The MOBILISE study: utilisation of ambulatory pumps in the inpatient setting to administer continuous antibiotic infusions-a randomised controlled trial.

In the inpatient setting, antibiotics are generally administered via bedside pumps with multiple daily dosing. Utilisation of a continuous antibiotic infusion (CAI) instead might have patient and nursing satisfaction, workflow efficiencies and infection control benefits. We aimed to study the utilisation of CAI in the inpatient setting for routine antibiotic administration. Patients receiving a peripherally inserted central venous catheter (PICC) for antibiotic administration were screened for the study. The patients were randomised to either (1) standard pump and intermittent antibiotic administration (IAA) or (2) CAI via an ambulatory pump. An accelerometer placed on the ankle was used to assess patient activity. Nursing and patient satisfaction surveys were also carried out. Forty patients met the study criteria for enrolment with 21 patients being enrolled in the CAI arm of the study. One hundred and five days of accelerometer recordings were available for analysis. The geometric mean activity was 45 min/day in the standard arm and 64 min/day in the CAI arm. This represented a 42% (95% CI: -14 to 133%, p = 0.16) difference in activity between the two groups. Nursing staff reported that they spent less time throughout their shift attending the antibiotic line or pump in patients who were in the CAI arm of the study (p < 0.001). In addition, patients in this arm of the study were more likely to recommend this method of administration of antibiotics to a family member (p =0.0001). The MOBILISE study showed nursing and patient satisfaction when CAI were utilised in the inpatient setting. A statistically non-significant difference in mobility was seen. The trial was registered (28/03/2018) with the Australia New Zealand Clinical Trials Registry (ACTRN12618000452291).

Association Between Minimum Inhibitory Concentration, Beta-lactamase Genes and Mortality for Patients Treated With Piperacillin/Tazobactam or Meropenem From the MERINO Study.

INTRODUCTION: This study aims to assess the association of piperacillin/tazobactam and meropenem minimum inhibitory concentration (MIC) and beta-lactam resistance genes with mortality in the MERINO trial. METHODS: Blood culture isolates from enrolled patients were tested by broth microdilution and whole genome sequencing at a central laboratory. Multivariate logistic regression was performed to account for confounders. Absolute risk increase for 30-day mortality between treatment groups was calculated for the primary analysis (PA) and the microbiologic assessable (MA) populations. RESULTS: In total, 320 isolates from 379 enrolled patients were available with susceptibility to piperacillin/tazobactam 94% and meropenem 100%. The piperacillin/tazobactam nonsusceptible breakpoint (MIC >16 mg/L) best predicted 30-day mortality after accounting for confounders (odds ratio 14.9, 95% confidence interval [CI] 2.8-87.2). The absolute risk increase for 30-day mortality for patients treated with piperacillin/tazobactam compared with meropenem was 9% (95% CI 3%-15%) and 8% (95% CI 2%-15%) for the original PA population and the post hoc MA populations, which reduced to 5% (95% CI -1% to 10%) after excluding strains with piperacillin/tazobactam MIC values >16 mg/L. Isolates coharboring extended spectrum ß-lactamase (ESBL) and OXA-1 genes were associated with elevated piperacillin/tazobactam MICs and the highest risk increase in 30-day mortality of 14% (95% CI 2%-28%). CONCLUSIONS: After excluding nonsusceptible strains, the 30-day mortality difference from the MERINO trial was less pronounced for piperacillin/tazobactam. Poor reliability in susceptibility testing performance for piperacillin/tazobactam and the high prevalence of OXA coharboring ESBLs suggests that meropenem remains the preferred choice for definitive treatment of ceftriaxone nonsusceptible Escherichia coli and Klebsiella.

Randomized clinical trial of negative pressure wound therapy as an adjunctive treatment for small-area thermal burns in children.

BACKGROUND: The efficacy of negative pressure wound therapy (NPWT) in the acute management of burns remains unclear. The purpose of this trial was to compare standard Acticoat™ and Mepitel™ dressings with combined Acticoat™, Mepitel™ and continuous NPWT to determine the effect of adjunctive NPWT on re-epithelialization in paediatric burns. METHODS: This two-arm, single-centre RCT recruited children with acute thermal burns covering less than 5 per cent of their total body surface area. The primary outcome was time to re-epithelialization. Blinded assessments were performed using photographs captured every 3-5 days until discharge. Secondary measures included pain, itch, grafting, perfusion and scar management referrals. RESULTS: Some 114 patients were randomized. Median time to re-epithelialization was 8 (i.q.r. 7-11) days in the NPWT group and 10 (8-14) days in the control group. In a multivariable model, NPWT decreased the expected time to wound closure by 22 (95 per cent c.i. 7 to 34) per cent (P = 0·005). The risk of referral to scar management was reduced by 60 (18 to 81) per cent (P = 0·013). Four participants in the control group and one in the NPWT group underwent grafting. There were no statistically significant differences between groups in pain, itch or laser Doppler measures of perfusion. Adverse events were rare and minor, although NPWT carried a moderate treatment burden, with ten patients discontinuing early. CONCLUSION: Adjunctive NPWT hastened re-epithelialization in small-area burn injuries in children, but had a greater treatment burden than standard dressings alone. Registration number: ACTRN12618000256279 ( http://ANZCTR.org.au).

ANTECEDENTES: La eficacia del tratamiento de las heridas con presión negativa (negative pressure wound therapy, NPWT) en el tratamiento agudo de las quemaduras sigue sin estar claro. El propósito de este ensayo clínico fue comparar los apósitos estándar del tipo Acticoat™ y Mepitel™ con la combinación de Acticoat™, Mepitel™ y NPWT continua para determinar el efecto de la adición de NPWT en la reepitelización de las quemaduras en pediatría. MÉTODOS: Ensayo controlado y aleatorizado, con dos brazos y unicéntrico, que reclutó niños con quemaduras térmicas agudas que afectaban < 5% de la superficie corporal total. El resultado primario fue el tiempo hasta la reepitelización. Se realizaron evaluaciones a ciegas utilizando fotografías tomadas cada 3-5 días hasta el alta hospitalaria. Las medidas secundarias incluían dolor, picor, injerto, perfusión y derivación para el tratamiento de las cicatrices. RESULTADOS: Se aleatorizaron un total de 114 pacientes. La mediana de tiempo hasta la reepitelización fue 8 días (rango intercuartílico, interquartile range, IQR 7-11) en el grupo NPWT y 10 días (8-14) en el grupo control. En el modelo multivariable, el uso de NPWT disminuyó los días previstos hasta el cierre de la herida en un 22% (i.c. del 95% 7-34%; P = 0,005). El riesgo de ser derivado para el tratamiento de la cicatriz se redujo en un 60% (18-81%; P = 0,013). Cuatro participantes en el grupo control y uno en el grupo NPWT fueron sometidos a injertos. No hubo diferencias estadísticamente significativas en el dolor, picor, o mediciones de la perfusión con Doppler laser. Los eventos adversos fueron raros y menores, aunque NPWT conllevó una carga de tratamiento moderada con 10 pacientes que lo suspendieron precozmente. CONCLUSIÓN: El tratamiento complementario de la herida con presión negativa acelera el tiempo hasta la reepitelización en quemaduras de pequeña extensión en niños, pero implica una mayor carga de tratamiento.

Frailty: A cost incurred by reproduction?

Evolutionary theories of senescence, such as the 'disposable soma' theory, propose that natural selection trades late survival for early fecundity. 'Frailty', a multidimensional measure of health status, may help to better define the long-term consequences of reproduction. We examined the relationship between parity and later life frailty (as measured by the Frailty Index) in a sample of 3,534 adults aged 65 years and older who participated in the English Longitudinal Study of Ageing. We found that the most parous adults were the most frail and that the parity-frailty relationship was similar for both sexes. Whilst this study provided some evidence for a 'parity-frailty trade-off', there was little support for our hypothesis that the physiological costs of childbearing influence later life frailty. Rather, behavioural and social factors associated with rearing many children may have contributed to the development of frailty in both sexes.

Measuring patient-centred long-term outcome following a bloodstream infection: a pilot study.

OBJECTIVES: To evaluate the sequential organ failure assessment (SOFA) and modified SOFA (mSOFA) scoring and a novel performance score based on the Karnofsky score for measuring outcome following a bloodstream infection (BSI). METHOD: This prospective observational cohort study assessed patients with BSI for mortality and functional outcomes with a novel performance score: the functional bloodstream infection score (FBIS). We also tested the SOFA and, given the difficulties with measuring SOFA on ward-based patients, the mSOFA over the first 7 days following a BSI for their association with outcomes. RESULTS: One hundred participants were prospectively recruited. Mortality at 52 weeks following BSI was 21% (21/100). Only 57% of survivors (39/69) were at their baseline functional status at 52 weeks. Stable or improved SOFA/mSOFA over the first 7 days was associated with survival and return to premorbid performance score (risk ratio 3.2, 95%CI 1.3-9.4, p < 0.01). CONCLUSIONS: The acute change in SOFA/mSOFA was associated with 52-week survival and return to premorbid functional performance. The FBIS measurement represents a simple and easy-to-apply measure of functional performance for patients with BSI and was associated with a high response rate (89%) from participants.

A prospective observational study of the change in systemic ionised calcium following 4% citrate locking of venous haemodialysis catheters in intensive care patients.

Traditionally heparin has been the anticoagulant of choice for venous dialysis catheter locking. There is systemic leakage of heparin catheter locking solutions at the time of injection. Alternative agents, such as citrate, are increasingly being used. We are not aware of any data in the critical care literature on the effect of citrate locking of venous dialysis catheters on systemic ionised calcium (iCa2+). To assess the effect of 4% citrate locking of venous dialysis catheters on systemic iCa2+ in intensive care patients we performed a prospective observational study of 50 paired samples in 26 intensive care patients receiving 4% citrate dialysis catheter locking in an adult tertiary intensive care unit between May 2016 and December 2016. Arterial blood gas (ABG) analysis was performed prior to venous dialysis catheter locking and a baseline iCa2+ result obtained. The catheter was locked with 4% citrate solution. A further ABG was sampled between 30 and 120 seconds later and the iCa2+ results were compared. Patients were observed for clinical signs of hypocalcaemia. On average, there was little difference between the pre- and post-catheter locking iCa2+ (median pre-locking iCa2+ 1.19 mmol/l, mean change of +0.004 mmol/l, 95% confidence interval [CI] -0.004 to 0.013, P=0.34). There was no evidence this difference differed by length of catheter P=0.26) or site of catheter P=0.85) insertion, but there was some evidence that this differed by receipt of citrate dialysis circuit anticoagulation P=0.013). Patients who received citrate dialysis circuit anticoagulation had an increase in catheter locking iCa2+ by 0.017 mmol/l (95% CI 0.00 to 0.028). Locking of venous dialysis catheters with 4% citrate solution has no clinically significant effect on systemic iCa2+ in intensive care patients with indwelling venous dialysis catheters.

Nasopharyngeal carriage and macrolide resistance in Indigenous children with bronchiectasis randomized to long-term azithromycin or placebo.

Although long-term azithromycin decreases exacerbation frequency in bronchiectasis, increased macrolide resistance is concerning. We investigated macrolide resistance determinants in a secondary analysis of a multicenter randomized controlled trial. Indigenous Australian children living in remote regions and urban New Zealand Maori and Pacific Islander children with bronchiectasis were randomized to weekly azithromycin (30 mg/kg) or placebo for up to 24 months and followed post-intervention for up to 12 months. Nurses administered and recorded medications given and collected nasopharyngeal swabs 3-6 monthly for culture and antimicrobial susceptibility testing. Nasopharyngeal carriage of Haemophilus influenzae and Moraxella catarrhalis was significantly lower in azithromycin compared to placebo groups, while macrolide-resistant Streptococcus pneumoniae and Staphylococcus aureus carriage was significantly higher. Australian children, compared to New Zealand children, had higher carriage overall, significantly higher carriage of macrolide-resistant bacteria at baseline (16/38 versus 2/40 children) and during the intervention (69/152 versus 22/239 swabs), and lower mean adherence to study medication (63 % versus 92 %). Adherence ≥70 % (versus <70 %) in the Australian azithromycin group was associated with lower carriage of any pathogen [odds ratio (OR) 0.19, 95 % confidence interval (CI) 0.07-0.53] and fewer macrolide-resistant pathogens (OR 0.34, 95 % CI 0.14-0.81). Post-intervention (median 6 months), macrolide resistance in S. pneumoniae declined significantly in the azithromycin group, from 79 % (11/14) to 7 % (1/14) of positive swabs, but S. aureus strains remained 100 % macrolide resistant. Azithromycin treatment, the Australian remote setting, and adherence <70 % were significant independent determinants of macrolide resistance in children with bronchiectasis. Adherence to treatment may limit macrolide resistance by suppressing carriage.

Cytokine profiling of docetaxel-resistant castration-resistant prostate cancer.

BACKGROUND: Docetaxel improves symptoms and survival in metastatic castration-resistant prostate cancer (CRPC). However, ∼50% of patients are chemoresistant. This study examined whether changes in cytokine levels predict for docetaxel resistance in vitro and in a clinical cohort. METHODS: PC3 cells or their docetaxel-resistant subline (PC3Rx) were co-cultured with U937 monocytes, with and without docetaxel treatment, and cytokine levels were measured. The circulating levels of 28 cytokines were measured pre-/post cycle 1 of docetaxel from 55 men with CRPC, and compared with prostate-specific antigen (PSA) response. RESULTS: PC3Rx-U937 co-culture expressed more cytokines, chiefly markers of alternative macrophage differentiation, compared with PC3-U937 co-culture. Docetaxel treatment enhanced cytokine production by PC3Rx-U937 co-culture, while reducing cytokine levels in PC3-U937. In patients, changes in the levels of seven circulating cytokines (macrophage inhibitory cytokine 1 (MIC1), interleukin (IL)-1ra, IL-1ß, IL-4, IL-6, IL-12 and IFNγ) after cycle 1 of docetaxel were associated with progressive disease (all P<0.05). The combination of changes in MIC1, IL-4 and IL-6 most strongly predicted PSA response (P=0.002). CONCLUSIONS: In vitro studies suggest docetaxel resistance is mediated, at least in part, by cytokines induced by the interaction between the docetaxel-resistant tumour cells and macrophages. Early changes in circulating cytokine levels were associated with docetaxel resistance in CRPC patients. When considered together, these data suggest a significant role for the inflammatory response and macrophages in the development of docetaxel resistance in CRPC.

Progressive increase in community-associated methicillin-resistant Staphylococcus aureus in Indigenous populations in northern Australia from 1993 to 2012.

Hospital-based studies have determined high rates of community-associated methicillin-resistant Staphylococcus aureus (MRSA) in Indigenous populations. However, there is a paucity of community-based data. We obtained 20 years (1993-2012) of data on S. aureus isolates (N = 20 210) collected from community clinics that provide services for Indigenous communities in the Northern Territory, Australia. Methicillin resistance increased from 7% to 24%, resistance to macrolides remained stable at ~25%, and there was a slight increase in resistance to trimethoprim-sulfamethoxazole. The increase in methicillin resistance is concerning for the Indigenous communities represented by this data, but it is also of significance if virulent MRSA clones emerge and spread more widely from such settings.

Methylated Glutathione S-transferase 1 (mGSTP1) is a potential plasma free DNA epigenetic marker of prognosis and response to chemotherapy in castrate-resistant prostate cancer.

BACKGROUND: Glutathione S-transferase 1 (GSTP1) inactivation is associated with CpG island promoter hypermethylation in the majority of prostate cancers (PCs). This study assessed whether the level of circulating methylated GSTP1 (mGSTP1) in plasma DNA is associated with chemotherapy response and overall survival (OS). METHODS: Plasma samples were collected prospectively from a Phase I exploratory cohort of 75 men with castrate-resistant PC (CRPC) and a Phase II independent validation cohort (n=51). mGSTP1 levels in free DNA were measured using a sensitive methylation-specific PCR assay. RESULTS: The Phase I cohort identified that detectable baseline mGSTP1 DNA was associated with poorer OS (HR, 4.2 95% CI 2.1-8.2; P<0.0001). A decrease in mGSTP1 DNA levels after cycle 1 was associated with a PSA response (P=0.008). In the Phase II cohort, baseline mGSTP1 DNA was a stronger predictor of OS than PSA change after 3 months (P=0.02). Undetectable plasma mGSTP1 after one cycle of chemotherapy was associated with PSA response (P=0.007). CONCLUSIONS: We identified plasma mGSTP1 DNA as a potential prognostic marker in men with CRPC as well as a potential surrogate therapeutic efficacy marker for chemotherapy and corroborated these findings in an independent Phase II cohort. Prospective Phase III assessment of mGSTP1 levels in plasma DNA is now warranted.

Human papillomavirus modifies the prognostic significance of T stage and possibly N stage in tonsillar cancer.

BACKGROUND: Despite the association with more advanced nodal stage, patients with human papillomavirus (HPV) positive oropharyngeal cancers have better outcomes. We examined whether the HPV can modify the effect of known prognostic factors in tonsillar cancer. PATIENTS AND METHODS: A total of 489 patients from 10 centres were followed up for recurrence or death for a median of 3.2 years. Determinants of the rate of locoregional recurrence, death from tonsillar cancer and overall survival were modelled using Cox regression. RESULTS: The prognostic value of T and N stages were modified by HPV as indicated by statistically significant interaction terms. After adjusting for age, gender and treatment, T stage appeared relevant only for HPV-positive cancers (where a higher T stage was associated with worse outcomes). There was some evidence that N stage was a more relevant prognostic factor for HPV-negative than -positive cancers. There was no evidence that the HPV modifies the effect of age, gender or grade on outcomes. CONCLUSIONS: This study suggests that the prognostic significance of the conventional staging system in tonsillar cancer is modified by HPV.