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

Abstract

Objectives: To explore whether a strategy of more intensive antibiotic therapy leads to emergence or prolongation of renal failure in intensive care patients.

Design: 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.

Setting: Nine mixed surgical/medical intensive care units across Denmark.

Participants: 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.

Interventions: 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).

Main outcome measures: 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.

Trial registration: ClinicalTrials.gov identifier: NCT00271752.

Conflict of interest statement

Competing interests: All authors have completed the Unified Competing Interest form at http://www.icmje.org/coi_disclosure.pdf (available on request from the corresponding author) and declare that the trial was funded mainly by the Danish State (Danish Research Council), and all authors state that they have no relationships with companies that might have an interest in the submitted work in the previous 3 years; their spouses, partners or children have no financial relationships that may be relevant to the submitted work, and all authors have no non-financial interests that may be relevant to the submitted work.

Figures

Figure 1

Estimated glomerular filtration rate (eGFR) during 10 days on cefuroxim, piperacillin/tazobactam and meropenem. Difference between eGFR in patients receiving piperacillin/tazobactam versus meropenem: day 1 (p=0.78), day 2 (p=0.18), day 3 (p=0.09), day 4 (p=0.008), day 5 (p=0.001), day 6 (p=0.001), day 7 (p=0.0004), day 8 (p=0.005), day 9 (p=0.006) and day 10 (p=0.02).