Does the use of fixed-extended-duration antibiotics improve patient outcomes compared to standard antibiotic durations in patients with complicated intra-abdominal infection?

Approved 09/03/2022, Leeds West REC (NHSBT Newcastle Blood Donor Centre, Holland Drive, Newcastle Upon Tyne, NE2 4NQ, United Kingdom; +44 (0)207 972 2504; leedswest.rec@hra.nhs.uk), ref: 22/YH/0023

Current primary outcome measure as of 26/03/2024:

Treatment failure within 180 days of randomisation. For in-patients, treatment failure is defined when a patient meets objective criteria for both inflammation and infection within a 5-day period. Meeting of the criteria for inflammation may precede or follow the date that criteria for infection were met (the first day of an eligible antibiotic treatment course). These criteria are:
Criteria for inflammation:
1.1 A fever (≥ 37.8 degrees Celsius) or hypothermia (≤36 degrees Celsius), plus
1.2 A neutrophilia (>7.5 x10^9/l) or neutropaenia (<1.8 x 109/L), plus
1.3 A CRP over 100 mg/l

PLUS, criteria for infection
2.1 Initiation of a new antibiotic treatment course of ≥ 5 days, or
2.2 A change in antibiotic treatment continued for ≥ 5 days, or
2.3 Initiation of a new antibiotic treatment, or a change in antibiotic treatment, and death within 5 days.

2.4 Bacteraemia with a recognised intestinal pathogen

New or changed antibiotic treatments must not be antibiotic prophylaxis, a change to achieve oral administration from intravenous antibiotics only, a change to reduce the spectrum of activity (targeted antibiotic treatment) or made due to antibiotic allergy only. New/changed antibiotics can include additional antibiotics, added to an ongoing treatment regimen. The first day of an eligible new/changed antibiotic treatment is called the antibiotic reference date. Inflammation 5 days either side of this antibiotic reference date can be assessed against the criteria for inflammation. A blinded endpoint committee will assess and classify data including but not limited to inflammation and antibiotic treatments to assign participants with treatment failure.

Once discharged, treatment failure requires re-admission to hospital and the in-patient criteria above to be met. Alternatively, they must have been admitted to hospital and have consumed antibiotics for > 48 hours prior to admission. Treatment failure cannot be assigned based on inflammation (fever, neutrophilia and CRP>100mg/L) detected within the 5 days after an operative procedure (surgical or radiological). Treatment failure can be assigned based on pre-operative inflammation and postoperative antibiotic changes. Treatment failure cannot be assigned due to evidence of inflammation or infection, as defined above, within the first 5 days of antibiotic treatment for the initial cIAI. If treatment is extended beyond the intervention duration this should be considered a new antibiotic treatment course.

Treatment failure measurement: A patient’s temperature is measured as part of routine clinical care
two to four times daily and recorded in their medical records when in hospital. Patients have the
neutrophil count and CRP measured, by means of a blood test, when admitted to hospital, or when an infection is suspected. It will be required that these blood tests are completed within 3 days of an
antibiotic prescription and monitored every 72 hours while receiving antibiotic therapy until there has been a reduction in CRP concentration of ≥25%, as per standard clinical practice. Patients’ medication charts will be assessed to identify new or changed antibiotic consumption. A blinded endpoint committee will review evidence of inflammation plus antibiotic consumption, in combination with documented antibiotic allergies and microbiology reports, from the preceding two weeks. This review will determine if antibiotic consumption is a new or change in antibiotic treatment, and not prophylaxis, a change made to achieve a narrowing of spectrum, an oral switch only or made due to allergy only. The Data Monitoring and Ethics Committee will audit the blinded endpoint committee and the audit will be reviewed within the internal pilot.

Intestinal pathogens include: Anaerobes (e.g., Bacteroides), Enterobacterales (e.g., Citrobacter,E.coli, Enterobacter, Klebsiella, Serratia), Enterococcus spp., Pseudomonas spp. and Streptococcus species.

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Previous primary outcome measure:

Treatment failure within 180 days of randomisation. For in-patients, treatment failure is defined when a patient meets objective criteria for both inflammation and infection within a 5-day period. Meeting of the criteria for inflammation may precede or follow the date that criteria for infection were met (the first day of an eligible antibiotic treatment course). These criteria are:
Criteria for inflammation:
1.1 A fever (≥ 37.8 degrees Celsius), plus
1.2 A neutrophilia (>7.5 x10^9/l), plus
1.3 A CRP over 100 mg/l
Criteria for infection (measured using patient records)
2.1 Initiation of a new antibiotic treatment course of ≥ 5 days, or
2.2 A change in antibiotic treatment continued for ≥ 5 days, or
2.3 Initiation of a new antibiotic treatment, or a change in antibiotic treatment, and death within 5 days

Current secondary outcome measures as of 26/03/2024:

1. Quality of life measured using the EQ-5D-5L questionnaire completed by patients at baseline, 30, 90 and 180 days after randomisation.
2. Patients will be categorised according to the worst outcome they experience over the 6-month follow-up period using a four-level ordinal classification, the Desirability Of Outcome Ranking (DOOR). The four levels will be: 1. no treatment failure, 2. treatment failure (as for the primary outcome), 3. treatment failure associated with sepsis (NEWS 6 in ward-based patients and SOFA 2 in ICU based patients), 4. treatment failure associated with death. Measured over the 180 days after randomisation.
3. Number and type of source control procedures measured by reviewing patient notes at 180 days after randomisation. The definition of source control used for this study is any procedure that stops the ongoing contamination of the peritoneal cavity and removes the majority of the contaminated intraperitoneal contents to the extent that no further acute interventions are felt to be necessary.
4. Relapse of cIAI measured by reviewing patient notes at 180 days after randomisation
5. All-cause mortality (time to event) measured by reviewing patient notes at 180 days after randomisation
6. Length of hospital stay measured by reviewing patient notes at 180 days after randomisation
7. Re-admission measured by reviewing patient notes at 180 days after randomisation
8. C. difficile infection measured by reviewing patient notes at 180 days after randomisation
9. Anti-microbial resistant (AMR) infections measured by reviewing patient notes at 180 days after randomisation. When standard treatment fails in patients with cIAI, antibiotics are often escalated to one of the carbapenem class of antibiotics. We will therefore use rates of carbapenem prescribing as a surrogate for AMR infections.
10. Days of antibiotic therapy (in-patient and outpatient) including anti-fungal therapy measured by reviewing patient notes and from a questionnaire completed by patients at 180 days after randomisation.
11. Acute kidney injury measured by reviewing patient notes at 180 days after randomisation and defined as: an increase in serum creatinine by ≥ 0.3 mg/dl (≥ 26.5 µmol/l) within 48 hours; or increase in serum creatinine to ≥ 1.5 times baseline, which is known or presumed to have occurred within the prior 7 days; or urine volume < 0.5 ml/kg/h for 6 hours (KDIGO Clinical Practice Guideline for Acute Kidney Injury).

12. Complications
13. Number of days on ventilation and days of renal replacement therapy.
14.Time to treatment failure and number of episodes of treatment failure.
15. Resource use completed by participant questionnaires at 30, 90 and 180 days.

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Previous secondary outcome measures:

1. Quality of life measured using EQ-5D-5L questionnaire completed by patients at baseline, 30, 90 and 180 days after randomisation
2. Patients will be categorised according to the worst outcome they experience over the 6-month follow-up period using a four-level ordinal classification, the Desirability Of Outcome Ranking (DOOR). The four levels will be: 1. no treatment failure, 2. treatment failure (as for the primary outcome), 3. treatment failure associated with sepsis (NEWS 6 in ward-based patients and SOFA 2 in ICU based patients), 4. treatment failure associated with death. Measured at 180 days after randomisation.
3. Number and type of source control procedures measured by reviewing patient notes at 180 days after randomisation
4. Relapse of cIAI measured by reviewing patient notes at 180 days after randomisation
5. All-cause mortality measured by reviewing patient notes at 180 days after randomisation
6. Length of hospital stay measured by reviewing patient notes at 180 days after randomisation
7. Re-admission measured by reviewing patient notes at 180 days after randomisation
8. C. difficile infection measured by reviewing patient notes at 180 days after randomisation
9. Anti-microbial resistant (AMR) infections measured by reviewing patient notes at 180 days after randomisation
10. Days of antibiotic therapy (in-patient and outpatient) measured by reviewing patient notes and from a questionnaire completed by patients at 180 days after randomisation
11. Acute kidney injury measured by reviewing patient notes at 180 days after randomisation