Clindamycin adjunctive therapy for severe Staphylococcus aureus treatment evaluation (CASSETTE)-an open-labelled pilot randomized controlled trial.

BACKGROUND: Combination antibiotic therapy with an antitoxin agent, such as clindamycin, is included in some guidelines for severe, toxin-mediated Staphylococcus aureus infections. The evidence to support this practice is currently limited to in vitro, animal and observational human case-series data, with no previous randomized controlled trials (RCTs). OBJECTIVES: This pilot RCT aimed to determine the feasibility of conducting a clinical trial to examine if adjunctive clindamycin with standard therapy has greater efficacy than standard therapy alone for S. aureus infections. METHODS: We performed an investigator-initiated, open-label, multicentre, pilot RCT (ACTRN12617001416381p) in adults and children with severe S. aureus infections, randomized to standard antibiotic therapy with or without clindamycin for 7 days. RESULTS: Over 28 months, across nine sites, 127 individuals were screened and 34 randomized, including 11 children (32%). The primary outcome-number of days alive and free of systemic inflammatory response syndrome ≤14 days-was similar between groups: clindamycin (3 days [IQR 1-6]) versus standard therapy (4 days [IQR 0-8]). The 90 day mortality was 0% (0/17) in the clindamycin group versus 24% (4/17) in the standard therapy group. Secondary outcomes-microbiological relapse, treatment failure or diarrhoea-were similar between groups. CONCLUSIONS: As the first clinical trial assessing adjunctive clindamycin for S. aureus infections, this study indicates feasibility and that adults and children can be incorporated into one trial using harmonized endpoints, and there were no safety concerns. The CASSETTE trial will inform the definitive S. aureus Network Adaptive Platform (SNAP) trial, which includes an adjunctive clindamycin domain and participants with non-severe disease.

Mucormycosis in Australia: contemporary epidemiology and outcomes.

Mucormycosis is the second most common cause of invasive mould infection and causes disease in diverse hosts, including those who are immuno-competent. We conducted a multicentre retrospective study of proven and probable cases of mucormycosis diagnosed between 2004-2012 to determine the epidemiology and outcome determinants in Australia. Seventy-four cases were identified (63 proven, 11 probable). The majority (54.1%) were caused by Rhizopus spp. Patients who sustained trauma were more likely to have non-Rhizopus infections relative to patients without trauma (OR 9.0, p 0.001, 95% CI 2.1-42.8). Haematological malignancy (48.6%), chemotherapy (42.9%), corticosteroids (52.7%), diabetes mellitus (27%) and trauma (22.9%) were the most common co-morbidities or risk factors. Rheumatological/autoimmune disorders occurred in nine (12.1%) instances. Eight (10.8%) cases had no underlying co-morbidity and were more likely to have associated trauma (7/8; 87.5% versus 10/66; 15.2%; p <0.001). Disseminated infection was common (39.2%). Apophysomyces spp. and Saksenaea spp. caused infection in immuno-competent hosts, most frequently associated with trauma and affected sites other than lung and sinuses. The 180-day mortality was 56.7%. The strongest predictors of mortality were rheumatological/autoimmune disorder (OR = 24.0, p 0.038 95% CI 1.2-481.4), haematological malignancy (OR = 7.7, p 0.001, 95% CI 2.3-25.2) and admission to intensive care unit (OR = 4.2, p 0.02, 95% CI 1.3-13.8). Most deaths occurred within one month. Thereafter we observed divergence in survival between the haematological and non-haematological populations (p 0.006). The mortality of mucormycosis remains particularly high in the immuno-compromised host. Underlying rheumatological/autoimmune disorders are a previously under-appreciated risk for infection and poor outcome.

Are physicians prepared for whole genome sequencing? a qualitative analysis.

Although the integration of whole genome sequencing (WGS) into standard medical practice is rapidly becoming feasible, physicians may be unprepared to use it. Primary care physicians (PCPs) and cardiologists enrolled in a randomized clinical trial of WGS received genomics education before completing semi-structured interviews. Themes about preparedness were identified in transcripts through team-based consensus-coding. Data from 11 PCPs and 9 cardiologists suggested that physicians enrolled in the trial primarily to prepare themselves for widespread use of WGS in the future. PCPs were concerned about their general genomic knowledge, while cardiologists were concerned about how to interpret specific types of results and secondary findings. Both cohorts anticipated preparing extensively before disclosing results to patients by using educational resources with which they were already familiar, and both cohorts anticipated making referrals to genetics specialists as needed. A lack of laboratory guidance, time pressures, and a lack of standards contributed to feeling unprepared. Physicians had specialty-specific concerns about their preparedness to use WGS. Findings identify specific policy changes that could help physicians feel more prepared, and highlight how providers of all types will need to become familiar with interpreting WGS results.

Knowing prior methicillin-resistant Staphylococcus aureus (MRSA) infection or colonization status increases the empirical use of glycopeptides in MRSA bacteraemia and may decrease mortality.

To compare the management and outcome of methicillin-resistant Staphylococcus aureus (MRSA) bacteraemia in patients known to be MRSA-colonized/infected (C-patients) with the management and outcome in those not known to be colonized/infected (NC-patients), we conducted a 10-year retrospective review of MRSA bacteraemia in an adult tertiary hospital. Clinical data were obtained by chart review, and mortality data from linked databases. Prior MRSA colonization/infection status was available to treating clinicians at the time of the bacteraemia as a 'Micro-Alert' tag on the patient's labels, in medical charts, and in electronic information systems. C-patients accounted for 35.4% of all MRSA bacteraemia episodes. C-patients were more likely to be indigenous, to be diabetic, or to have a history of previous S. aureus infection. Markers of illness severity (Simplified Acute Physiology Score (SAPS)-II, need for admission to the intensive-care unit, length of stay, and metastatic seeding) were similar in both groups. Empirical therapy included a glycopeptide in 49.3% of C-patients vs. 18.9% of NC-patients (p <0.01), and contained an antibiotic to which the MRSA isolate tested susceptible in vitro in 56.7% of C-patients vs. 45.1% of NC-patients (p 0.13). All-cause 7-day and 30-day mortality were 7.5% vs. 18.9% (p 0.04), and 22.4% vs. 31.1% (p 0.20), in the C-patient and NC-patient groups, respectively. Knowing MRSA colonization status was significantly associated with lower 30-day mortality in Cox regression analysis (p <0.01). These data suggest that mortality from MRSA bacteraemia is lower in C-patients, which may reflect the earlier use of glycopeptides. The low use of empirical glycopeptides in septic patients known to be previously MRSA-colonized/infected may represent a missed opportunity for infection control to positively impact on clinical management.

Vancomycin minimum inhibitory concentration, host comorbidities and mortality in Staphylococcus aureus bacteraemia.

We reported an association between elevated vancomycin MIC and 30-day mortality in patients with Staphylococcus aureus bacteraemia (SAB), including patients with methicillin-susceptible S. aureus (MSSA) treated with flucloxacillin. A detailed analysis of comorbidities and disease severity scores in the same cohort of patients was performed to ascertain if unknown clinical parameters may have influenced these results. The association between elevated vancomycin MIC and 30-day mortality in SAB remained significant (p 0.001) on multivariable logistic regression analysis even when accounting for clinical factors. In addition, the association persisted when restricting analysis to patients with MSSA bacteraemia treated with flucloxacillin. This suggests that elevated vancomycin MIC is associated with but not causally linked to an organism factor that is responsible for increased mortality.

Formal infectious diseases consultation is associated with decreased mortality in Staphylococcus aureus bacteraemia.

To determine the impact of infectious diseases consultation (IDC) in Staphylococcus aureus bacteraemia. All MRSA bacteraemia and a random subset of MSSA bacteraemia were retrospectively analysed. Out of 599 SAB episodes, 162 (27%) were followed by an IDC. Patients with IDC were younger and more frequently intravenous drug users, but fewer resided in a long-term care facility or were indigenous. Hospital length of stay was longer (29.5 vs 17 days, p < 0.001), and endocarditis (19.1% vs 7.3%, p < 0.001) and metastatic seeding (22.2% vs 10.1%, p < 0.001) were more frequent in the IDC group; however, SAPS II scores were lower in the IDC group (27 vs 37, p < 0.001). ICU admission rates in the two groups were similar. The isolate tested susceptible to empirical therapy more frequently in the IDC group (88.9% vs 78.0%, p = 0.003). Seven-day (3.1 vs 16.5%), 30-day (8.0% vs 27.0%) and 1-year mortality (22.2% vs 44.9%) were all lower in the IDC group (all p < 0.001). Multivariate analysis showed that effective initial therapy was the only variable associated with the protective effect of IDC. In patients with SAB, all-cause mortality was significantly lower in patients who had an IDC, because of the higher proportion of patients receiving effective initial antibiotics.

Prevalence of nasal methicillin-resistant Staphylococcus aureus colonization in healthcare workers in a Western Australian acute care hospital.

Due to a longstanding comprehensive "search and destroy policy", methicillin-resistant Staphylococcus aureus (MRSA) is not endemic in Western Australian (WA) acute care hospitals. As the prevalence of MRSA in the community has increased, healthcare workers (HCW) are at risk of importing MRSA into hospitals. We aimed to determine the prevalence of and risk factors for nasal MRSA colonization in our HCW population. A period prevalence study was conducted at an 850-bed tertiary hospital. Basic demographics and a nasal swab were obtained. A total of 1,542 HCWs employed in our centre were screened for MRSA, of whom 3.4% (n = 52) were colonized. MRSA colonization was more common in patient care assistants (6.8%) and nurses (5.2%) than in allied health professionals (1.7%) and doctors (0.7%) (p < 0.01). Working in "high-risk" wards that cared for MRSA colonized/infected patients was the strongest risk factor for HCW MRSA colonization (p < 0.001). ST1-IV and ST78-IV (the most common community clones in the region) were the most frequently identified clones. In conclusion, MRSA colonization of HCWs occurs primarily in HCWs caring for patients colonized or infected with MRSA. Surveillance screening of HCWs should be regularly performed on wards with patients with high MRSA colonization prevalence to prevent further spread in the hospital.

Clinical and laboratory features of invasive community-onset methicillin-resistant Staphylococcus aureus infection: a prospective case-control study.

Differences between the features of invasive community-onset methicillin-resistant Staphylococcus aureus (cMRSA) and methicillin-susceptible S. aureus (cMSSA) infections are incompletely understood. Fifty-seven patients with invasive cMRSA infection were prospectively identified at two teaching hospitals; for each cMRSA case, two cases of invasive cMSSA infection acted as controls. The primary outcome was 30-day all-cause mortality. Patients with invasive cMRSA infection were more likely to be Aboriginal (25% vs. 14%, age-adjusted odds ratio [OR] 2.5, p = 0.037), reside in a long-term care facility and/or have been hospitalised in the previous year (51% vs. 34%, p = 0.04) and less likely to have endocarditis (2% vs. 12%, p = 0.02) or require admission to an intensive care unit or high-dependency area (7% vs. 21%, p = 0.02). All-cause mortality at 30 days was similar in the cMRSA and cMSSA groups (9% vs. 7%, p = 0.68). Panton-Valentine leukocidin (PVL) genes were detected in a similar proportion of cMRSA and cMSSA isolates (32% vs. 27%, p = 0.49) and the presence of PVL genes was associated with younger age (35 years vs. 55 years, p < 0.001), Aboriginal ethnicity (38% vs. 10%, p < 0.001), skin and soft-tissue infection (54% vs. 19%, p < 0.001), lower illness severity at presentation (SAPS II score 9 vs. 21, p = 0.001) and shorter hospitalisation (9 days vs. 24 days, p < 0.001). Patients with "PVL-positive" and "PVL-negative" S. aureus infection had similar 30-day all-cause mortality (4% vs. 9%, p = 0.28). Few clinical features differentiated patients with invasive cMRSA infection from those with infection caused by cMSSA. Invasive "PVL-positive" S. aureus infection was associated with less morbidity but similar mortality to "PVL-negative" infection.

Risk factors and outcomes of methicillin-resistant Staphylococcus aureus bacteraemia in critically ill patients: a case control study.

Methicillin-resistant Staphylococcus aureus (MRSA) infection is an increasing threat to critically ill patients in many intensive care units. MRSA bacteraemia is an extreme form of MRSA infection and is a significant cause of morbidity and mortality. This case control study aimed to assess the risk factors and outcomes of MRSA bacteraemia compared to methicillin-susceptible Staphylococcus aureus (MSSA) bacteraemia. A total of 21 MRSA bacteraemia and 60 randomly selected MSSA bacteraemia episodes, admitted to the intensive care unit at Royal Perth Hospital between 1997 and 2007, were considered. There was a suggestion that hospitalisation within the preceding six months (P = 0.087) and residence in a long-term care facility (P = 0.065) were associated with a higher risk of MRSA bacteraemia. MRSA bacteraemia was more often treated with antibiotics to which the pathogen was not susceptible in vitro (38.1% vs 0%, P = 0.001), resulting in a longer duration of fever (median 7.0 vs 2.0 days, P= 0.009) and bacteraemia (mean 3.2 vs 0.6 days, P = 0.005) and a higher incidence of metastatic seeding of infection (52.4% vs 21.7%, P = 0.012) as compared to MSSA bacteraemia. While in-hospital mortality between MRSA and MSSA was similarly high (47.6% vs 38.3% for MRSA and MSSA respectively, P = 0.607), a significant proportion of the patients who had MRSA bacteraemia died within five years of hospital discharge (36.4%, hazard ratio 26.0, 95% confidence interval 1.90 to 356.7, P = 0.015). Infections contributed to 75% of the deaths after hospital discharge in patients who had an episode of MRSA bacteraemia. MRSA bacteraemia carries a much worse long-term prognosis than MSSA bacteraemia and that could be explained by recurrent MRSA infections and residual confounding.

Community-associated versus healthcare-associated methicillin-resistant Staphylococcus aureus bacteraemia: a 10-year retrospective review.

The objective was to compare the epidemiology and outcome of healthcare- (HA-) and community-associated (CA-) MRSA bacteraemia. A 10-year retrospective study of MRSA bacteraemia was carried out. Episodes were classified according to established criteria. Molecular typing was performed on a subset of isolates. Of 197 MRSA bacteraemia episodes, 178 (90.4%) were classified as HA-MRSA and 19 (9.6%) as CA-MRSA. All-cause 7- and 30-day mortality rates were similar in the HA and CA-MRSA bacteraemia groups; however, 1-year mortality was higher in the HA-MRSA bacteraemia group (48.3% vs 21.1% [p = 0.023]). Thirty-day all-cause mortality was significantly lower if empiric antimicrobial therapy included agent(s) to which the isolate tested susceptible, compared with patients receiving "inactive" therapy (19% vs 35.1% [p = 0.011]). The majority of MRSA bacteraemia episodes were caused by clones known to circulate in the community. All-cause mortality is as high in HA- as in CA-MRSA bacteraemia. Thirty-day mortality was significantly reduced if the patient received an antibiotic with activity against the MRSA isolate.

[Utility of procalcitonin for the diagnosis and the follow-up of infections in febrile neutropenic patients]. / Utilité de la procalcitonine dans le diagnostic et le suivi des infections chez les patients neutropéniques fébriles.

Procalcitonin is a marker of severe bacterial infections in non-neutropenic patients. The goal of this review is to assess its utility in the management of neutropenic patients. A delayed treatment of infection in this setting results in severe morbidity and high mortality. As traditional diagnostic tools often fail to exclude infection when fever occurs, all these patients receive empirical antimicrobial therapies during long periods of time. Present knowledge suggests that procalcitonin may contribute to identify patients in whom 1) antibiotics could be stopped in the absence of bacterial infection, 2) investigations and adjustments of the antimicrobial therapy for persistent fever are needed. The use of procalcitonin for the management of febrile neutropenic patients should be studied prospectively.

Form and movement in stereokinetic cycloids: motion lost and found.

In exploring stereokinesis, we devised flat cycloidal display figures which, when rotated on a disc in the frontal plane, are perceived as illusory three-dimensional forms with movement in depth; the dominant percepts were of twisted loops with an internal writhing motion. These dominant forms could be convincingly represented by stereo pairs derived from the flat display; related forms, not seen in the illusion, could also be constructed, seeming to show a selectivity for preferred stereokinetic forms by the perceptual system. Models were made of the stereo forms; when rotated, they showed similar illusions and selectivity. We suggest that the illusions arise because some components of the real motion do not appear in the sensory field. The perceptual system accommodates for this by constructing percepts which are not necessarily veridical but do reconcile form and motion into a coherent unity. The results are discussed in relation to concepts of invariance and rigidity, and with regard to the creative response to sensory data by the perceptual system.

Elements for a report card: one institution's experience moving from theory to trial.

The emerging computerized patient record, the movement toward a unified nursing language, and increasing accountability to the public for clinical outcomes are converging forces that require a coherent plan if nursing is to evaluate outcomes. The article describes a nursing service and school of nursing's approach and beginning experiences in identifying concepts and indicators that are useful to clinicians. These concepts and indicators have the potential to be embedded in a concurrent information system that would feed a data repository used retrospectively by clinicians and researchers. The article also discusses results to date and lessons learned.

Stereokinetic interaction effects involving static and slowly moving identical figures.

Here a new depth effect evoked by the spatial and temporal interaction in 2-D of a slowly moving circle (optimally at 0.6 rads/sec) with an identical static circle is reported. Typically, respondents report that with increasing adjacency, commencing with separations of a few diameters, the moving circle appears in a different plane of depth to the static circle, it then usually appears to "dip" onto the static circle and after complete coincidence with it to rise away from it. This effect, together with a number of associated descriptions are commented upon, in addition to observations when viewing overlapped static circles and overlapped circles in motion, this latter stimulus condition evoking the stereokinetic effect. The authors have previously suggested that contour "sliding," which simulates motion parallax, is the key to understanding stereokinesis. The stimulus conditions giving rise to this new effect directly simulate the motion parallax information present in a retinal image.

The subjective effects of low-dose propofol. A double-blind study to evaluate dimensions of sedation and consciousness with low-dose propofol.

In this study the subjective effects (sedation and mood) of subanaesthetic doses of propofol were examined in 28 healthy male volunteers. A computer model was used to predict the infusion profiles necessary to obtain steady state propofol plasma concentrations of 0.3 microgram.ml-1, 0.6 microgram.ml-1, 0.9 microgram.ml-1. Objective measures of sedation from saccadic eye movement and choice reaction time gave significant dose responses at each level but a battery of psychometric tests failed to show dose-related subjective responses. Of particular note in the subjective data is the lack of a difference between groups or even of a consistent trend within the data. This suggests that a low concentration of propofol in plasma does not induce euphoria or a sense of well-being. The anecdotal evidence available for mood changes with propofol therefore remains unsubstantiated.

Interaction of H2-receptor antagonists and benzodiazepine sedation. A double-blind placebo-controlled investigation of the effects of cimetidine and ranitidine on recovery after intravenous midazolam.

H2-receptor antagonists differentially inhibit cytochrome P450 and this may affect the rate at which benzodiazepines are metabolised. However, it is not known whether this delayed clearance results in prolonged psychomotor impairment. In a randomised double-blind trial 28 healthy volunteers received two single doses of midazolam (0.07 mg.kg-1) at an interval of one week during which they took cimetidine 400 mg, ranitidine 150 mg or placebo, each twice daily. Recovery from the benzodiazepine was monitored on each occasion over a 12 h period using a battery of psychometric tests. There was wide individual variation in performance; however, an overall measure of impairment indicated a significant difference at 2.5 h (p < 0.05), the cimetidine group having a high impairment score. This decrement appeared to be in cognitive and psychomotor functions and was not reflected in the subjective assessment.

Propofol in short gynaecological procedures. Comparison of recovery over 2 days after anaesthesia with propofol or thiopentone as sole anaesthetic agent.

Recovery was assessed over 48 hours after anaesthesia with propofol or thiopentone as sole anaesthetic agent in 36 unpremedicated gynaecological patients. Immediate recovery, as measured by the Steward scale, was shown to be quicker for the patients given propofol. At one hour postoperatively the thiopentone group showed impaired visual-motor coordination on the aiming test (p less than 0.01) and dexterity task (p less than 0.05), and a slowing of reaction time (p less than 0.01). Patients given propofol showed only an increase in reaction time (p less than 0.05). By 2 hours the thiopentone group showed impairment only in the aiming task (p less than 0.05). No further significant impairment was detected at 4, 24 or 48 hours. However, patients reported symptoms throughout the 48 hours indicative of residual drug effects. There was a substantial practice effect with some tests which may have obscured impairment. It can be argued therefore that the better recovery profile after propofol is still evident at 24 hours.

Longitudinal studies of virulence factors of Pseudomonas aeruginosa in cystic fibrosis.

Among 111 strains of Pseudomonas aeruginosa from 49 children with cystic fibrosis, duration of colonization correlated with bacterial phenotype. We confirmed that P. aeruginosa from chronically colonized patients tended to be less motile, produce lower levels of protease and elastase, to be more sensitive to normal serum and to be polyagglutinating or untypable with standard antisera. We also showed that phospholipase and heat-stable hemolysin, concerned in metabolism of inorganic phosphate, and exotoxin A, were lower in these isolates. In longitudinal studies there was a decrease in virulence properties when isolates from the same patient were compared. No reversion from altered phenotype to 'wild-type' characteristics was found.