Kidney failure related to broad-spectrum antibiotics in critically ill patients: secondary end point results from a 1200 patient randomised trial

<jats:sec><jats:title>Objectives</jats:title><jats:p>To explore whether a strategy of more intensive antibiotic therapy leads to emergence or prolongation of renal failure in intensive care patients.</jats:p></jats:sec><jats:sec><jats:title>Design</jats:title><jats:p>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.</jats:p></jats:sec><jats:sec><jats:title>Setting</jats:title><jats:p>Nine mixed surgical/medical intensive care units across Denmark.</jats:p></jats:sec><jats:sec><jats:title>Participants</jats:title><jats:p>1200 adult intensive care patients, 18+ years, expected to stay +24 h. Exclusion criteria: bilirubin >40 mg/dl, triglycerides >1000 mg/dl, increased risk from blood sampling, pregnant/breast feeding and psychiatric patients.</jats:p></jats:sec><jats:sec><jats:title>Interventions</jats:title><jats:p>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).</jats:p></jats:sec><jats:sec><jats:title>Main outcome measures</jats:title><jats:p>Primary end point: estimated glomerular filtration rate (eGFR) <60 ml/min/1.73 m<jats:sup>2</jats:sup>. Secondary end points: (1) delta eGFR after starting/stopping a drug and (2) RIFLE criterion<jats:italic>Risk</jats:italic>‘R’,<jats:italic>Injury</jats:italic>‘I’ and<jats:italic>Failure</jats:italic>‘F’. Analysis was by intention to treat.</jats:p></jats:sec><jats:sec><jats:title>Results</jats:title><jats:p>28-day mortality was 31.8% and comparable (Jensen<jats:italic>et al</jats:italic>, 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<jats:sup>2</jats:sup>, 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<jats:sup>2</jats:sup>/24 h while exposed to this drug (95% CI 0.7 to 1.3 ml/min/1.73 m<jats:sup>2</jats:sup>/24 h) vs meropenem: 2.9 ml/min/1.73 m<jats:sup>2</jats:sup>/24 h (2.5 to 3.3 ml/min/1.73 m<jats:sup>2</jats:sup>/24 h)); after discontinuing piperacillin/tazobactam, the renal recovery rate increased: 2.7 ml/min/1.73 m<jats:sup>2</jats:sup>/24 h (2.3 to 3.1 ml/min/1.73 m<jats:sup>2</jats:sup>/24 h)). eGFR <60 ml/min/1.73 m<jats:sup>2</jats:sup>in the two groups at entry and at last day of follow-up was 57% versus 55% and 41% versus 39%, respectively.</jats:p></jats:sec><jats:sec><jats:title>Conclusions</jats:title><jats:p>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.</jats:p></jats:sec><jats:sec><jats:title>Trial registration</jats:title><jats:p>ClinicalTrials.gov identifier:<jats:ext-link xmlns:xlink="http://www.w3.org/1999/xlink" ext-link-type="clintrialgov" xlink:href="NCT00271752">NCT00271752</jats:ext-link>.</jats:p></jats:sec>