Early switch from intravenous to oral antibiotic therapy in patients with cancer who have low-risk neutropenic sepsis: the EASI-SWITCH RCT.

Background: Neutropenic sepsis is a common complication of systemic anticancer treatment. There is variation in practice in timing of switch to oral antibiotics after commencement of empirical intravenous antibiotic therapy. Objectives: To establish the clinical and cost effectiveness of early switch to oral antibiotics in patients with neutropenic sepsis at low risk of infective complications. Design: A randomised, multicentre, open-label, allocation concealed, non-inferiority trial to establish the clinical and cost effectiveness of early oral switch in comparison to standard care. Setting: Nineteen UK oncology centres. Participants: Patients aged 16 years and over receiving systemic anticancer therapy with fever (≥ 38°C), or symptoms and signs of sepsis, and neutropenia (≤ 1.0 × 109/l) within 24 hours of randomisation, with a Multinational Association for Supportive Care in Cancer score of ≥ 21 and receiving intravenous piperacillin/tazobactam or meropenem for < 24 hours were eligible. Patients with acute leukaemia or stem cell transplant were excluded. Intervention: Early switch to oral ciprofloxacin (750 mg twice daily) and co-amoxiclav (625 mg three times daily) within 12-24 hours of starting intravenous antibiotics to complete 5 days treatment in total. Control was standard care, that is, continuation of intravenous antibiotics for at least 48 hours with ongoing treatment at physician discretion. Main outcome measures: Treatment failure, a composite measure assessed at day 14 based on the following criteria: fever persistence or recurrence within 72 hours of starting intravenous antibiotics; escalation from protocolised antibiotics; critical care support or death. Results: The study was closed early due to under-recruitment with 129 patients recruited; hence, a definitive conclusion regarding non-inferiority cannot be made. Sixty-five patients were randomised to the early switch arm and 64 to the standard care arm with subsequent intention-to-treat and per-protocol analyses including 125 (intervention n = 61 and control n = 64) and 113 (intervention n = 53 and control n = 60) patients, respectively. In the intention-to-treat population the treatment failure rates were 14.1% in the control group and 24.6% in the intervention group, difference = 10.5% (95% confidence interval 0.11 to 0.22). In the per-protocol population the treatment failure rates were 13.3% and 17.7% in control and intervention groups, respectively; difference = 3.7% (95% confidence interval 0.04 to 0.148). Treatment failure predominantly consisted of persistence or recurrence of fever and/or physician-directed escalation from protocolised antibiotics with no critical care admissions or deaths. The median length of stay was shorter in the intervention group and adverse events reported were similar in both groups. Patients, particularly those with care-giving responsibilities, expressed a preference for early switch. However, differences in health-related quality of life and health resource use were small and not statistically significant. Conclusions: Non-inferiority for early oral switch could not be proven due to trial under-recruitment. The findings suggest this may be an acceptable treatment strategy for some patients who can adhere to such a treatment regimen and would prefer a potentially reduced duration of hospitalisation while accepting increased risk of treatment failure resulting in re-admission. Further research should explore tools for patient stratification for low-risk de-escalation or ambulatory pathways including use of biomarkers and/or point-of-care rapid microbiological testing as an adjunct to clinical decision-making tools. This could include application to shorter-duration antimicrobial therapy in line with other antimicrobial stewardship studies. Trial registration: This trial is registered as ISRCTN84288963. Funding: This award was funded by the National Institute for Health and Care Research (NIHR) Health Technology Assessment programme (NIHR award ref: 13/140/05) and is published in full in Health Technology Assessment; Vol. 28, No. 14. See the NIHR Funding and Awards website for further award information.

Neutropenic sepsis, or infection with a low white blood cell count, can occur following cancer treatment. Usually patients receive treatment with intravenous antibiotics (antibiotics delivered into a vein) for two or more days. Patients at low risk of complications from their infection may be able to have a shorter period of intravenous antibiotics benefitting both patients and the NHS. The trial compared whether changing from intravenous to oral antibiotics (antibiotics taken by mouth as tablets or liquid) 12­24 hours after starting antibiotic treatment ('early switch') is as effective as usual care. Patients could take part if they had started intravenous antibiotics for low-risk neutropenic sepsis. Patients were randomly allocated to 'early switch' or to usual care. The main outcome measured was treatment failure. Treatment failure happened if fever persisted or recurred despite antibiotics, if patients needed to change antibiotics, if they needed to be re-admitted to hospital or needed to be admitted to intensive care within 14 days or died. We had originally intended that 628 patients would take part, but after review of the design of the study the number needed to take part was revised to 230. We were not able to complete the trial as planned as unfortunately only 129 patients took part. As the trial was smaller than expected we were not able to draw conclusions as to whether 'early switch' is no less effective than usual care. Our findings suggest that 'early switch' might result in a shorter time in hospital initially; however, treatment failure was more likely to occur, meaning some patients had to return to hospital for further antibiotics. There were no differences in side effects and no serious complications from treatment or treatment failure (such as intensive care admission or death) among the 65 patients in the 'early switch' group. Patients were satisfied with 'early switch'. Early switch may be a treatment option for some patients with low-risk neutropenic sepsis who would prefer a shorter duration of hospital admission but accept a risk of needing hospital re-admission.

Early switch to oral antibiotic therapy in patients with low-risk neutropenic sepsis (EASI-SWITCH): a randomized non-inferiority trial.

OBJECTIVES: To determine whether early switch to oral antibiotic treatment in adults with neutropenic sepsis at low risk of complications is non-inferior to switching later. METHODS: This non-inferiority, parallel-group, randomized, open-label clinical trial enrolled UK adults hospitalized with neutropenic sepsis. Participants were randomly assigned to either switch to oral ciprofloxacin plus co-amoxiclav within 12-24 hours or to continue intravenous treatment for at least 48 hours. The primary outcome was a composite measure of treatment failure, 14 days after randomization. The non-inferiority margin was 15%. RESULTS: There were 129 participants from 16 centres and 125 were assessed for the primary outcome. Of these, 113 patients completed protocolized treatment and comprised the per-protocol population. In total, 9 (14.1%) of 64 patients in the standard care arm met the primary end point, compared with 15 (24.6%) of 61 in the early switch arm, giving a risk difference of 10.5% (1-sided 95% CI, -∞% to 22%; p 0.14). In the per-protocol population, 8 (13.3%) of the 60 patients in the standard care arm met the primary end point, compared with 9 (17%) of 53 in the intervention arm giving a risk difference of 3.7% (one-sided 95% CI, -∞% to 14.8%; p 0.59). Duration of hospital stay was shorter in the intervention arm (median 2 [inter-quartile range (IQR) 2-3] vs. 3 days [IQR 2-4]; p 0.002). DISCUSSION: Although non-inferiority of early oral switch was found in the per-protocol population, the intervention was not non-inferior in the intent-to-treat population.

Early switch from intravenous to oral antibiotic therapy in patients with cancer who have low-risk neutropenic sepsis (the EASI-SWITCH trial): study protocol for a randomised controlled trial.

BACKGROUND: Neutropenic sepsis remains a common treatment complication for patients receiving systemic anti-cancer treatment. The UK National Institute for Health and Care Excellence have not recommended switching from empirical intravenous antibiotics to oral antibiotics within 48 h for patients assessed as low risk for septic complications because of uncertainty about whether this would achieve comparable outcomes to using intravenous antibiotics for longer. The UK National Institute for Health Research funded the EASI-SWITCH trial to tackle this uncertainty. METHODS: The trial is a pragmatic, randomised, non-inferiority trial that aims to establish the clinical and cost-effectiveness of early switching from intravenous to oral antibiotics in cancer patients with low-risk neutropenic sepsis. Patients ≥ 16 years, receiving systemic anti-cancer treatment (acute leukaemics/stem cell transplants excluded), with a temperature of > 38 °C, neutrophil count ≤ 1.0 × 109/L, MASCC (Multinational Association of Supportive Care in Cancer) score ≥ 21 and receiving IV piperacillin/tazobactam or meropenem for less than 24 h are eligible to participate. Patients are randomised 1:1 either (i) to switch to oral ciprofloxacin and co-amoxiclav within 12-24 h of commencing intravenous antibiotics, completing at least 5 days total antibiotics (intervention), or (ii) to continue intravenous antibiotics for at least 48 h, with ongoing antibiotics being continued at the physician's discretion (control). Patients are discharged home when their physician deems it appropriate. The primary outcome measure is a composite of treatment failures as assessed at day 14. The criteria for treatment failure include fever persistence or recurrence 72 h after starting intravenous antibiotics, escalation from protocolised antibiotics, hospital readmission related to infection/antibiotics, critical care support or death. Based on a 15% treatment failure rate in the control group and a 15% non-inferiority margin, the recruitment target is 230 patients. DISCUSSION: If the trial demonstrates non-inferiority of early switching to oral antibiotics, with potential benefits for patient quality of life and resource savings, this finding will have significant implications for the routine clinical management of those with low-risk neutropenic sepsis. TRIAL REGISTRATION: ISRCTN: 84288963. Registered on the 1 July 2015. https://doi.org/10.1186/ISRCTN84288963. EudraCT: 2015-002830-35.

Chasing the Golden Hour - Lessons learned from improving initial neutropenic sepsis management.

Neutropenic sepsis remains a time critical and potentially fatal complication of systemic anti-cancer therapy. A target 'door to needle' time of one hour for first dose empirical intravenous antibiotics continues to be promoted nationally. A baseline audit (June 2011) highlighted shortfalls in care in the Belfast Trust, with only 15% of patients receiving antibiotics within sixty minutes. A multi-professional group within the Trust was established to try and initiate the improvements in neutropenic sepsis recognition and initial management that were urgently required. A number of strategies have been developed over the last five years. Firstly an integrated care pathway was introduced, which is currently used by nursing and medical staff for patients presenting with suspected neutropenic sepsis, through acute cancer centre assessment areas and emergency departments, as well as inpatients developing neutropenic sepsis. An initial reaudit June 2012 demonstrated improvement (62% meeting 1hour target), but a subsequent audit, January 2013, was disappointing (only 50% meeting 1hour target). In response, a new compact, user-friendly care pathway was introduced. A range of other measures have also been subsequently introduced. Patients' care is continually monitored through simple ward based documentation, completed after initial treatment of each neutropenic sepsis episode. A patient group direction facilitates nurse led prescribing and administration of first dose antibiotics. Regular multidisciplinary education sessions and improved access to regional guidelines have also been prioritised. From November 2013, consistently greater than 80% of patients have met the one hour target. Recent data continues to be encouraging; in July 2016 100% of patients received first doses within sixty minutes, in October 95% of patients. Significant sustained improvements in meeting the sixty minute target have been demonstrated. The combination of measures ensures neutropenic sepsis is considered and basic clinical care delivered quickly and safely, through a co-ordinated standardised approach, to avoid complications.

Improving the safety of chemotherapy prescribing in oncology through the introduction of an assessment proforma.

Chemotherapy remains a high risk treatment with the potential to cause significant patient morbidity and mortality. In the UK the Manual for Cancer Services: Chemotherapy Measures provides national quality measures for essential elements that should be incorporated and documented in chemotherapy assessments. It was recognised that in the outpatient oncology chemotherapy unit in the Cancer Centre, Belfast City Hospital, Northern Ireland, that the written records of chemotherapy assessments were sub-optimal. At baseline (December 2015) median completion of chemotherapy assessment documentation was only 63%, based on a scoring system incorporating key assessment parameters from the Manual for Cancer Services and Belfast Trust standards for record keeping. A target of median chemotherapy assessment documentation being at least 95% complete was set. A paper chemotherapy assessment proforma was developed and introduced over an eight month period, using small tests of change and continuous data collection and feedback. The proportion of chemotherapy assessments documented using the proforma increased, as it was adjusted to be more user friendly and particularly after it started being pre-filed in medical notes. Increased use of the proforma correlated with improvement in completeness of chemotherapy assessment documentation. From week 29 to project completion (week 33), following proformas being routinely pre-filed and uptake increasing, assessments were on average 97% complete. Documentation of a patient's performance status, a critical aspect of the assessment, also improved to a median of 99% over the last seven weeks of the project from a baseline of 88%. The proforma has been positively viewed by staff with 94% agreeing it promotes safety. The introduction of a chemotherapy assessment proforma is a simple measure which can result in improved documentation of chemotherapy assessments, including performance status. It also serves as a prompt for safe decision making regarding chemotherapy prescriptions, enhancing the quality of outpatient chemotherapy care being delivered.

Acute Kidney Injury: It's as easy as ABCDE.

Acute kidney injury (AKI) is a common, serious problem which has been found to be poorly managed. Early recognition and action is critical in potentially slowing or reversing its course and facilitating timely referral to specialist services. In this quality improvement project, multidisciplinary education sessions and a simple 'ABCDE' checklist to aid AKI management were introduced in a district general hospital. The incidence of AKI (defined as 26umol/l rise in creatinine), its recognition and management were measured hospital wide. AKI recognition was improved by educating the entire multidisciplinary team to identify three key early warning signs: a rise in serum creatinine, urine output of <500mls in 24 hours and systolic blood pressure of <90mmHg. The 'ABCDE' checklist (Address drugs, Boost blood pressure, Calculate fluid balance, Dip urine, Exclude obstruction) was introduced to prompt AKI management. A four week educational programme was delivered, initially on a pilot ward, to doctors, nurses, nursing assistants and pharmacists. AKI recognition and implementation of the 'ABCDE' checklist were measured. Prior to project introduction 16% of patients developed AKI, but were recognised within 24 hours in only 31% of cases, with 80% of 'ABCDE' steps implemented in only 20%. Following multidisciplinary education, AKI recognition improved to 100%, with 80% of 'ABCDE' steps implemented in 67% of cases. These results were replicated when the project was rolled out across the surgical directorate (120 beds) and in the 40 bed medical admission unit. Prevention and treatment of AKI should be a core competency of all clinical staff. Educating and empowering the multidisciplinary team to implement simple interventions improves standards and should be the foundation of strategies targeting AKI. Through this study significant improvements have been demonstrated in AKI recognition and management, positively impacting on patient safety, quality of care and patients' and staff experience.