin was monitored. Genotyping of these strains was performed by means of PFGE., Results: Ten patients were selected: four with ventilator-associated pneumonia, and six with other infections (one catheter-related bacteraemia, five surgical infections). Three patients died, two of whom were considered therapeutic failures. In five of the seven patients who were cured, other procedures were also performed such as surgical drainage or catheter removal. In vitro development of high resistance to rifampicin was shown in seven (70%). PFGE demonstrated that initial isolates and high-resistant strains belonged to the same clones., Conclusions: The results of our study argue against the use of a rifampicin/imipenem combination for the treatment of carbapenem-resistant A. baumannii infections. However, combinations of rifampicin with other antibiotics merit further studies.

Background: Monitoring of plasma aminoglycoside and vancomycin concentrations is a measure of good clinical practice in critically ill patients. However, the frequency and application of this practice in Spanish hospitals is unknown., Methods: Observational, multicenter study based on a survey designed by the Study Group for Infection in the Critically Ill Patient of the Sociedad Española de Enfermedades Infecciosas y Microbiología Clínica (SEIMC, Spanish Society of Infectious Diseases and Clinical Microbiology). The survey was sent to the 221 general hospitals with a more than 150-bed capacity included in the hospital directory. Questions regarding the antibiotics monitored, hospital services involved, systems used to report the results, and levels of intervention were included., Results: Information was recorded from 56 (25.3%) hospitals with a total of 36,886 beds, among which 933 (2.5%) corresponded to critically ill patients. In 47 (83.9%) hospitals, plasma concentrations of one or two antibiotics were determined: vancomycin in 47 (83.9% of the total), amikacin in 41 (73.2%), and gentamicin in 40 (71.2%). Analyses were performed by the following services: Biochemistry in 34%, Pharmacy in 25.5% and Pharmacology in 8.5%. Only 57.4% of services recommended dose adjustments according to the results obtained, using eight different dose adjustment models., Conclusions: In 16% of the hospitals surveyed, monitoring of antibiotic concentrations was not performed in daily practice. There was considerable variation in all phases of the process, especially with regard to adjustment of plasma antibiotic concentrations. Consensus recommendations established by all the Services implicated are required to standardize monitoring of plasma antibiotic concentrations.

The dramatically increased frequency of antibiotic resistance has led to intensive efforts towards developing new families of antibiotics. Membrane-active antibiotic peptides such as polymyxin B (PxB) hold promise as the next generation of antibiotics, since they rarely spur the evolution of resistance. At low concentrations in the membrane, PxB forms vesicle-vesicle contacts and induces lipid exchange without leakage or fusion, a phenomenon that can explain its specificity towards gram-negative bacteria by contact formation between the two phospholipids interfaces in the periplasmatic space. In this work, the interaction of PxB and the nonantibiotic derivative polymyxin B nonapeptide (PxB-NP) with monolayers of Escherichia coli membrane lipids (ECL) has been studied by thermodynamic and structural methods. PxB inserts itself into ECL monolayers as a conformation that forms intermembrane contacts with vesicles injected underneath, and induces lipid exchange when the monolayer surface pressure is set at 32 mN/m (membrane equivalence pressure) or net transfer vesicle-to-monolayer at lower surface pressures. Thermodynamic analysis of the compression isotherms of mixed monolayers indicates that PxB inserts into the monolayer with an expansion of the mean molecular area, implying that peptide and lipids form nonideal mixtures. At low concentrations, corresponding to the membrane-membrane contact form of PxB, the mixed monolayers present positive excess energy values (deltaGm(Ex)), and atomic force microscopy (AFM) imaging reveals structures of approximately 120-nm diameter that protrude from the lipid surface approximately 0.7 nm. At concentrations of PxB above 4 mol %, thermodynamic analysis gives a very high deltaGm(Ex), corresponding to nonfavorable interactions, and AFM images show round structures of 20-30 nm diameter. PxB-NP behaves in a totally different way, in agreement with its inability to form vesicle-vesicle contacts and its lack of antibiotic effect. These results are discussed in the light of the mechanism of action of PxB on the membrane of gram-negative bacteria., (2004 Wiley Periodicals, Inc.)

Objective: To investigate an outbreak of carbapenem-resistant Pseudomonas aeruginosa (CRPA) in a urology ward., Methods: Patients infected or colonized with CRPA were prospectively identified by daily laboratory surveillance. Routine infection-control measures were reinforced, disinfection protocols were revised, and a surveillance program was set up, analyzing cross-transmission in the nursing ward and environment cultures from urology wards and the operating theater. CRPA isolates from clinical and environment samples were studied by pulsed-field gel electrophoresis (PFGE), following XbaI and SpeI restriction., Results: From February 1998 to September 2000, 59 adult urology patients were colonized or infected by CRPA. All patients had been operated on prior to identification of the CRPA isolate and 79% of these procedures were performed in the same cystoscopy room. No patients had received prior carbapenem therapy. No cross-transmission was detected, and environment cultures from the urology ward and theater were negative except for five samples collected in the cystoscopy room. PFGE identified a single clone in the isolates from different patients and the environment samples., Conclusions: The PFGE analysis indicated that the CRPA outbreak resulted from the contamination of the cystoscopy room via an unsealed drain. The outbreak ended when the drain was sealed.

The effects of antibiotic treatment on the results of protected specimen brushing (PSB) in ventilator-associated pneumonia were prospectively assessed by performing this procedure before antibiotic treatment, and 12, 24, 48 and 72 h after initiation of antibiotic treatment, in 35 ventilated patients who developed pneumonia during mechanical ventilation. The number of micro-organisms isolated, their concentration (colony-forming units (cfu) mL(-1)), and the number of cases with a positive PSB (> or =10(3) cfu x mL(-1)) were evaluated. Within 12 h of the initiation of effective antibiotic treatment a rapid, significant decrease in the numbers of organisms isolated, their individual concentrations and the percentage of positive PSB results were observed. Certain bacterial species (Streptococcus pneumoniae, Haemophilus influenzee) appeared to be more vulnerable to antibiotics than others (Staphylococcus aureus, Pseudomonas aeruginosa, Acinetobacter baumanni). This data confirms that prior antibiotic treatment, even after only a few hours of activity, significantly decreases the sensitivity of protected brush specimen; this effect appears to be particularly marked among the species involved in early ventilator associated pneumonia.

There is growing concern about the increasing rates of resistance among human pathogens. These high rates of resistance, which are a consequence of antibiotic misuse, highlight the need for a thorough revision of strategies that deal with the proper use of antibiotics. The so-called 'optimal use of all antibiotics', restriction guidelines and use of a combination of antibiotics are well established strategies in most hospitals but new potential strategies, such as dosage optimization and antibiotic cycling, require further study and evaluation. Cycling antibiotic therapy consists of the scheduled replacement of one antibiotic for another, in order to avoid the development of bacterial resistance. Initial studies suggest that this strategy could be useful in reducing the rates of bacterial resistance as well as the incidence of nosocomial infections caused by Gram-negative bacilli in intensive care unit patients. This strategy, however, does not prevent antibiotic misuse and needs to be applied in a complete antibiotic policy program.

Enteroaggregative Escherichia coli (EAggEC) isolates were identified as a cause of traveller's diarrhoea in 50 (9%) of 517 patients and their antimicrobial susceptibility was determined. Molecular epidemiological characterisation and investigation of the mechanisms of acquisition of quinolone resistance among nalidixic acid-resistant EAggEC strains was performed. Seventeen (34%) of 50 patients needed antimicrobial therapy, because of persistence of symptoms in nine cases and the severity of symptoms in eight cases. Ampicillin and tetracycline resistance was high, whereas chloramphenicol and co-trimoxazole showed moderate activity and amoxicillin plus clavulanic acid, nalidixic acid and ciprofloxacin showed very good activity. Resistance to nalidixic acid was demonstrated in three isolates, two from patients who had travelled to India. In all three strains the resistance was linked to mutations in the gyrA gene alone or in both gyrA and parC genes. Although ciprofloxacin shows excellent in-vitro activity and could be useful in the treatment of traveller's diarrhoea in patients travelling abroad, it may not be useful in patients who have journeyed to India or to Mexico.

An outbreak due to extended-spectrum beta-lactamase-producing Klebsiella pneumoniae (ESBL-KP) was detected from May 1993 to June 1995. A total of 145 patients, particularly patients in intensive care units (ICUs) (107 patients [72%]), were colonized or infected. Infection developed in 92 (63%) patients, and primary bacteremia caused by ESBL-KP was the most frequent infection (40 of 92 patients [43%]). A single clone of ESBL-KP was identified by pulsed-field gel electrophoresis analysis throughout the whole period, and no molecular epidemiological relationship could be found between the epidemic strain and non-ESBL-KP isolates. To determine risk factors for ESBL-KP infection weekly rectal swabs were obtained in three serial incidence surveys (470 patients); the probabilities of carriage of ESBL-KP in the digestive tract were 33% (October and November 1993), 40% (May and June 1994), and 0% (October and November 1995) at 10 days of ICU admission. A logistic regression model identified prior carriage of ESBL-KP in the digestive tract (odds ratio, 3.4; 95% confidence interval 1.1 to 10.4) as an independent variable associated with ESBL-KP infection. A statistically significant correlation was observed between the restricted use of oxyimino-beta-lactams (189 defined daily doses [DDD]/ 1,000 patient-days to 24 DDD/1,000 patient-days) and the trends of ESBL-KP infection (r = 0.7; P = 0.03).