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.

Predictive factors for mortality in patients with methicillin-resistant Staphylococcus aureus bloodstream infection: impact on outcome of host, microorganism and therapy.

Mortality related to methicillin-resistant Staphylococcus aureus (MRSA) bloodstream infection (BSI) remains high, despite changes in the epidemiology. To analyze the current predictive factors for mortality we conducted a prospective study in a large cohort of patients with MRSA-BSI from 21 Spanish hospitals. Epidemiology, clinical data, therapy and outcome were recorded. All MRSA strains were analysed, including susceptibility to antibiotics and molecular characterization. Vancomycin MICs (V-MIC) were tested by the E-test and microdilution methods. Time until death was the dependent variable in a Cox regression analysis. Overall, 579 episodes were included. Acquisition was nosocomial in 59% and vascular catheter was the most frequent source (38%). A dominant PFGE genotype was found in 368 (67%) isolates, which belonged to Clonal Complex (CC)5 and carried SCCmecIV and agr2. Microdilution V-MIC50 and V-MIC90 were 0.7 and 1.0 mg/L, respectively. Initial therapy was appropriate in 66% of episodes. Overall mortality was observed in 179 (32%) episodes. The Cox-regression analysis identified age >70 years (HR 1.88), previous fatal disease (HR 2.16), Pitt score >1 (HR 3.45), high-risk source (HR 1.85) and inappropriate initial treatment (HR 1.39) as independent predictive factors for mortality. CC5 and CC22 (HR 0.52 and 0.45) were associated with significantly lower mortality rates than CC8. V-MIC ≥1.5 did not have a significant impact on mortality, regardless of the method used to assess it.

Single restraint stress sensitizes acute chewing movements induced by haloperidol, but not if the 5-HT1A agonist 8-OH-DPAT is given prior to stress.

The objective of this study was two-fold: (i) to analyze behavioral sensitization to haloperidol 2 weeks after single restraint stress, and (ii) to establish the effects of 8-OH-DPAT treatment prior to stress on sensitized behavioral responses. Overall behavior was analyzed and not only catalepsy, but also sedation (immobility), grooming, exploration and vacuous chewing movements were evaluated. Results indicated that single restraint stress induced a long-lasting sensitization of acute vacuous chewing movements induced by haloperidol (0.25, 0.5 mg/kg i.p.). Interestingly, this behavioral sensitization was prevented by 8-OH-DPAT (0.35 mg/kg s.c.) prior to stress. Finally, haloperidol-induced sedation was not disrupted by either restraint stress or 8-OH-DPAT treatment.

Ciprofloxacin and trimethoprim-sulfamethoxazole versus placebo in acute uncomplicated Salmonella enteritis: a double-blind trial.

The role of ciprofloxacin and trimethoprim-sulfamethoxazole (TMP-SMZ) was evaluated in empiric treatment of uncomplicated Salmonella enteritis in a comparative, double-blind trial. Patients were randomized to receive ciprofloxacin (500 mg), TMP-SMZ (160/800 mg), or placebo orally twice daily for 5 days. There were 65 evaluatable patients with acute, uncomplicated, culture-confirmed Salmonella enteritis. Duration of diarrhea, abdominal pain, or vomiting and time to defervescence were not significantly different for patients treated with ciprofloxacin, TMP-SMZ, or placebo; there also were no significant differences with respect to full resolution of symptoms for ciprofloxacin versus placebo (point estimate, 0.2 days; 95% confidence interval [CI], -0.5 to 0.9 days) or for TMP-SMZ versus placebo (point estimate, 0.2 days; 95% CI, -1.0 to 0.6 days). The rate of clearance of salmonellae from stools was not significantly different among the groups.