Continuous Infusion Piperacillin-tazobactam for the Treatment of Cystic Fibrosis (PIPE-CF)

• Change in FEV1 [ Time Frame: Baseline, Day 0, and Day 14 ] [ Designated as safety issue: No ]
  FEV1 will be measured upon enrollment (day 0). FEV1 will also be measured at end of therapy (day 14). If FEV1 is available when patient was stable, prior to enrollment, this value will be treated as baseline FEV1. Change in FEV1 will be calculated from baseline (if available) to day 14 and also Day 0 to day 14
  
  

• Piperacillin serum concentrations [ Time Frame: Day 3 ] [ Designated as safety issue: Yes ]

  Serum piperacillin concentration will be measured as follows:

  • Intermittent infusion arm: prior to dose (trough), 30 minutes (after completion of infusion), and at 4 hours
  • Continuous infusion arm: collected at the same time as in the intermittent infusion arm
  
  
• Time to next pulmonary exacerbation [ Time Frame: Patients will be followed up to 52 weeks from time of enrollement ] [ Designated as safety issue: Yes ]
  Patients will be followed for time of next subsequent pulmonary exacerbation for up to 52 weeks after completion of receiving study drug. Next pulmonary exacerbation is defined as requiring admission to a hospital for receipt of I.V. antibiotics because of a diagnosis of pulmonary exacerbation.
  
  
• Change in Cystic Fibrosis Questionnaire-Revised (CFQ-R) Score [ Time Frame: Day 0 and day 14 ] [ Designated as safety issue: No ]
  The validated CFQ-R will be administered to patients at time of enrollment at end of therapy
  
  
• Change in sputum density of Pseudomonas aeruginosa [ Time Frame: Day 0, day 3, and day 14 ] [ Designated as safety issue: No ]
  Sputum density of Pseudomonas aeruginosa will be determined at enrollment, day 3, and at end of therapy
  
  
• Change in weight [ Time Frame: Day 0 and day 14 ] [ Designated as safety issue: No ]
  The change in weight will be documented from enrollment to end of therapy
  
  
• Time to defervescence [ Time Frame: Day 0 to day 14 ] [ Designated as safety issue: No ]
  Temperature will be taken multiple times daily according to standard of care. If patients present febrile, time until patient is afebrile and remains afebrile for 24 hours will be recorded.
  
  
• Time to normalization of white blood cell count [ Time Frame: Day to day 14 ] [ Designated as safety issue: No ]
  White blood cell (WBC) count will be measured once daily. If patient presents with WBC count greater than 11.0 x 10^3/mL, time until patient has WBC less than 11.0 x 10^3/mL will be recorded.
  
  
• Clinical failure of treatment [ Time Frame: Day 14 ] [ Designated as safety issue: No ]
  Failure of treatment will be defined as patient needing I.V. antibiotics beyond the 14 days allowed in this study. The primary medical team (along with a blinded investigator) treating the patient will determine whether patient requires additional therapy.
  
  

All patients will receive combination therapy to include piperacillin-tazobactam 400 mg/kg/day (based on piperacillin component, actual body weight) not to exceed 16 grams and tobramycin 12 mg/kg/day extended interval dosing (once daily). Patients randomized to the continuous infusion group will receive a one-time loading dose of 100 mg/kg over 30 minutes followed immediately by initiation of the continuous infusion.

Other antibiotics with activity against Pseudomonas aeruginosa are not allowed. Patients may receive an antibiotic for treatment of Staphylococcus aureus if deemed appropriate.

Other treatments for pulmonary exacerbation of cystic fibrosis will be left up to the control of the treating physician. Patients will receive a total of 14 days of therapy. If deemed appropriate, patients may be discharged to home where they will continue to receive blinded treatment via an infusion pump. Patients will be evaluated after completing their 14 day course of antibiotics (end of therapy).