Effect of Vancomycin or Daptomycin With vs Without an Antistaphylococcal ß-Lactam on Mortality, Bacteremia, Relapse, or Treatment Failure in Patients With MRSA Bacteremia: A Randomized Clinical Trial.

Importance: Methicillin-resistant Staphylococcus aureus (MRSA) bacteremia is associated with mortality of more than 20%. Combining standard therapy with a ß-lactam antibiotic has been associated with reduced mortality, although adequately powered randomized clinical trials of this intervention have not been conducted. Objective: To determine whether combining an antistaphylococcal ß-lactam with standard therapy is more effective than standard therapy alone in patients with MRSA bacteremia. Design, Setting, and Participants: Open-label, randomized clinical trial conducted at 27 hospital sites in 4 countries from August 2015 to July 2018 among 352 hospitalized adults with MRSA bacteremia. Follow-up was complete on October 23, 2018. Interventions: Participants were randomized to standard therapy (intravenous vancomycin or daptomycin) plus an antistaphylococcal ß-lactam (intravenous flucloxacillin, cloxacillin, or cefazolin) (n = 174) or standard therapy alone (n = 178). Total duration of therapy was determined by treating clinicians and the ß-lactam was administered for 7 days. Main Outcomes and Measures: The primary end point was a 90-day composite of mortality, persistent bacteremia at day 5, microbiological relapse, and microbiological treatment failure. Secondary outcomes included mortality at days 14, 42, and 90; persistent bacteremia at days 2 and 5; acute kidney injury (AKI); microbiological relapse; microbiological treatment failure; and duration of intravenous antibiotics. Results: The data and safety monitoring board recommended early termination of the study prior to enrollment of 440 patients because of safety. Among 352 patients randomized (mean age, 62.2 [SD, 17.7] years; 121 women [34.4%]), 345 (98%) completed the trial. The primary end point was met by 59 (35%) with combination therapy and 68 (39%) with standard therapy (absolute difference, -4.2%; 95% CI, -14.3% to 6.0%). Seven of 9 prespecified secondary end points showed no significant difference. For the combination therapy vs standard therapy groups, all-cause 90-day mortality occurred in 35 (21%) vs 28 (16%) (difference, 4.5%; 95% CI, -3.7% to 12.7%); persistent bacteremia at day 5 was observed in 19 of 166 (11%) vs 35 of 172 (20%) (difference, -8.9%; 95% CI, -16.6% to -1.2%); and, excluding patients receiving dialysis at baseline, AKI occurred in 34 of 145 (23%) vs 9 of 145 (6%) (difference, 17.2%; 95% CI, 9.3%-25.2%). Conclusions and Relevance: Among patients with MRSA bacteremia, addition of an antistaphylococcal ß-lactam to standard antibiotic therapy with vancomycin or daptomycin did not result in significant improvement in the primary composite end point of mortality, persistent bacteremia, relapse, or treatment failure. Early trial termination for safety concerns and the possibility that the study was underpowered to detect clinically important differences in favor of the intervention should be considered when interpreting the findings. Trial Registration: ClinicalTrials.gov Identifier: NCT02365493.

Paediatric community-associated Staphylococcus aureus: a retrospective cohort study.

AIM: We aimed to characterise the demographic and clinical features of paediatric community-associated Staphylococcus aureus (CA-SA) infection. We aimed to identify factors associated with methicillin-resistant S.aureus (MRSA) infection evident at the point of care with the potential to guide antibiotic choice. METHODS: A retrospective chart review in 2008 of CA-SA infections at the Children's Hospital at Westmead (CHW), a 300-bed tertiary paediatric hospital in western Sydney, Australia. We calculate rates of MRSA and perform univariate and multivariate analysis for predictors of MRSA. RESULTS: Of 431 patients with CA-SA infections, 19.3% were MRSA. In univariate analysis, MRSA was predicted by age greater than 1 year, Aboriginal race, rural/regional residence, previous history of skin and soft tissue infection (SSTI) or a family history of SSTI, at least 48 h of antibiotics active against methicillin-sensitive S.aureus (MSSA), invasive infection and abscess formation. In a multivariate analysis factors that independently predicted MRSA in the entire cohort, and in the non-invasive subgroup included abscess formation, a family history of staphylococcal infection or SSTI, Aboriginal ethnicity, at least 48 h of anti-MSSA antibiotics at presentation, presentation during spring and age greater than 1 year. CONCLUSIONS: One fifth of CA-SA infections at our tertiary paediatric hospital in 2008 were MRSA. Several clinical and demographic factors evident at the point of care were highly significant predictors of CA-MRSA infection.

Comparison of human metapneumovirus and respiratory syncytial virus in children admitted to a paediatric intensive care unit.

AIM: To describe the clinical presentation and course of children admitted to the paediatric intensive care unit (PICU) with human metapneumovirus (hMPV) infection, and compare them with children admitted to the PICU with respiratory syncytial virus (RSV) infection. METHODS: hMPV was identified by immunofluorescence in 22 children admitted to the PICU over a 16-month period. The medical records of these children were reviewed retrospectively, and their clinical and laboratory data were compared with 66 children admitted to the PICU with positive tests for RSV over the same period. RESULTS: Children admitted to the PICU with hMPV were significantly older than children with RSV (P= 0.003). Children with hMPV presented more commonly with pneumonia or pneumonitis (29% vs. 16%), and less commonly with bronchiolitis (43% vs. 68%) than RSV (P= 0.13). Invasive ventilation was required in 10 patients (48%) with hMPV, and non-invasive ventilation was required in a further 5 (28%), similar to patients with RSV. Children with hMPV were more likely to have an underlying co-morbidity (P= 0.11). CONCLUSIONS: Children admitted to the PICU with hMPV have a similar disease presentation and severity as children admitted with RSV, including some with extremely severe disease who require additional ventilatory or cardiovascular support. Children with hMPV are likely to be older than those with RSV, and more likely to present with pneumonia and less likely to present with bronchiolitis.

Ventilator-associated pneumonia in a tertiary paediatric intensive care unit: a 1-year prospective observational study.

OBJECTIVES: To determine the incidence, risk factors and impact of ventilator-associated pneumonia (VAP) in a mixed tertiary paediatric intensive care unit. DESIGN: Prospective observational study. METHODS: Patients in the intensive care unit who were mechanically ventilated for more than 48 hours were assessed daily, according to criteria for a diagnosis of VAP. Potential risk factors for VAP, if present, were documented. RESULTS: Of 692 invasively ventilated patients, 269 (38.9%) were ventilated for > 48 hours and met no exclusion criteria. Eighteen (6.7%) patients had episodes of VAP, and the VAP incidence density was 7.02 per 1000 intubation days. The mean admission Paediatric Index of Mortality 2 risk of death was similar in patients with and without VAP (0.084 v 0.056; P =0.8). Patients with VAP (compared with patients without VAP) had a longer median duration of ICU stay, (19.35 v 7.35 days; P < 0.001), duration of ventilation (11.99 v 4.92 days; P=0.024) and duration of hospital stay (35.5 v 20 days; P < 0.001). Univariate analysis showed that reintubation, absence of tube feeding and absence of stress ulcer prophylaxis were risk factors for VAP. While backward selection removed reintubation as a positive predictor during multivariate analysis, tube feeds (hazard ratio (HR), 0.27; 95% CI, 0.09-0.85; P = 0.02) and stress ulcer prophylaxis (HR, 0.29; 95% CI, 0.11-0.76; P = 0.01) were independently associated with reduced VAP incidence. CONCLUSIONS: VAP in children is associated with significant morbidity and increased length of hospital stay. Enteral feeding and stress ulcer prophylaxis while intubated are associated with lower VAP hazards.

The safety of candidate vaginal microbicides since nonoxynol-9: a systematic review of published studies.

OBJECTIVE: To gain a greater understanding of published safety data for candidate vaginal microbicides. DESIGN: A systematic review of human safety trials of candidate vaginal microbicides - agents designed to protect women against HIV and other sexually transmitted infections. METHODS: Trials were published in peer-reviewed journals, and publication cut-off was August week 4, 2008. Trials of nonoxynol-9 were excluded, as were trials without a control group, trials that enrolled only male participants or reported on the investigation of a product for the treatment of a genital infection. RESULTS: Twenty-one trials of 11 products, involving 1465 women, satisfied review criteria. Most trials reported on genital epithelial findings and urogenital symptoms and a number reported a range of other local and systemic toxicity endpoints. Trials were generally of short duration (2 weeks or less) with small sample sizes. There were few findings of significant difference between women in active and control arms. Among the products assessed in more than one study, there were significantly more genital findings with intact epithelium in recipients of PRO2000 [relative risk (RR) 1.68, 95% confidence interval (CI) 1.08-2.60] and a lower incidence of bacterial vaginosis in dextrin sulphate recipients (RR 0.61, 95% CI 0.42-0.88). CIs were generally very wide, and most studies were unable to exclude differences of a substantial magnitude between treated and control women. CONCLUSION: Larger and longer safety studies are necessary to detect clinically important toxicities, including those that indicate a potential increase in HIV risk, and provide assurance that agents are ready for large-scale effectiveness trials.