Single-dose PK Study of Ceftazidime-Avibactam In Hospitalized Children Receiving Systemic Antibiotics for Nosocomial Pneumonia
Condition: Hospitalized Children With Suspected or Confirmed Nosocomial Pneumonia
MeSH terms: Pneumonia; Healthcare-Associated Pneumonia
Intervention: Ceftazidime-avibactam
Intervention description: Single intravenous infusion of ceftazidime-avibactam over 2 hours. Dosage will vary depending upon age, weight and renal function.
Intervention MeSH terms: Ceftazidime; Avibactam; Avibactam, ceftazidime drug combination
Phase: Phase 1
Study type: Interventional
Primary purpose: Basic Science
Intervention model: Single Group Assignment
Intervention model description: Non-randomized, single arm
Masking: None (Open Label)
Enrollment: 4.0
Sex: All
Minimum age: 3 Months
Maximum age: 17 Years
Healthy volunteers: No
Keywords: nosocomial pneumonia, NP

Summary:

      This is a multicenter, multinational, open label single dose pharmacokinetic (PK) study
      enrolling at least 32 subjects. The study aims to characterize the pharmacokinetics (PK) of a
      single intravenous dose of CAZ AVI in pediatric subjects aged 3 months to less than 18 years
      who are receiving systemic antibiotic therapy for suspected or confirmed nosocomial
      pneumonia, including ventilator associated pneumonia.
    

Eligibility criteria:

        Inclusion Criteria:

        Subjects must meet all of the following inclusion criteria to be eligible for enrollment
        into the study:

          1. Evidence of a personally signed and dated informed consent document indicating that
             the subject's parent(s), legal guardian, or legally acceptable representative has been
             informed of all pertinent aspects of the study. As appropriate per local requirements
             informed assent of subjects must also be documented.

          2. Willing and able to comply with scheduled visits, treatment plan, laboratory tests,
             and other study procedures.

          3. Male or female children age ≥3 months to <18 years at Screening:

               1. Cohort 1: age 12 years to <18 years;

               2. Cohort 2: age 6 years to <12 years;

               3. Cohort 3: age 2 years to <6 years;

               4. Cohort 4: age 3 months to <2 years (must be born ≥37 weeks gestational age).

          4. Hospitalized, receiving systemic antibiotic therapy for the treatment of a suspected
             or confirmed HAP or VAP meeting the following criteria, and expected to require
             hospitalization until after the follow up evaluations are completed on Day 3 (48 hours
             after the end of infusion):

               1. Onset of symptoms ≥48 hours after admission or <7 days after discharge from an
                  inpatient acute or chronic care facility;

               2. New or worsening infiltrate on chest X ray;

               3. At least 1 of the following systemic signs prior to the initiation of treatment
                  for Nosocomial Pneumonia:

             i. Fever (temperature >38°C) or hypothermia (rectal/core temperature <35°C); ii. White
             blood cell (WBC) count >10,000 cells/mm3, or WBC count <4,500 cells/mm3, or >15% band
             forms.

             d. At least 2 of the following respiratory signs or symptoms: i. A new onset of cough
             (or worsening of cough). ii. Production of purulent sputum or endotracheal secretions.
             iii. Auscultatory findings consistent with pneumonia/pulmonary consolidation (eg,
             rales, rhonchi, bronchial breath sounds, dullness to percussion, egophony).

             iv. Dyspnea, tachypnea or hypoxemia (O2 saturation <90% or PaO2 <60 mmHg while
             breathing room air).

             v. A need for mechanical ventilation or, for already ventilated subjects, acute
             changes made in the ventilator support system to enhance oxygenation, as determined
             by, for example arterial blood gas or worsening PaO2/FiO2.

          5. Likely to survive the current illness or hospitalization.

          6. Sufficient IV access (peripheral or central) to receive study drug and dedicated
             access for PK sampling.

        Exclusion Criteria:

        Subjects with any of the following characteristics/conditions will not be included in the
        study:

          1. Investigator site staff members directly involved in the conduct of the study and
             their family members, site staff members otherwise supervised by the Investigator, or
             subjects who are Pfizer employees, including their family members, directly involved
             in the conduct of the study.

          2. Participation in other studies involving investigational drug(s) within 30 days prior
             to study entry and/or during study participation.

          3. Other acute or chronic medical or psychiatric condition including recent (within the
             past year) or active suicidal ideation or behavior or laboratory abnormality that may
             increase the risk associated with study participation or investigational product
             administration or may interfere with the interpretation of study results and, in the
             judgment of the Investigator, would make the subject inappropriate for entry into this
             study.

          4. Past or current history of epilepsy or seizure disorder (excluding childhood febrile
             seizures.

          5. Severe renal impairment defined as creatinine clearance (CrCL) ≤30 mL/min/1.73 m2
             calculated using the child's measured height (length) and serum creatinine with the
             Bedside Schwartz equation (Schwartz, Munoz, et al., 2009):3 CrCL (mL/min/1.73 m2) =

          6. Documented history of any hypersensitivity or allergic reaction to any β lactam
             antibiotic.

          7. Pregnant female subjects; breastfeeding female subjects; fertile male subjects and
             female subjects of childbearing potential who are unwilling or unable to use a highly
             effective method of contraception as outlined in this protocol for the duration of the
             study and for at least 28 days after the last dose of CAZ AVI.

          8. Acute hepatitis in the prior 6 months, a prior history of cirrhosis, acute hepatic
             failure, or acute decompensation of chronic hepatic failure; and/or any of the
             following blood test results, for any individual, when assessed for eligibility:

               1. Bilirubin >3 × upper limit of normal (ULN), unless isolated hyperbilirubinemia is
                  directly related to the acute infection or due to known Gilbert's disease;

               2. ALT or AST >3 × ULN values used by the laboratory performing the test. Subjects
                  with values >3 × ULN and <5 × ULN are eligible if this value is acute and
                  directly related to the infectious process being treated. This must be
                  documented;

               3. ALP >3 × ULN. Subjects with values >3 × ULN and <5 × ULN are eligible if this
                  value is acute and directly related to the infectious process being treated. This
                  must be documented.

          9. Any condition (eg, septic shock, burns, cystic fibrosis, acute hemodynamic
             instability, including those conditions not responding to pressor support) that would
             make the patient, in the opinion of the Investigator, unsuitable for the study (eg,
             would place a patient at risk; compromise the quality of the data; or interfere with
             the absorption, distribution, metabolism, or excretion of CAZ AVI).

         10. Receipt of a blood or blood component or scheduled for transfusion within the PK
             sampling period (eg, red blood cells, fresh frozen plasma, platelets) transfusion
             during the 24 hour period before enrollment.

         11. Body mass index (BMI) below the 5th percentile or above the 95th percentile for
             height, age, and weight except for children <2 years of age as BMI is not considered a
             screening tool for healthy weight in children under 2 years of age.

         12. Treatment with ceftazidime within 12 hours of CAZ AVI administration or treatment with
             ceftazidime within 24 hours of CAZ AVI administration in subjects with renal
             impairment (CrCL ≤50 mL/min/1.73 m2).

         13. Treatment with potent inhibitors of OAT1 and/or OAT3 (eg, probenecid, p aminohippuric
             acid (PAH), or teriflunomide).