Anna-Karin Smekal: Antibiotic concentrations in the ICU

Abstract

Severe infections are life-threatening conditions and common cause of emergency admission to intensive care units (ICU). Initial adequate antibiotic treatment is known to be crucial for the outcome. However, mortality and morbidity remain high.

The overall aim of this thesis was to investigate strategies for optimising antibiotic concentrations, pharmacokinetic/pharmacodynamic (PK/PD) target fulfilment and dosing in ICU patients during the early phase of infection.

In a prospective multi-centre study on the first 72 h of treatment with one of three β-lactams, cefotaxime, piperacillin-tazobactam or meropenem, 138 ICU patients were included.

We found a high proportion of ICU patients not reaching the PK/PD targets suggested by European experts. Younger age, signs of augmented renal clearance, treatment with cefotaxime, and non-urinary tract infections were identified as risk factors for target failure where early therapeutic drug monitoring (TDM) could be encouraged.

When further investigating the impact of different minimum inhibitory concentration (MIC) parameters on the PK/PD target attainment, the current use of  MICWCS,  based on the bacterial worst case scenario (WCS), instead of the MICECOFF (epidemiological cut-off (ECOFF)) based on the actual causative bacterial pathogen was found to overestimate target failure with risk of overdosing.

In predictions of target attainment using different infusion durations, we found that target attainment rates for primary pathogen scenarios were high regardless of infusion type, indicating that short infusion (SI) is sufficient in most community-acquired infections except for infections with S. aureus treated with cefotaxime, where a higher daily dose than 6 g is needed. In WCS-pathogens, reflecting infections with P. aeruginosa, SI was insufficient and routine use of extended (EI) or continuous (CI) infusions could be beneficial for piperacillin-tazobactam and meropenem. However, the risk of toxicity might increase and individualised TDM is warranted.

In a retrospective single-centre study of 255 ICU patients treated with gentamicin, the use of estimated gentamicin clearance CL derived from measured 8 h concentrations was found to be a potential exogenous marker of renal function in patients in an early phase of the severe infection which could improve dosing of renally eliminated drugs like the β-lactams.