Table 1

The key components of inclusion/exclusion criteria and endpoints for infectious CIS in paediatric AB CTs

Community-acquired pneumonia (CAP)
Inclusion criteriaExclusion criteriaEfficacy endpoints
  • Chest X-ray with new infiltrates in a lobar or multilobar distribution.

AND
  • A minimum number (at least 3–4) of new onset:

    • Cough.

    • Fever.

    • Dyspnoea.

    • Tachypnoea.

    • Pleuritic chest pain.


AND
  • At least one finding on percussion and/or auscultation typical of consolidation.

  • Chronic/underlying conditions (eg, moderate or severe asthma, cystic fibrosis, immunodeficiency, malignancy).

  • Pneumonia secondary to aspiration or a specific obstruction (eg, malignancy and inhaled foreign body).

Timing for evaluation:
  • End of treatment (EOT).

  • Test of cure (TOC) 5–10 days after the EOT.

  • Follow-up 28 days after randomisation.


Clinical cure:
  • Resolution or significant improvement of the baseline signs and symptoms documented at TOC visit AND discontinuation of antibiotics.


OR
Treatment failure:
  • Any change, modification, or discontinuation of allocated AB therapy because of deterioration in patient’s condition, development of serious intercurrent illness or complications.

  • Persistence of signs and symptoms present at the enrolment.

  • Relapse of the hypoxemic pneumonia during the following 2 weeks.

  • Death (up to 28 days post-randomisation).

Ventilator-associated pneumonia (VAP) and hospital-acquired Pneumonia (HAP)
Inclusion criteriaExclusion criteriaEfficacy endpoints
HAP:
  • Hospitalised for at least 48 hours before onset or onset within 7 days of hospital discharge.


AND
  • Chest X-ray with new infiltrates in a lobar or multilobar distribution.


AND
  • Minimum number of clinical features (as suggested for CAP but not including the signs on examination and auscultation).


VAP:
  • Clinical and radiographic features as for HAP.


AND
  • Mechanical ventilation via an endotracheal or nasotracheal tube for at least 48 hours.


Combined HAP/VAP studies: enrol representative samples in each category (at least 25%–30% VAP).
  • VAP population: patients receiving only non-invasive positive pressure ventilation.

Timing for evaluation:
  • End of treatment (EOT).

  • Test of cure (TOC) 7–14 days after the EOT.

  • Follow-up 28 days after randomisation.


Clinical cure:
  • Resolution or significant improvement of the baseline signs and symptoms documented at EOT visit AND discontinuation of antibiotics.


OR
Treatment failure:
  • Any change, modification, or discontinuation of allocated AB therapy because of deterioration in patient’s condition, development of serious intercurrent illness or complications.

  • Persistence of signs and symptoms present at the enrolment.

  • Relapse of the pneumonia during the following 2 weeks.

  • Death (up to 28 days post-randomisation).

Complicated urinary tract infections (UTI)19 (including pyelonephritis, renal abscess, catheter-related UTI, bacteraemia from urinary tract without specification)
Inclusion criteriaExclusion criteriaEfficacy endpoints
  • Abnormal urinary dipstick test (leucocyte esterase >1+, or nitrite positive) OR

  • Urinalysis (≥5 white cell counts per high-power field in centrifuged urine or ≥10 white cell counts per mm3 in uncentrifuged urine and bacteriuria with any bacteria per high-power field).

AND
  • At least two of the following clinical or biological signs:

    • Fever with temperature of 38°C or higher.

    • General, non-specific signs (for children <2 years irritability, vomiting, diarrhoea, feeding problems; for children >2 years abdominal or flank pain, urgency, frequency, dysuria, or suprapubic tenderness).

    • C-reactive protein or procalcitonin concentrations elevated according to the local laboratory.


AND
  • Positive urine culture result with no more than two species of micro-organisms OR

  • Spontaneously voided urine with ≥105 micro-organisms per mL of urine OR

  • Suprapubic aspirate or urinary catheter with ≥104 micro-organisms per mL of urine OR

  • Positive blood culture result and no other recognised cause.

  • Chronic/underlying conditions (eg, known UT abnormalities, malignancy, immunodeficiency, shock).

Timing for evaluation:
  • End of treatment (EOT).

  • Test of cure (TOC) 5–7 days after the EOT.

  • Follow-up 28 days after randomisation.


Treatment success:
Concomitant clinical and microbiological evaluation for the TOC
  • Clinical cure defined as defervescence.

  • Microbiological cure defined as urine sterilisation.

Suspected or proven neonatal severe bacterial infection
Inclusion criteria20 Exclusion criteriaEfficacy endpoints
At least two clinical symptoms and at least two laboratory signs in presence of or as a result of suspected or proven infection.
Clinical criteria:
  • Hyperthermia or hypothermia and/or temperature instability.

  • Reduced urinary output or hypotension or mottled skin or impaired peripheral perfusion.

  • Apnoea or increased oxygen requirement or requirement for ventilation support.

  • Bradycardia spells or tachycardia and/or rhythm instability.

  • Feeding intolerance or abdominal distension.

  • Lethargy or hypotonia or irritability.

  • Skin and subcutaneous lesions, such as petechial rash.


Laboratory criteria:
  • WBC count <4000 or >20 000 cells/mm3.

  • Platelet count <100 000/mm3.

  • CRP >1.5 mg/dL or procalcitonin ≥2 ng/mL.

  • Glucose intolerance as expressed by blood glucose values >180 mg/dL confirmed at least two times or hypoglycaemia <40 mg/dL (2.5 mmol/L).

  • Acidosis as characterised by base excess <−10 mmol/L or lactate with value above 2 mmol/L.

  • Major underlying conditions or major congenital malformations.

  • Deep seated localised infection (including osteomyelitis, endocarditis and meningitis).

Timing for evaluation:
  • End of Treatment (EOT).

  • Test of Cure (TOC) 7–10 days after the EOT.

  • Long-term follow-up 28 days after randomisation.


Clinical cure:
  • Resolution or significant improvement of the baseline clinical signs and symptoms of infection AND microbiological eradication or presumed eradication (in case of positive blood culture) AND no new symptoms suggestive to neonatal sepsis.


OR
Treatment failure, any of the following:
  • Death up to 28 days post-randomisation.

  • Persistence of signs and symptoms present at the enrolment.

  • Clinical deterioration: emergence of any sign of critical illness at any time or re-emergence of a sign of clinical severe infection after initial disappearance.

  • Any change, modification, or discontinuation of allocated AB therapy because of deterioration in patient's condition, development of serious intercurrent illness or complications.

Complicated intra-abdominal infections (cIAI) (including localised infections (eg, biliary and non-biliary organ-specific infections, abscesses, postsurgical secondary infections) and diffuse peritonitis. 10% of patients should have a diagnosis other than complicated appendicitis)
Inclusion criteriaExclusion criteriaEfficacy endpoints
Diagnosis of cIAI established during procedures such as laparotomy, laparoscopy or percutaneous drainage
  • Patient has organisms cultured from purulent material from intra-abdominal space obtained during a surgical operation for the current infection or needle aspiration OR

  • Organisms cultured from drainage from surgically placed drain (eg, closed suction drainage system, open drain, T-tube drain) OR

  • Organisms cultured from blood and radiographic evidence of infection (eg, abnormal findings on ultrasound, CT scan, MRI, or radiolabel scans (gallium, technetium, etc) or on abdominal X-ray).


AND
  • At least two of the following signs or symptoms with no other recognised cause:

    • Fever (>38.5°C).

    • Nausea.

    • Vomiting.

    • Abdominal pain.

    • Jaundice.

  • Chronic/underlying conditions affecting surgical decision making or that would limit recovery (eg, haemophilia, severe cardiac or respiratory comorbidities).

Timing for evaluation:
  • End of treatment (EOT).

  • Test of cure (TOC) 7–10 days after the EOT.

  • Long-term follow-up 28 days after randomisation.


Clinical cure:
  • Clearance of infection with resolution of the baseline signs and symptoms such that no additional antibacterial therapy or surgical or percutaneous intervention is required at EOT AND eradication or presumed eradication of micro-organisms.


OR
Treatment failure:
  • Any change, modification, or discontinuation of allocated AB therapy because of deterioration in patient's condition, development of serious intercurrent illness or complications (eg, abscess, wound infection, prolonged fever >3 days, prolonged bacteraemia), need for additional antibiotics, need for operative or percutaneous intervention.

Acute bacterial skin and skin structure infections (ABSSSI) (including surgical wound infections, deep abscesses, cellulitis and erysipelas)
Inclusion criteriaExclusion criteriaEfficacy endpoints
  • Diagnosis of ABSSSI requiring systemic antibiotic treatment, with at least one of the following:

    • Drainage/discharge.

    • Erythema.

    • Fluctuance.

    • Heat/localised warmth.

    • Pain/tenderness to palpation.

    • Swelling/induration.

AND at least two of the following:
  • Fever or hypothermia.

  • Leucocytosis or leucopenia or a left shift of band neutrophils.

  • Tachycardia (98th percentile for age).21

  • Tachypnoea (2 SD of normal for age).21

  • Chronic/underlying conditions that would limit recovery (eg, neutropenia, diabetes, other immunodeficiencies).

  • Patients with suspected and/or confirmed osteomyelitis or septic arthritis.

  • Patients with mild infections that do not need systemic antibiotics.

Timing for evaluation:
  • End of Treatment (EOT).

  • Test of cure (TOC) 7–10 days after the EOT.

  • Long-term follow-up (LFU) 28 days after randomisation.


Clinical cure:
  • Resolution or significant improvement of the baseline clinical signs and symptoms of infection at EOT visit AND

  • No need for additional antibiotics.


OR
Treatment failure:
  • Persistence or progression of signs and symptoms or development of new lesions at a different site.

  • Any change, modification, or discontinuation of allocated AB therapy because of deterioration in patient’'s condition, development of serious intercurrent illness or complications.

  • AB, antibiotics; CIS, clinical infectious syndromes; CT, clinical trial.