title: Kidney failure related to broad-spectrum antibiotics in critically ill patients: secondary end point results from a 1200 patient randomised trial.
abstract: OBJECTIVE
  To explore whether a strategy of more intensive antibiotic therapy leads to emergence or prolongation of renal failure in intensive care patients.
  
  
  METHODS
  Secondary analysis from a randomised antibiotic strategy trial (the Procalcitonin And Survival Study). The randomised arms were conserved from the primary trial for the main analysis.
  
  
  METHODS
  Nine mixed surgical/medical intensive care units across Denmark.
  
  
  METHODS
  1200 adult intensive care patients, 18+ years, expected to stay +24 h.
  
  
  METHODS
  bilirubin >40 mg/dl, triglycerides >1000 mg/dl, increased risk from blood sampling, pregnant/breast feeding and psychiatric patients.
  
  
  METHODS
  Patients were randomised to guideline-based therapy ('standard-exposure' arm) or to guideline-based therapy supplemented with antibiotic escalation whenever procalcitonin increased on daily measurements ('high-exposure' arm).
  
  
  METHODS
  Primary end point: estimated glomerular filtration rate (eGFR) <60 ml/min/1.73 m(2). Secondary end points: (1) delta eGFR after starting/stopping a drug and (2) RIFLE criterion Risk 'R', Injury 'I' and Failure 'F'. Analysis was by intention to treat.
  
  
  RESULTS
  28-day mortality was 31.8% and comparable (Jensen et al, Crit Care Med 2011). A total of 3672/7634 (48.1%) study days during follow-up in the high-exposure versus 3016/6949 (43.4%) in the 'standard-exposure arm were spent with eGFR <60 ml/min/1.73 m(2), p<0.001. In a multiple effects model, 3 piperacillin/tazobactam was identified as causing the lowest rate of renal recovery of all antibiotics used: 1.0 ml/min/1.73 m(2)/24 h while exposed to this drug (95% CI 0.7 to 1.3 ml/min/1.73 m(2)/24 h) vs meropenem: 2.9 ml/min/1.73 m(2)/24 h (2.5 to 3.3 ml/min/1.73 m(2)/24 h)); after discontinuing piperacillin/tazobactam, the renal recovery rate increased: 2.7 ml/min/1.73 m(2)/24 h (2.3 to 3.1 ml/min/1.73 m(2) /24 h)). eGFR <60 ml/min/1.73 m(2) in the two groups at entry and at last day of follow-up was 57% versus 55% and 41% versus 39%, respectively.
  
  
  CONCLUSIONS
  Piperacillin/tazobactam was identified as a cause of delayed renal recovery in critically ill patients. This nephrotoxicity was not observed when using other beta-lactam antibiotics.
  
  
  BACKGROUND
  ClinicalTrials.gov identifier: NCT00271752.
authors.affiliation: Copenhagen HIV Programme, University of Copenhagen, Copenhagen, Denmark.
authors.forename: Jens-Ulrik Stæhr
authors.initials: JU
authors.lastname: Jensen
authors.forename: Lars
authors.initials: L
authors.lastname: Hein
authors.forename: Bettina
authors.initials: B
authors.lastname: Lundgren
authors.forename: Morten Heiberg
authors.initials: MH
authors.lastname: Bestle
authors.forename: Thomas
authors.initials: T
authors.lastname: Mohr
authors.forename: Mads Holmen
authors.initials: MH
authors.lastname: Andersen
authors.forename: Klaus Julius
authors.initials: KJ
authors.lastname: Thornberg
authors.forename: Jesper
authors.initials: J
authors.lastname: Løken
authors.forename: Morten
authors.initials: M
authors.lastname: Steensen
authors.forename: Zoë
authors.initials: Z
authors.lastname: Fox
authors.forename: Hamid
authors.initials: H
authors.lastname: Tousi
authors.forename: Peter
authors.initials: P
authors.lastname: Søe-Jensen
authors.forename: Anne Øberg
authors.initials: AØ
authors.lastname: Lauritsen
authors.forename: Ditte Gry
authors.initials: DG
authors.lastname: Strange
authors.forename: Nanna
authors.initials: N
authors.lastname: Reiter
authors.forename: Katrin
authors.initials: K
authors.lastname: Thormar
authors.forename: Paul Christian
authors.initials: PC
authors.lastname: Fjeldborg
authors.forename: Kim Michael
authors.initials: KM
authors.lastname: Larsen
authors.forename: Niels-Erik
authors.initials: NE
authors.lastname: Drenck
authors.forename: Maria Egede
authors.initials: ME
authors.lastname: Johansen
authors.forename: Lene Ryom
authors.initials: LR
authors.lastname: Nielsen
authors.forename: Christian
authors.initials: C
authors.lastname: Ostergaard
authors.forename: Jesper
authors.initials: J
authors.lastname: Kjær
authors.forename: Jesper
authors.initials: J
authors.lastname: Grarup
authors.forename: Jens D
authors.initials: JD
authors.lastname: Lundgren