Evaluation of Safety,Pharmacokinetics and Efficacy of CAZ-AVI With Metronidazole in Children Aged 3 Months to 18 Years Old With Complicated Intra-abdominal Infections (cIAIs).
Evaluation of Safety,Pharmacokinetics and Efficacy of CAZ-AVI With Metronidazole in Children Aged 3 Months to 18 Years Old With Complicated Intra-abdominal Infections (cIAIs).
This study will assess the safety , efficacy and pharmacokinetics of ceftazidime avibactam
 and metronidazole versus meropenem in paediatric population (from 3 months to less than 18
 years of age )with complicated intra-abdominal infections (cIAIs)
This is a multicentre, multinational, single blind, randomised and active controlled trial of
 intravenous ceftazidime avibactam in combination with metronidazole versus meropenem.
 Patients will receive intravenous (IV) treatment for a minimum of 72 hours (3 full days, ie,
 9 doses) before having the option to switch to an oral therapy. The decision to switch to
 oral therapy is entirely at the Investigator's discretion, if the patient has good or
 sufficient clinical response, and the patient is tolerating oral fluids or food.Patients will
 be assessed for safety and efficacy throughout the study, and blood samples will be taken for
 pharmacokinetic (PK) assessment. The duration of each patient's participation in the study
 will be a minimum of 27 days to a maximum of 50 days after start of study treatment (defined
 as the time point at which first dose of study treatment is administered) at which time there
 will be a late follow up (LFU) assessment visit. The LFU is to be performed 20 to 35 days
 after the last dose of any treatment.The assessments at the test of cure (TOC) visit should
 be performed in person 8 to 15 days after last dose of any study drug (IV or oral). The
 maximum duration of IV study drug or oral switch therapy is up to Day 15.
Inclusion Criteria:

 1. Must be ≥3 calendar months to <18 years of age. Patients aged ≥3 calendar months to <1
 year must have been born at term (defined as gestational age ≥37 weeks).

 2. Written informed consent from parent(s) or other legally acceptable representative(s),
 and informed assent from patient (if age appropriate according to local regulations)

 3. If female and has reached menarche, or has reached Tanner stage 3 development (even if
 not having reached menarche) (refer to Appendix E for further details on Tanner
 staging), the patient is authorised to participate in this clinical study if the
 following criteria are met:

 At screening:

 (i) Patient reports sexual abstinence for the prior 3 months or reports use of at least 1
 of the acceptable methods of contraception, including an intrauterine device (with copper
 banded coil), levonorgestrel intrauterine system (eg, Mirena®), or regular
 medroxyprogesterone injections (Depo-Provera®); or (b) Patient agrees to initiate sexual
 abstinence from the time of screening until 7 days after end of treatment with study drug;
 and (ii) Patient is advised to avoid conception from the time of screening until 7 days
 after receipt of study drug and agrees not to attempt pregnancy from the time of screening
 until 7 days after end of treatment with study drug; and (iii) Patient is provided
 guidelines regarding continuation of abstinence, initiation of abstinence, or about allowed
 contraception; and (iv) Patient has a negative serum β-human chorionic gonadotropin (β-hCG)
 test just prior to study entry. Since serum tests may miss an early pregnancy, relevant
 menstrual history and sexual history, including methods of contraception, should be
 considered. Note: if the result of the serum β-hCG test cannot be obtained prior to dosing
 of investigational product, a patient may be enrolled on the basis of a negative urine
 pregnancy test, though a serum β-hCG test result must still be obtained.

 4. Must, based on the judgment of the Investigator, require hospitalisation initially and
 antibacterial therapy for 7 to 15 days in addition to surgical intervention for the
 treatment of the current cIAI 5. Require surgical intervention (eg, laparotomy,
 laparoscopic surgery or percutaneous drainage) to manage the cIAI 6. Must have clinical
 evidence of cIAI as follows: (i) Pre-operative enrolment inclusion:

 1. Requires surgical intervention that is expected to be completed within 24 hours of
 enrolment Laparotomy, laparoscopy, or percutaneous drainage

 2. Evidence of a systemic inflammatory response (at least 1): Fever (defined as oral
 temperature >38.5°C, or equivalent to method used) or hypothermia (with a core body or
 rectal temperature <35°C, or equivalent to method used) Elevated white blood cells
 (WBC) (>15000 cells/mm3) C-reactive protein (CRP) levels (>10 mg/L)

 3. Physical Findings consistent with intra-abdominal infection, such as:

 Abdominal pain and/or tenderness Localised or diffuse abdominal wall rigidity
 Abdominal mass

 4. Intention to send specimens from the surgical intervention for culture

 5. (Optional) Supportive radiologic findings of intra-abdominal infection, such as
 perforated intraperitoneal abscess detected on: Computed tomography (CT) scan or
 Magnetic resonance imaging (MRI) or Ultrasound (ii) Intra-operative/postoperative
 enrolment inclusion(in cases of postoperative enrolment, must be within 24 hours after
 the time of incision)::

 Visual confirmation of intra-abdominal infection associated with peritonitis at laparotomy,
 laparoscopy or percutaneous drainage (to be confirmed pending feasibility); must have 1 of
 these diagnoses:

 1. Appendiceal perforation or peri-appendiceal abscess

 2. Cholecystitis with gangrenous rupture or perforation or progression of the infection
 beyond the gallbladder wall

 3. Acute gastric or duodenal perforations, only if operated on >24 hours after singular
 perforation occurs

 4. Traumatic perforation of the intestines, only if operated on >12 hours after
 perforation occurs

 5. Secondary peritonitis (but not spontaneous bacterial peritonitis associated with
 cirrhosis and chronic ascites)

 Exclusion Criteria:

 1. Involvement in the planning and/or conduct of the study (applies to both AstraZeneca
 staff and/or staff at the study site)

 2. Previous enrolment or randomisation in the present study

 3. Participation in another clinical study with an investigational product (IP) during
 the last 30 days before the first dose of IV study drug or have previously
 participated in the current study or in another study of CAZ-AVI (in which an active
 agent was received)

 4. History of hypersensitivity reactions to carbapenems, cephalosporins, penicillin,
 other β lactam antibiotics metronidazole or to nitroimidazole derivatives

 5. Concurrent infection, that may interfere with the evaluation of response to the study
 antibiotics at the time of randomisation

 6. Patient needs effective concomitant systemic antibacterials (oral, IV, or
 intramuscular) in addition to those designated in the 2 study groups (CAZ-AVI plus
 metronidazole group or meropenem group) (see Section 7.8)

 7. Receipt of non-study systemic antibacterial drug therapy for cIAI for a continuous
 duration of more than 24 hours during the 72 hours preceding the first dose of IV
 drug, except in proven resistant organisms and/or worsening of the clinical condition
 for more than 24 hours. More than 2 consecutive doses are not permitted if the
 individual doses are expected to give >12 hours' cover (ie, giving a total cover of
 >24 hours.) For patients enrolled after a surgical procedure, only 1 dose of non study
 antibiotics is permitted postoperatively

 8. Patient is considered unlikely to survive the 6 to 8 week study period

 9. Patient is unlikely to respond to 7 to 15 days of treatment with antibiotics

 10. Patient is receiving haemodialysis or peritoneal dialysis

 11. Diagnosis of abdominal wall abscess confined to musculature of the abdominal wall or
 ischaemic bowel disease without perforation, traumatic bowel perforation requiring
 surgery within 12 hours of perforation, or perforation of gastroduodenal ulcers
 requiring surgery within 24 hours of perforation (these are considered situations of
 peritoneal soiling before the infection has become established)

 12. Simple (uncomplicated), non-perforated appendicitis or gangrenous appendicitis without
 rupture into the peritoneal cavity identified during a surgical procedure OR presence
 of primary peritonitis (ie, spontaneous bacterial peritonitis) or peritonitis
 associated with cirrhosis or chronic ascites

 13. At the time of randomisation, patient is known to have a cIAI caused by pathogens
 resistant to the study antimicrobials planned to be used in the study

 14. Presence of any of the following clinically significant laboratory abnormalities:

 1. Haematocrit <25% or haemoglobin <8 g/dL (<80g/L , <4.9 mmol/L)

 2. Serum alanine aminotransferase (ALT) or aspartate aminotransferase (AST) >3×the
 age-specific upper limit of normal (ULN), or total bilirubin >2×ULN (except known
 Gilbert's disease) For a) to b): unless if these values are acute and directly
 related to the infectious process being treated.

 15. Creatinine clearance<30 mL/min /1.73 m2 calculated using the child's measured height
 (length) and serum creatinine within the updated "bedside" Schwartz formula (Schwartz
 et al, 2009):

 CrCl (mL/min/1.73m2)=0.413×height (length) (cm)/serum creatinine (mg/dL)

 16. History of seizures, excluding well-documented febrile seizure of childhood

 17. Any situation or condition that would make the patient, in the opinion of the
 Investigator, unsuitable for the study (eg, would place a patient at risk or
 compromise the quality of the data) or may interfere with optimal participation in the
 study

 18. If female, currently pregnant or breast feeding