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).
- Conditions
- Complicated Intra-abdominal Infections
- Interventions
- Registration Number
- NCT02475733
- Lead Sponsor
- Pfizer
- Brief Summary
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)
- Detailed Description
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.
Recruitment & Eligibility
- Status
- COMPLETED
- Sex
- All
- Target Recruitment
- 83
- 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).
- Written informed consent from parent(s) or other legally acceptable representative(s), and informed assent from patient (if age appropriate according to local regulations)
- 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.
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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:
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Requires surgical intervention that is expected to be completed within 24 hours of enrolment Laparotomy, laparoscopy, or percutaneous drainage
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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)
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Physical Findings consistent with intra-abdominal infection, such as:
Abdominal pain and/or tenderness Localised or diffuse abdominal wall rigidity Abdominal mass
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Intention to send specimens from the surgical intervention for culture
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(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:
- Appendiceal perforation or peri-appendiceal abscess
- Cholecystitis with gangrenous rupture or perforation or progression of the infection beyond the gallbladder wall
- Acute gastric or duodenal perforations, only if operated on >24 hours after singular perforation occurs
- Traumatic perforation of the intestines, only if operated on >12 hours after perforation occurs
- Secondary peritonitis (but not spontaneous bacterial peritonitis associated with cirrhosis and chronic ascites)
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Involvement in the planning and/or conduct of the study (applies to both AstraZeneca staff and/or staff at the study site)
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Previous enrolment or randomisation in the present study
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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)
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History of hypersensitivity reactions to carbapenems, cephalosporins, penicillin, other β lactam antibiotics metronidazole or to nitroimidazole derivatives
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Concurrent infection, that may interfere with the evaluation of response to the study antibiotics at the time of randomisation
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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)
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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
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Patient is considered unlikely to survive the 6 to 8 week study period
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Patient is unlikely to respond to 7 to 15 days of treatment with antibiotics
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Patient is receiving haemodialysis or peritoneal dialysis
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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)
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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
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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
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Presence of any of the following clinically significant laboratory abnormalities:
- Haematocrit <25% or haemoglobin <8 g/dL (<80g/L , <4.9 mmol/L)
- 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.
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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)
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History of seizures, excluding well-documented febrile seizure of childhood
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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
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If female, currently pregnant or breast feeding
Study & Design
- Study Type
- INTERVENTIONAL
- Study Design
- PARALLEL
- Arm && Interventions
Group Intervention Description CAZ-AVI and metronidazole Ceftazidime -avibactam CAZ-AVI to be administered every 8 hours as a 2 hour infusion (CAZ-AVI dose and frequency of IV administration will depend upon body weight and renal function) followed by metronidazole (no later than 30 minutes after CAZ-AVI infusion ) to be administered every 8 hours as 20 to 30 minutes infusion CAZ-AVI and metronidazole Metronidazole CAZ-AVI to be administered every 8 hours as a 2 hour infusion (CAZ-AVI dose and frequency of IV administration will depend upon body weight and renal function) followed by metronidazole (no later than 30 minutes after CAZ-AVI infusion ) to be administered every 8 hours as 20 to 30 minutes infusion Meropenem Meropenem administered every 8 hours infused over 15 to 30 minutes or up to 1 hour or infusion duration as per local guidelines.
- Primary Outcome Measures
Name Time Method Percentage of Participants With Cephalosporin Class Effects and Additional Adverse Events (AEs) Baseline until the LFU visit (up to a maximum study duration of 50 days) Percentage of participants with Cephalosporin class effects (defined as adverse event of special interest (AEoSI) within the safety topics (ST) of hypersensitivity/anaphylaxis) and additional AEs (which included AEs of seizures, diarrhea, renal disorder, and liver disorder relevant to the cephalosporin class within the ST and AEs with preferred term in the system organ class of nervous system disorder system organ class based on MedDRA 20.0) were reported in this outcome measure.
Change From Baseline in Respiratory Rate at End of Intravenous Therapy (EOIV) Visit Baseline, EOIV visit (anytime from Day 4 up to 16) EOIV visit occurred within 24 hours after completion of last infusion of the study drug.
Change From Baseline in Body Weight at End of Intravenous Therapy (EOIV) Visit Baseline, EOIV visit (anytime from Day 4 up to 16) EOIV visit occurred within 24 hours after completion of last infusion of the study drug.
Percentage of Participants With Abnormal Physical Examination Findings at End of Intravenous Therapy (EOIV) Visit EOIV visit (anytime from Day 4 up to 16) Physical examination included an assessment of the following: general appearance, skin, head and neck (including ears, eyes, nose and throat), lymph nodes, thyroid, respiratory system, cardiovascular system, abdomen, musculoskeletal system (including spine and extremities), and neurological system. Participants with new or aggravated abnormal physical examination findings with regard to baseline findings were reported. Abnormality in physical examinations were based on blinded observer's discretion. EOIV visit occurred within 24 hours after completion of last infusion of the study drug.
Percentage of Participants With Potentially Clinically Significant Abnormalities in Laboratory Parameters Baseline until the LFU visit (up to a maximum study duration of 50 days) Criteria for potentially clinically significant laboratory abnormalities: Chemistry (calcium: \<0.7\*lower limit of normal range \[LLN\] and \>30 percent decrease from baseline \[DFB\]; alanine aminotransferase \[ALT\]: \>3\*upper limit of normal range \[ULN\] and \>300 percent IFB; alanine aminotransferase \[AST\]: \>3\*ULN and \>300 percent IFB) and hematology (platelets: \>2\*ULN and \>100 percent IFB). LFU visit occurred within 20 to 35 days after last dose of study treatment (IV or oral).
Percentage of Participants With Electrocardiogram (ECG) Parameter QTcF: > 450, >480 and >500 Millisecond (ms) Baseline until the EOIV visit (anytime from Day 4 to 16) ECG parameters included maximum QT intervals using Fridericia's correction (QTcF). Maximum QTcF \>450 millisecond (ms); maximum QTcF \>480 ms; and maximum QTcF \>500 ms. EOIV visit occurred within 24 hours after completion of last infusion of the study drug.
Change From Baseline in Body Temperature at End of Intravenous Therapy (EOIV) Visit Baseline, EOIV visit (anytime from Day 4 up to 16) EOIV visit occurred within 24 hours after completion of last infusion of the study drug.
Percentage of Participants With Creatinine Clearance (CrCl) at Test of Cure (TOC) Visit TOC visit (up to a maximum study duration of 50 days) CrCl is a measure of GMFR, an index of kidney function. It is the volume of blood plasma that is cleared of creatinine by the kidneys per unit time. Percentage of participants with CrCl in the following categories were reported: \<30 mL/min/1.73 m\^2, \>=30 to \<50 mL/min/1.73 m\^2, \>=50 mL/min/1.73 m\^2 to \<80 mL/min/1.73 m\^2, and \>=80 mL/min/1.73 m\^2. TOC visit occurred within 8 to 15 days after last dose of any study drug (IV or oral).
Percentage of Participants With Treatment-Emergent Adverse Events (AEs) and Serious Adverse Events (SAEs) Baseline until the LFU visit (up to a maximum study duration of 50 days) An AE was any untoward medical occurrence in a participant who received study drug without regard to possibility of causal relationship. An SAE was an AE resulting in any of the following outcomes or deemed significant for any other reason: death; initial or prolonged in-patient hospitalization; life-threatening experience (immediate risk of dying); persistent or significant disability/incapacity; congenital anomaly. Treatment-emergent AEs were events between first dose of study drug and up to late follow-up (LFU) visit (20 to 35 days after last dose of study treatment \[IV or oral\]) that were absent before treatment or that worsened relative to pretreatment state. AEs included both SAE and non-SAE.
Change From Baseline in Pulse Rate at End of Intravenous Therapy (EOIV) Visit Baseline, EOIV visit (anytime from Day 4 up to 16) EOIV visit occurred within 24 hours after completion of last infusion of the study drug.
Change From Baseline in Systolic Blood Pressure (SBP) and Diastolic Blood Pressure (DBP) at End of Intravenous Therapy (EOIV) Visit Baseline, EOIV visit (anytime from Day 4 up to 16) EOIV visit occurred within 24 hours after completion of last infusion of the study drug.
Percentage of Participants With Creatinine Clearance (CrCl) at Late Follow-up (LFU) Visit LFU visit (up to a maximum study duration of 50 days) CrCl is a measure of GMFR, an index of kidney function. It is the volume of blood plasma that is cleared of creatinine by the kidneys per unit time. Percentage of participants with CrCl in the following categories were reported: \<30 mL/min/1.73 m\^2, \>=30 to \<50 mL/min/1.73 m\^2, \>=50 mL/min/1.73 m\^2 to \<80 mL/min/1.73 m\^2, and \>=80 mL/min/1.73 m\^2. LFU visit occurred within 20 to 35 days after last dose of study treatment (IV or oral).
Percentage of Participants With Creatinine Clearance (CrCl) at Day 7 Day 7 CrCl is a measure of glomerular filtration rate (GMFR), an index of kidney function. It is the volume of blood plasma that is cleared of creatinine by the kidneys per unit time. Percentage of participants with CrCl in the following categories were reported: \<30 mL/min/1.73 m\^2, \>=30 to \<50 mL/min/1.73 m\^2, \>=50 mL/min/1.73 m\^2 to \<80 mL/min/1.73 m\^2, and \>=80 mL/min/1.73 m\^2.
Percentage of Participants With Creatinine Clearance (CrCl) at End of Intravenous Therapy (EOIV) Visit EOIV visit (anytime from Day 4 up to 16) CrCl is a measure of GMFR, an index of kidney function. It is the volume of blood plasma that is cleared of creatinine by the kidneys per unit time. Percentage of participants with CrCl in the following categories were reported: \<30 mL/min/1.73 m\^2, \>=30 to \<50 mL/min/1.73 m\^2, \>=50 mL/min/1.73 m\^2 to \<80 mL/min/1.73 m\^2, and \>=80 mL/min/1.73 m\^2. EOIV visit occurred within 24 hours after completion of last infusion of the study drug.
- Secondary Outcome Measures
Name Time Method Plasma Concentrations of Ceftazidime and Avibactam 15, 30-90, 300-360 minutes post-dose on Day 3 Percentage of Participants With Favorable Clinical Response (CR) at End of 72 Hours Treatment: Intent-to-treat (ITT) Analysis Population End of 72 hours study drug treatment on Day 1 Favorable CR was defined as resolution of all acute signs and symptoms of complicated intra- abdominal infection (cIAIs), or improvement to such an extent that no further antimicrobial therapy was required, or improvement but not enough to switch to oral therapy and still on IV study drug at end of 72 hours and had met following criterion: absence of new signs and symptoms, improvement in at least 1 symptom/sign (fever, pain, tenderness, elevated White Blood Cells \[WBCs\], elevated c-reactive protein) from baseline and no worsening symptom/sign.
Percentage of Participants With Favorable Clinical Response (CR) at End of Intravenous Therapy (EOIV) Visit: Intent-to-treat (ITT) Analysis Population EOIV visit (anytime from Day 4 up to 16) Favorable CR was resolution of all acute signs and symptoms of cIAI or improvement to such an extent that no further antimicrobial therapy was required, or improvement in participants who had switch to oral therapy and met the following criterion: afebrile (temperature \<=38.0°C) for at least 24 hours, absence of new and improvement in at least 1 symptom or sign (fever, pain, tenderness, elevated WBCs, elevated c-reative-protein) from baseline and worsening of none. EOIV visit occurred within 24 hours after completion of last infusion of the study drug.
Percentage of Participants With Favorable Clinical Response (CR) at End of Treatment (EOT) Visit: Intent-to-treat (ITT) Analysis Population EOT visit (up to Day 17) Favorable CR was resolution of all acute signs and symptoms of cIAI, or improvement to such an extent that no further antimicrobial therapy was required. EOT visit occurred within 48 hours after completion of the last dose of oral switch therapy or at time of premature discontinuation/early withdrawal from study (if on oral switch therapy).
Percentage of Participants With Favorable Clinical Response (CR) at Test of Cure (TOC) Visit: Intent-to-treat (ITT) Analysis Population TOC visit (up to a maximum study duration of 50 days) Favorable CR was resolution of all acute signs and symptoms of cIAI, or improvement to such an extent that no further antimicrobial therapy was required. TOC visit occurred within 8 to 15 days after last dose of any study drug (IV or oral).
Percentage of Participants With Favorable Clinical Response (CR): Clinically Evaluable (CE) Analysis Population End of 72 hours study drug treatment on Day 1, EOIV (anytime from Day 4 up to 16), EOT visit (up to Day 17) and TOC visit (up to a maximum study duration of 50 days) Favorable CR was resolution of all acute signs and symptoms of cIAI, or improvement to such an extent that no further antimicrobial therapy was required, or improvement in participants who had switch to oral therapy and met the following criterion: afebrile (temperature \<=38.0°C) for at least 24 hours, absence of new and improvement in at least 1 symptom or sign (fever, pain, tenderness, elevated WBCs, elevated c-reative-protein) from baseline and worsening of none. EOIV visit occurred within 24 hours after completion of last infusion of the study drug. EOT visit occurred within 48 hours after completion of last dose of oral switch therapy or at time of premature discontinuation/early withdrawal from study (if on oral switch therapy). TOC visit occurred within 8 to 15 days after last dose of any study drug (IV or oral).
Percentage of Participants With Favorable Microbiological Response: Microbiological Intent-to-treat (Micro-ITT) Population EOIV visit (Day 4 up to 16), EOT visit (up to Day 17), TOC visit (up to a maximum study duration of 50 days) and LFU visit (up to a maximum study duration of 50 days) Favorable microbiological response was achieved when all baseline pathogens were eradicated or presumed eradicated based on investigator's discretion. EOIV visit occurred within 24 hours after completion of last infusion of the study drug. EOT visit occurred within 48 hours after completion of last dose of oral switch therapy or at time of premature discontinuation/early withdrawal from study if on oral switch therapy (which occurred within the maximum study treatment duration of 15 days). EOIV visit occurred within 24 hours after completion of last infusion of the study drug. TOC visit occurred within 8 to 15 days after last dose of any study drug (IV or oral). LFU visit occurred within 20 to 35 days after last dose of study treatment (IV or oral).
Percentage of Participants With Favorable Microbiological Response: Microbiologically Evaluable (ME) Population EOIV visit (Day 4 up to 16), EOT visit (up to Day 17), TOC visit (up to a maximum study duration of 50 days) and LFU visit (up to a maximum study duration of 50 days) Favorable microbiological response was achieved when all baseline pathogens were eradicated or presumed eradicated based on investigator's discretion. EOIV visit occurred within 24 hours after completion of last infusion of the study drug. EOT visit occurred within 48 hours after completion of last dose of oral switch therapy or at time of premature discontinuation/early withdrawal from study if on oral switch therapy (which occurred within the maximum study treatment duration of 15 days). TOC visit occurred within 8 to 15 days after last dose of any study drug (IV or oral). LFU visit occurred within 20 to 35 days after last dose of study treatment (IV or oral).
Percentage of Participants With Clinical Relapse at Late Follow-up (LFU) Visit: Clinically Evaluable (CE) Population LFU visit (up to a maximum study duration of 50 days) A participant was said to have clinical relapse if met either 1 of the following criteria: reappearance or worsening of signs and symptoms of cIAI that required further antimicrobial therapy and/or surgery, or death after TOC in which cIAI was contributory. LFU visit occurred within 20 to 35 days after last dose of study treatment (IV or oral).
Percentage of Participants With Clinical Relapse at Late Follow-up (LFU) Visit: Microbiologically Evaluable (ME) Population LFU visit (up to a maximum study duration of 50 days) A participant was said to have clinical relapse if me either 1 of the following criteria: reappearance or worsening of signs and symptoms of cIAI that required further antimicrobial therapy and/or surgery, or death after TOC in which cIAI was contributory. LFU visit occurred within 20 to 35 days after last dose of study treatment (IV or oral).
Percentage of Participants With Emergent Infections: Microbiological Intent-to-treat (Micro-ITT) Population Baseline up to 50 days Emergent infections were categorized as super infections and new infections. Superinfection: An intra-abdominal culture identified pathogen other than a baseline pathogen during the course of active treatment with study therapy along with worsening signs and symptoms of infection requiring alternative antimicrobial therapy. New infection: An intra-abdominal culture identified pathogen other than a baseline pathogen at any time after study treatment had finished along with worsening signs and symptoms of infection requiring alternative antimicrobial therapy. Participants with any (super infections or new infections) of the infections were reported.
Percentage of Participants With Emergent Infections at Test of Cure (TOC) Visit: Microbiologically Evaluable Population TOC visit (up to a maximum study duration of 50 days) Emergent Infections was an intra-abdominal culture identified pathogen other than a baseline pathogen during the course of active treatment with study therapy along with worsening signs and symptoms of infection requiring alternative antimicrobial therapy, new infection was an intra-abdominal culture identified pathogen other than a baseline pathogen at any time after study treatment has finished along with worsening signs and symptoms of infection requiring alternative antimicrobial therapy. TOC visit occurred within 8 to 15 days after last dose of any study drug (IV or oral). Participants with any (super infections or new infections) of the infections were reported.
Trial Locations
- Locations (35)
CHOC Children's
🇺🇸Orange, California, United States
Oblastni Nemocnice Kolin, a.s., Nemocnice Stredoceskeho Kraje, Detske oddeleni
🇨🇿Kolin III, Czechia
Rady Children's Hospital San Diego
🇺🇸San Diego, California, United States
Spitalul Clinic de Urgenta pentru Copii "Sf. Maria" Iasi, Sectia Chirurgie Pediatrica II
🇷🇴Iasi, Romania
Hospital Universitario Germans Trias i Pujol
🇪🇸Badalona, Barcelona, Spain
Hospital Clinico San Carlos
🇪🇸Madrid, Spain
Lekarna Oblastni Nemocnice Kolin, a.s.
🇨🇿Kolin III, Czechia
Krajska zdravotni, a.s. - Nemocnice Most, o.z., Detske a dorostove oddeleni
🇨🇿Most, Czechia
State Budgetary Educational Institution of Higher Professional Education
🇷🇺Smolensk, Smolensk Region, Russian Federation
Hospital Universitario Fundacion Jimenez Diaz
🇪🇸Madrid, Spain
The Children's Hospital at Saint Francis
🇺🇸Tulsa, Oklahoma, United States
Department of Pediatrics, Mackay Memorial Hospital
🇨🇳Taipei, Taiwan
Celal Bayar Universitesi Hafsa Sultan Hastanesi
🇹🇷Manisa, Turkey
Semmelweis Egyetem, II. sz. Gyermekgyogyaszati Klinika
🇭🇺Budapest, Hungary
Eskisehir Osmangazi Universitesi Saglik Uygulama ve Arastirma Hastanesi
🇹🇷Eskisehir, Turkey
Lekarna Nemocnice Most, o.z.
🇨🇿Most, Czechia
Hospital de Sant Joan de Deu
🇪🇸Esplugues de LLobregat, Barcelona, Spain
ProMedica Toledo Children's Hospital
🇺🇸Toledo, Ohio, United States
Lekarna Fakultni Nemocnice Ostrava
🇨🇿Ostrava - Poruba, Czechia
Fakultni Nemocnice Ostrava - Klinika Detskeho Lekarstvi
🇨🇿Ostrava - Poruba, Czechia
Thomayerova Nemocnice, Klinika detske chirurgie a traumatologie 3.LF UK a TN
🇨🇿Praha 4 - Krc, Czechia
Nemocnice Strakonice, a.s. - Detske oddeleni
🇨🇿Strakonice, Czechia
Lekarna Nemocnice Strakonice
🇨🇿Strakonice, Czechia
Lekarna Thomayerovy Nemocnice
🇨🇿Praha 4 - Krc, Czechia
Pecsi Tudomanyegyetem, AOK, Klinikai Kozpont, Gyermekgyogyaszati Klinika
🇭🇺Pecs, Hungary
General Children's Hospital of Athens "P. & A.Kyriakou"
🇬🇷Athens, Attica, Greece
Tolna Megyei Balassa Janos Korhaz, Gyermekgyogyaszati Osztaly
🇭🇺Szekszard, Hungary
General Hospital of Thessaloniki "Hippokratio"
🇬🇷Thessaloniki, Macedonia, Greece
Kanizsai Dorottya Korhaz, Csecsemo es Gyermekgyogyaszati Osztaly
🇭🇺Nagykanizsa, Hungary
Uniwersytecki Szpital Dzieciecy w Lublinie
🇵🇱Lublin, Poland
Szegedi Tudomanyegyetem, Szent-Gyorgyi Albert Klinikai Kozpont
🇭🇺Szeged, Hungary
Hospital Universitario y Politecnico la Fe
🇪🇸Valencia, Spain
Cukurova Universitesi Tip Fakultesi Balcali Hastanesi
🇹🇷Adana, Turkey
Kaohsiung Veterans General Hospital
🇨🇳Kaohsiung, Taiwan
Taichung Veterans General Hospital
🇨🇳Taichung, Taiwan