Daptomycin plus fosfomycin versus daptomycin monotherapy in treating MRSA: protocol of a multicentre, randomised, phase III trial.

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.

Fosfomycin versus meropenem in bacteraemic urinary tract infections caused by extended-spectrum β-lactamase-producing Escherichia coli (FOREST): study protocol for an investigator-driven randomised controlled trial.

INTRODUCTION Finding therapeutic alternatives to carbapenems in infections caused by extended-spectrum β-lactamase-producing Escherichia coli (ESBL-EC) is imperative. Although fosfomycin was discovered more than 40 years ago, it was not investigated in accordance with current standards and so is not used in clinical practice except in desperate situations. It is one of the so-called neglected antibiotics of high potential interest for the future. METHODS AND ANALYSIS The main objective of this project is to demonstrate the clinical non-inferiority of intravenous fosfomycin with regard to meropenem for treating bacteraemic urinary tract infections (UTI) caused by ESBL-EC. This is a 'real practice' multicentre, open-label, phase III randomised controlled trial, designed to compare the clinical and microbiological efficacy, and safety of intravenous fosfomycin (4 g/6 h) and meropenem (1 g/8 h) as targeted therapy for this infection; a change to oral therapy is permitted after 5 days in both arms, in accordance with predetermined options. The study design follows the latest recommendations for designing trials investigating new options for multidrug-resistant bacteria. Secondary objectives include the study of fosfomycin concentrations in plasma and the impact of both drugs on intestinal colonisation by multidrug-resistant Gram-negative bacilli. ETHICS AND DISSEMINATION Ethical approval was obtained from the Andalusian Coordinating Institutional Review Board (IRB) for Biomedical Research (Referral Ethics Committee), which obtained approval from the local ethics committees at all participating sites in Spain (22 sites). Data will be presented at international conferences and published in peer-reviewed journals. DISCUSSION This project is proposed as an initial step in the investigation of an orphan antimicrobial of low cost with high potential as a therapeutic alternative in common infections such as UTI in selected patients. These results may have a major impact on the use of antibiotics and the development of new projects with this drug, whether as monotherapy or combination therapy. TRIAL REGISTRATION NUMBER NCT02142751. EudraCT no: 2013-002922-21. Protocol V.1.1 dated 14 March 2014.

The Times They Are a-Changin': Carbapenems for Extended-Spectrum-β-Lactamase-Producing Bacteria.

Several antimicrobial agents are being investigated as alternatives to carbapenems in the treatment of infections caused by ESBL-producing Enterobacteriaceae, which may be useful in avoiding overuse of carbapenems in the context of recent global spread of carbapenem-resistant Enterobacteriaceae. The most promising candidates for invasive infections so far are β-lactam/β-lactamase inhibitor combinations and cephamycins.

Impact of inadequate empirical therapy on the mortality of patients with bloodstream infections: a propensity score-based analysis.

The impact of the adequacy of empirical therapy on outcome for patients with bloodstream infections (BSI) is key for determining whether adequate empirical coverage should be prioritized over other, more conservative approaches. Recent systematic reviews outlined the need for new studies in the field, using improved methodologies. We assessed the impact of inadequate empirical treatment on the mortality of patients with BSI in the present-day context, incorporating recent methodological recommendations. A prospective multicenter cohort including all BSI episodes in adult patients was performed in 15 hospitals in Andalucía, Spain, over a 2-month period in 2006 to 2007. The main outcome variables were 14- and 30-day mortality. Adjusted analyses were performed by multivariate analysis and propensity score-based matching. Eight hundred one episodes were included. Inadequate empirical therapy was administered in 199 (24.8%) episodes; mortality at days 14 and 30 was 18.55% and 22.6%, respectively. After controlling for age, Charlson index, Pitt score, neutropenia, source, etiology, and presentation with severe sepsis or shock, inadequate empirical treatment was associated with increased mortality at days 14 and 30 (odds ratios [ORs], 2.12 and 1.56; 95% confidence intervals [95% CI], 1.34 to 3.34 and 1.01 to 2.40, respectively). The adjusted ORs after a propensity score-based matched analysis were 3.03 and 1.70 (95% CI, 1.60 to 5.74 and 0.98 to 2.98, respectively). In conclusion, inadequate empirical therapy is independently associated with increased mortality in patients with BSI. Programs to improve the quality of empirical therapy in patients with suspicion of BSI and optimization of definitive therapy should be implemented.

UV-fixed-thick-blotch preparation improves sensitivity of auramine staining.

We describe here a very simple modification of the auramine staining procedure based on preparation of a UV-fixed thick blotch which allowed us to reach an overall sensitivity of 0.82 (592 acid-fast bacillus [AFB]-positive specimens/722 initial respiratory specimens with positive mycobacterial culture) and sensitivities of 0.93 (526 AFB-positive specimens/564 culture-positive specimens) for Mycobacterium tuberculosis complex and 0.42 (66 AFB-positive specimens/158 culture-positive specimens) for nontuberculous mycobacteria.

Proadrenomedullin: An effective prognostic biomarker in septic patients

Background: Measurement of biomarkers is a potential approach to early prediction of mortality in septic patients. The purpose of this study was to asses the prognostic value of proadrenomedullin (pADM) in adult patients with sepsis with a single measurement in the first 24 hours after the onset of severe sepsis or septic shock. Conclusions: The protein pADM is an important prognostic biomarker of survival when measured on admission of septic patients to the ICU.

C-reactive protein, procalcitonin, lactate and score apache II in septic patients' prognosis.

Background: APACHE-II IS a score, based on several clinical and analytical measurements within 24 hours of admission in Intensive Care Unit (ICU). C-Reactive Protein (CRP), Lactate and recently Procalcitonin (PCT), also are biomarkers for the assessment of septic patients. The aim of this study was to find out if CRP, lactate and PCT during the first 24 hours from severe sepsis or septic shock onset, improved prediction of the APACHE II in terms of prognosis. Conclusions: CRP improves the prediction of patients with sepsis used in conjunction with the APACHE II score in severe sepsis and, lactate along with the CRP are the best precictors of survival in the cases of septic shock. The PCT did not show any predictive value.

Evaluation of the speed-oligo direct Mycobacterium tuberculosis assay for molecular detection of mycobacteria in clinical respiratory specimens.

We present the first evaluation of a novel molecular assay, the Speed-oligo Direct Mycobacterium tuberculosis (SO-DMT) assay, which is based on PCR combined with a dipstick for the detection of mycobacteria and the specific identification of M. tuberculosis complex (MTC) in respiratory specimens. A blind evaluation was carried out in two stages: first, under experimental conditions on convenience samples comprising 20 negative specimens, 44 smear- and culture-positive respiratory specimens, and 11 sputa inoculated with various mycobacterium-related organisms; and second, in the routine workflow of 566 fresh respiratory specimens (4.9% acid-fast bacillus [AFB] smear positives, 7.6% MTC positives, and 1.8% nontuberculous mycobacteria [NTM] culture positives) from two Mycobacterium laboratories. SO-DMT assay showed no reactivity in any of the mycobacterium-free specimens or in those with mycobacterium-related organisms. Compared to culture, the sensitivity in the selected smear-positive specimens was 0.91 (0.92 for MTC and 0.90 for NTM), and there was no molecular detection of NTM in a tuberculosis case or vice versa. With respect to culture and clinical data, the sensitivity, specificity, and positive and negative predictive values for the SO-DMT system in routine specimens were 0.76 (0.93 in smear positives [1.0 for MTC and 0.5 for NTM] and 0.56 in smear negatives [0.68 for MTC and 0.16 for NTM]), 0.99, 0.85 (1.00 in smear positives and 0.68 in smear negatives), and 0.97, respectively. Molecular misidentification of NTM cases occurred when testing 2 gastric aspirates from two children with clinically but not microbiologically confirmed lung tuberculosis. The SO-DMT assay appears to be a fast and easy alternative for detecting mycobacteria and differentiating MTC from NTM in smear-positive respiratory specimens.

Analysis of genes encoding penicillin-binding proteins in clinical isolates of Acinetobacter baumannii.

There is limited information on the role of penicillin-binding proteins (PBPs) in the resistance of Acinetobacter baumannii to β-lactams. This study presents an analysis of the allelic variations of PBP genes in A. baumannii isolates. Twenty-six A. baumannii clinical isolates (susceptible or resistant to carbapenems) from three teaching hospitals in Spain were included. The antimicrobial susceptibility profile, clonal pattern, and genomic species identification were also evaluated. Based on the six complete genomes of A. baumannii, the PBP genes were identified, and primers were designed for each gene. The nucleotide sequences of the genes identified that encode PBPs and the corresponding amino acid sequences were compared with those of ATCC 17978. Seven PBP genes and one monofunctional transglycosylase (MGT) gene were identified in the six genomes, encoding (i) four high-molecular-mass proteins (two of class A, PBP1a [ponA] and PBP1b [mrcB], and two of class B, PBP2 [pbpA or mrdA] and PBP3 [ftsI]), (ii) three low-molecular-mass proteins (two of type 5, PBP5/6 [dacC] and PBP6b [dacD], and one of type 7 (PBP7/8 [pbpG]), and (iii) a monofunctional enzyme (MtgA [mtgA]). Hot spot mutation regions were observed, although most of the allelic changes found translated into silent mutations. The amino acid consensus sequences corresponding to the PBP genes in the genomes and the clinical isolates were highly conserved. The changes found in amino acid sequences were associated with concrete clonal patterns but were not directly related to susceptibility or resistance to β-lactams. An insertion sequence disrupting the gene encoding PBP6b was identified in an endemic carbapenem-resistant clone in one of the participant hospitals.

Klebsiella pneumoniae strains producing extended-spectrum beta-lactamases in Spain: microbiological and clinical features.

Extended-spectrum β-lactamases (ESBL) of the CTX-M, SHV, and TEM families were recognized in 76 (67%), 31 (27%), and 6 (5%) isolates, respectively, among 162 ESBL-producing Klebsiella pneumoniae (ESBL-Kp) strains obtained in a multicenter study in Spain. Predisposing factors for ESBL-Kp acquisition included invasive procedures, mechanical ventilation, and previous antimicrobial use.

Riesgo de infección en pacientes de diálisis peritoneal: factores potencialmente relacionados

Comunicaciones Posters

Effect of statin therapy in the outcome of bloodstream infections due to Staphylococcus aureus: a prospective cohort study.

INTRODUCTION Statins have pleiotropic effects that could influence the prevention and outcome of some infectious diseases. There is no information about their specific effect on Staphylococcus aureus bacteremia (SAB). METHODS A prospective cohort study including all SAB diagnosed in patients aged ≥18 years admitted to a 950-bed tertiary hospital from March 2008 to January 2011 was performed. The main outcome variable was 14-day mortality, and the secondary outcome variables were 30-day mortality, persistent bacteremia (PB) and presence of severe sepsis or septic shock at diagnosis of SAB. The effect of statin therapy at the onset of SAB was studied by multivariate logistic regression and Cox regression analysis, including a propensity score for statin therapy. RESULTS We included 160 episodes. Thirty-three patients (21.3%) were receiving statins at the onset of SAB. 14-day mortality was 21.3%. After adjustment for age, Charlson index, Pitt score, adequate management, and high risk source, statin therapy had a protective effect on 14-day mortality (adjusted OR = 0.08; 95% CI: 0.01-0.66; p = 0.02), and PB (OR = 0.89; 95% CI: 0.27-1.00; p = 0.05) although the effect was not significant on 30-day mortality (OR = 0.35; 95% CI: 0.10-1.23; p = 0.10) or presentation with severe sepsis or septic shock (adjusted OR = 0.89; CI 95%: 0.27-2.94; p = 0.8). An effect on 30-day mortality could neither be demonstrated on Cox analysis (adjusted HR = 0.5; 95% CI: 0.19-1.29; p = 0.15). CONCLUSIONS Statin treatment in patients with SAB was associated with lower early mortality and PB. Randomized studies are necessary to identify the role of statins in the treatment of patients with SAB.

Impact of the MIC of piperacillin-tazobactam on the outcome of patients with bacteremia due to extended-spectrum-β-lactamase-producing Escherichia coli.

We investigated the impact of the piperacillin-tazobactam MIC in the outcome of 39 bloodstream infections due to extended-spectrum-β-lactamase-producing Escherichia coli. All 11 patients with urinary tract infections survived, irrespective of the MIC. For other sources, 30-day mortality was lower for isolates with a MIC of ≤ 2 mg/liter than for isolates with a higher MIC (0% versus 41.1%; P = 0.02).

Pigment production by Streptococcus agalactiae in quasi-defined media.

A quasi-defined medium that supports the growth of Streptococcus agalactiae as pigmented colonies has been developed. The medium contains starch, a peptic digest of albumin, amino acids, nucleosides, vitamins, and salts. The presence of free cysteine, which could be replaced with other sulphur-containing compounds and to a lesser degree by reducing agents, was required for pigment formation.