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.

Impact of prompt catheter withdrawal and adequate antimicrobial therapy on the prognosis of hospital-acquired parenteral nutrition catheter-related bacteraemia.

Catheter-related bacteraemia (CRB) is a cause of death in hospitalized patients, and parenteral nutrition (PN) is a risk factor. We aim to describe the prognosis of PN-CRB and the impact of catheter extraction within 48 h from bacteraemia. All consecutive hospitalized adult patients with CRB (2007-2012) were prospectively enrolled. Factors associated with 30-day mortality were determined by logistic regression analysis. Among 847 episodes of CRB identified, 291 (34%) episodes were associated with short-term catheter use for PN. Cure was achieved in 236 (81%) episodes, 42 (14.5%) patients died within the first 30 days, 7 (2.5%) relapsed, and 6 (2%) had re-infection. On multivariate analysis, previous immunosuppressive therapy (OR 5.62; 95% CI 1.69-18.68; p 0.0048) and patient age (OR 1.05; 95% CI 1.02-1.07; p 0.0009) were predictors of 30-day mortality, whereas catheter removal within 48 h of bacteraemia onset (OR 0.26; 95% CI 0.12-0.58; p 0.0010) and adequate empirical antibiotic treatment (OR 0.36; 95% CI 0.17-0.77; p 0.0081) were protective factors. Incidence of PN-CRB decreased from 5.36 episodes/1000 days of PN in 2007 to 2.9 in 2012, yielding a 46.1% rate reduction (95% CI 15.7-65.5%), which may be attributable to implementation of a multifaceted prevention strategy. In conclusion, short-term PN-CRB accounted for one-third of all episodes of CRB in our setting, and 14.5% of patients died within 30 days following bacteraemia. Our findings suggest that prompt catheter removal and adequate empirical antibiotic treatment could be protective factors for 30-day mortality. Concomitantly with implementation of a multifaceted prevention strategy, PN-CRB incidence was reduced by half.

Gram-negative prosthetic joint infection: outcome of a debridement, antibiotics and implant retention approach. A large multicentre study.

We aim to evaluate the epidemiology and outcome of gram-negative prosthetic joint infection (GN-PJI) treated with debridement, antibiotics and implant retention (DAIR), identify factors predictive of failure, and determine the impact of ciprofloxacin use on prognosis. We performed a retrospective, multicentre, observational study of GN-PJI diagnosed from 2003 through to 2010 in 16 Spanish hospitals. We define failure as persistence or reappearance of the inflammatory joint signs during follow-up, leading to unplanned surgery or repeat debridement>30 days from the index surgery related death, or suppressive antimicrobial therapy. Parameters predicting failure were analysed with a Cox regression model. A total of 242 patients (33% men; median age 76 years, interquartile range (IQR) 68-81) with 242 episodes of GN-PJI were studied. The implants included 150 (62%) hip, 85 (35%) knee, five (2%) shoulder and two (1%) elbow prostheses. There were 189 (78%) acute infections. Causative microorganisms were Enterobacteriaceae in 78%, Pseudomonas spp. in 20%, and other gram-negative bacilli in 2%. Overall, 19% of isolates were ciprofloxacin resistant. DAIR was used in 174 (72%) cases, with an overall success rate of 68%, which increased to 79% after a median of 25 months' follow-up in ciprofloxacin-susceptible GN-PJIs treated with ciprofloxacin. Ciprofloxacin treatment exhibited an independent protective effect (adjusted hazard ratio (aHR) 0.23; 95% CI, 0.13-0.40; p<0.001), whereas chronic renal impairment predicted failure (aHR, 2.56; 95% CI, 1.14-5.77; p 0.0232). Our results confirm a 79% success rate in ciprofloxacin-susceptible GN-PJI treated with debridement, ciprofloxacin and implant retention. New therapeutic strategies are needed for ciprofloxacin-resistant PJI.

Efficacy of teicoplanin-gentamicin given once a day on the basis of pharmacokinetics in humans for treatment of enterococcal experimental endocarditis.

With the aim of investigating home therapy for enterococcal endocarditis, we compared the efficacy of teicoplanin combined with gentamicin given once a day or in three daily doses (t.i.d.) with the standard treatment, ampicillin plus gentamicin administered t.i.d., for treating experimental enterococcal endocarditis. The antibiotics were administered by using "human-like pharmacokinetics" (H-L), i.e, pharmacokinetics like those in humans, that simulated the profiles of these drugs in human serum. Animals with catheter-induced endocarditis were infected intravenously with 10(8) CFU of Enterococcus faecalis EF91 (MICs and MBCs of ampicillin, gentamicin, and teicoplanin, 0.5 and 32, 16 and 32, and 0.5 and 1 microg/ml, respectively) and were treated for 3 days with ampicillin H-L at 2 g every 4 h plus gentamicin H-L at 1 mg/kg every 8 h, or teicoplanin H-L at 10 mg/kg every 24 h, alone or combined with gentamicin, administered at dose of H-L at 1 mg/kg every 8 h or H-L at 4.5 mg/kg every 24 h. The results of therapy for experimental endocarditis due to EF91 showed that teicoplanin alone was as effective as ampicillin alone in reducing the bacterial load (P > 0.05). The combination of ampicillin or teicoplanin with gentamicin was more effective than the administration of both drugs alone in reducing the log(10)CFU/gram of aortic vegetation (P < 0.01 and P < 0.05, respectively). Teicoplanin plus gentamicin H-L at 4.5 mg/kg, both administered every 24 h, showed an efficacy equal to the "gold standard," ampicillin plus gentamicin H-L at 1 mg/kg t.i.d. (P > 0.05). Increasing the interval of administration of gentamicin to a single daily dose combined with teicoplanin resulted in a reduction of bacteria in the vegetations equivalent to that achieved with the recommended regimen of ampicillin plus thrice-daily gentamicin in the treatment of experimental endocarditis due to E. faecalis. Teicoplanin plus gentamicin, both administered once a day, may be useful home therapy for selected cases of enterococcal endocarditis.

Treatment of experimental pneumonia due to penicillin-resistant Streptococcus pneumoniae in immunocompetent rats.

A model of pneumonia due to Streptococcus pneumoniae resistant to penicillin was developed in immunocompetent Wistar rats and was used to evaluate the efficacies of different doses of penicillin, cefotaxime, cefpirome, and vancomycin. Adult Wistar rats were challenged by intratracheal inoculation with 3 x 10(9) CFU of one strain of S. pneumoniae resistant to penicillin (MICs of penicillin, cefotaxime, cefpirome, and vancomycin, 2, 1, 0.5, and 0.5 microg/ml, respectively) suspended in brain heart broth supplemented with 0.7% agar. The rats experienced a fatal pneumonia, dying within 5 days and with peak mortality (70 to 80%) occurring 48 to 72 h after infection, and the bacterial counts in the lungs persisted from 8.87 +/- 0.3 log10 CFU/g of lung at 24 h of the infection to 9.1 +/- 0.3 log10 CFU/g at 72 h. Four hours after infection the animals were randomized into the following treatment groups: (i) control without treatment, (ii) penicillin G at 100,000 IU/kg of body weight every 2 h, (iii) penicillin G at 250,000 IU/kg every 2 h, (iv) cefotaxime at 100 mg/kg every 2 h, (v) cefpirome at 200 mg/kg every 2 h, and (vi) vancomycin at 50 mg/kg every 8 h. Two different protocols were used for the therapeutic efficacy studies: four doses of beta-lactams and one dose of vancomycin or eight doses of beta-lactams and two doses of vancomycin. Results of the therapy for experimental pneumonia caused by penicillin-resistant S. pneumoniae showed that initially, all the antimicrobial agents tested had similar efficacies, but when we prolonged the treatment, higher doses of penicillin, cefotaxime, and cefpirome were more effective than penicillin at lower doses in decreasing the residual bacterial titers in the lungs. Also, when we extended the treatment, vancomycin was more efficacious than penicillin at lower doses but was less efficacious than higher doses of penicillin or cefpirome. The model that we have developed is simple and amenable for inducing pneumonia in immunocompetent rats and could be used to explore the pathophysiology and to evaluate optimal therapy of this infection in the immunocompetent host.

[Treatment and outcome of pneumococcal meningitis in adults. Study of a recent series of 70 episodes]. / Terapéutica y evolución de la meningitis neumocócica en el adulto. Estudio de una serie reciente de 70 episodios.

BACKGROUND: Pneumococcal meningitis (PM) is an infection with high morbidity and mortality. The aim of this study was to evaluate the most relevant clinical, epidemiologic and evolutive characteristics of a recent series of adult patients with this disease. METHODS: Over a period of 10 years all the patients with PM diagnosed by isolation of this microorganism in the cerebrospinal fluid (CSF) were evaluated from a clinical, therapeutic and evolutive points of view. The impact of the new therapies in the disease and the variables associated with mortality were analyzed. RESULTS: Seventy episodes of PM were diagnosed, 60% being found in patients over the age of 50 years. The male/female relationship was 2/1. Fifty-three percent of the patients had other underlying diseases. Acute otitis media (AOM) was the source in 34% of the cases, in 11% the patients had a fistula of CSF and in 9% a pneumonia. At the time of diagnosis 74% of the patients had some degree of reduction in the level of consciousness and in 40% of the episodes the presence of neurologic local manifestations were observed. A decrease in sensitivity to penicillin was observed in 33% of the microorganisms isolated. Third generation cephalosporins were used as initial treatment in 57 episodes and penicillin in other 11 episodes. Adjuvant treatment with dexamethasone, mannitol and/or diphenylhydantoin was administered in 54% of the patients. Overall mortality was 23%: the factors associated with an unfavourable evolution were the existence of underlying disease, deep alteration in the level of consciousness at the time of diagnosis, the coexistence of pneumonia and the absence of adjuvant therapy. CONCLUSIONS: Mortality in pneumococcal meningitis is high. The most relevant risk factor is the initial degree of consciousness. Adjuvant therapies probably determine a reduction in the rate of mortality.