Population Pharmacokinetic (PK) Study of Zinforo (Ceftaroline) in Critical Care Patients With Early-onset Pneumonia and Normal or Augmented Renal Clearance
Population Pharmacokinetic (PK) Study of Zinforo (Ceftaroline) in Critical Care Patients With Early-onset Pneumonia and Normal or Augmented Renal Clearance
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.
Inclusion Criteria:

 -  Hospitalized in ICU

 -  Under mechanical ventilation

 -  Developing early-onset (during the seven days following hospital admission) pneumonia
 caused by Gram positive and/or Gram negative bacteria.

 -  Having an augmented or normal renal clearance defined by a directly measured
 creatinine clearance, using MD-RD:

 -  normal clearance: between 80 and 130 mL/min/1.73m²

 -  augmented clearance: more than or equal to 130 mL/min/1.73m²

 Exclusion Criteria:

 -  Having one or more risk factors of multi drug resistant bacteria:

 -  antibiotic treatment in last 3 months

 -  high level resistance in the unit

 -  immunosuppression

 -  one or more pneumonia risks factors, whose one hospitalization of more than 48
 hours in past 90 days,

 -  living in medical care house,

 -  chronic hemodialysis,

 -  home based wound care

 -  resistant bacteria in the family environment

 -  Morbidly obese subjects (BMI>40 kg/m²)

 -  Septic shock

 -  Ceftaroline administered in past 14 days before inclusion

 -  Diuretic treatment

 -  Suspicion or confirmation pneumonia ceftaroline-resistant bacteria

 -  Known hypersensitivity due to Ceftaroline or cephalosporin antibiotics

 -  Known hypersensitivity due to Gentamicin or aminoglycosides antibiotics

 -  Hypersensitivity due beta lactamin antibiotics

 -  Anemia