• Jens-Ulrik Stæhr Jensen, Lars Hein, Bettina Lundgren, Morten Heiberg Bestle, Thomas Mohr, Mads Holmen Andersen, Klaus Julius Thornberg, Jesper Løken, Morten Steensen, Zoë Fox, Hamid Tousi, Peter Søe-Jensen, Anne Øberg Lauritsen, Ditte Gry Strange, Nanna Reiter, Katrin Thormar, Paul Christian Fjeldborg, Kim Michael Larsen, Niels-Erik Drenck, Maria Egede Johansen, Lene Ryom Nielsen, Christian Ostergaard, Jesper Kjær, Jesper Grarup, Jens D Lundgren, and Procalcitonin And Survival Study (PASS) Group.
• Copenhagen HIV Programme, University of Copenhagen, Copenhagen, Denmark.
• BMJ Open. 2012 Jan 1;2(2):e000635.

ObjectivesTo explore whether a strategy of more intensive antibiotic therapy leads to emergence or prolongation of renal failure in intensive care patients.DesignSecondary 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.SettingNine mixed surgical/medical intensive care units across Denmark.Participants1200 adult intensive care patients, 18+ years, expected to stay +24 h.Exclusion Criteriabilirubin >40 mg/dl, triglycerides >1000 mg/dl, increased risk from blood sampling, pregnant/breast feeding and psychiatric patients.InterventionsPatients 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).Main Outcome MeasuresPrimary 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.Results28-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.ConclusionsPiperacillin/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.Trial RegistrationClinicalTrials.gov identifier: NCT00271752.

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