Population Pharmacokinetic (PK) Study of Zinforo (Ceftaroline) in Critical Care Patients With Early-onset Pneumonia and Normal or Augmented Renal Clearance
Condition: Pneumonia
MeSH terms: Pneumonia
Study type: Interventional
Phase: Phase 1

Summary: 
      Pneumonia is the most frequent infection in critically ill patients and remains a significant
      challenge to intensivists world-wide due to persisting high mortality and morbidity.
      Compelling evidence suggests that appropriate antibiotic therapy remains the most important
      intervention to improve patients' outcome, including the administration of a suitable
      molecule at an optimized dosage regimen. A vast array of pathophysiological changes can occur
      in critically ill patients that can complicate antibiotic dosing. Knowledge of the
      pharmacokinetic and pharmacodynamic properties of the antibiotics used for the management of
      critically ill patients is essential for selecting the antibiotic dosing regimens, which will
      optimize patient outcomes. Changes in volume of distribution (Vd) and clearance (CL) of
      antibiotics have been noted in these patients, which may affect the antibiotic concentration
      at the target site. It follows that the pharmacodynamic parameters that determine antibiotic
      efficacy, which can vary between antibiotic classes, may also be affected. Optimization of
      these parameters is necessary to maximize the rate of response through patient recovery and
      minimized antibiotic resistance.

      In a multicenter observational study in critically ill patients with normal plasma renal
      indices at admission, about 65% of patients manifested augmented creatinine clearance on at
      least one occasion in the first seven study days. Augmented creatinine clearance may
      significantly impact drug pharmacokinetics for a variety of renally eliminated
      pharmaceuticals (such as low-molecular weight heparins, aminoglycosides, glycopeptides, and
      β-lactams), leading to subtherapeutic concentrations and potentially adverse clinical
      outcomes. Currently little data exist that describe the consequences of augmented creatinine
      clearance on antibiotics PK.

      Ceftaroline (600 mg bid) is a cephalosporin with expanded gram-positive activity, including
      MRSA and penicillin-resistant streptococcus, which was approved by the US Food and Drug
      Administration (FDA) on October 29, 2010 for the treatment of acute bacterial SSSIs and
      community-acquired bacterial pneumonia. Ceftaroline showed also good activity against some of
      the common gram-negative respiratory pathogens (eg, Haemophilus influenzae, Moraxella
      catarrhalis, Neisseria meningitidis, and Pasteurella multocida). However, it does not display
      clinically relevant activity against Pseudomonas aeruginosa, Stenotrophomonas maltophilia, or
      Acinetobacter baumannii. Ceftaroline also lacks activity against gram-negative organisms with
      extended-spectrum β-lactamases. Importantly, because ceftaroline appears to induce AmpC
      β-lactamases despite MIC values in susceptible range, ittheoretically should be avoided in
      gram-negative bacteria known to harbor inducible AmpC β-lactamases (eg, Serratia, Proteus,
      Citrobacter, Morganella, Enterobacter, Providencia, and P. aeruginosa). In patients,
      ceftaroline is given as a prodrug, ceftaroline fosamil. After intravenous administration, the
      prodrug is rapidly transformed by plasma phosphatase enzymes to its bioactive metabolite. The
      pharmacokinetics of ceftaroline has been evaluated in single and multiple dose studies in
      healthy volunteers, in subjects with various degrees of renal impairment and in healthy
      elderly subjects. The volume of distribution is equal to 20.3 L, which corresponds to
      extracellular fluid volume. The protein binding is low (20%). The main route of elimination
      is via renal excretion, with a clearance estimated to160 mL/min close to the creatinine
      clearance. The elimination half-live is 2.6 h in adults with normal renal function.
      Unfortunately, no PK study has been performed in infected critically ill patients with
      augmented creatinine clearance. The best PK-PD index predicting drug efficacy is %Time>CMI. A
      bacteriostatic effect is achieved when free drug concentrations exceed the MIC for 30 to 40%
      of the dose administration interval (30 to 40%T>MIC). Near maximum organism kill is achieved
      at 50 to 60%T>MIC (30%T>MIC for Staphylococcus aureus).

      This project aims to characterize ceftaroline PK in patients with early-onset pneumonia and
      augmented creatinine clearance. The choice of ceftaroline is justified by its spectrum
      suitable for micro-organisms commonly encountered in early onset pneumonia, including
      methicillin-resistant Staphylococcus aureus. Secondary main objective is to predict the
      probably of reaching PK-PD targets using Monte Carlo simulations under various scenario in
      order to identify optimal ceftaroline administration schemes in critical care patients with
      various degrees of renal impairment.
    


Intervention name(s): Ceftaroline
Intervention type(s): Drug
Intervention MeSH terms: Ceftaroline fosamil
Intervention model: Single Group Assignment
Masking: None (Open Label)
Primary purpose: Treatment