Effect of therapeutic drug monitoring of piperacillin/tazobactam on sepsis‑related organ dysfunction

Emerging evidence suggests that in patients with sepsis, insufficient antibiotic exposure is associated with worse clinical outcomes. Up to 50% of critically ill patients receiving a β-lactam antibiotic with regimens based on the manufacturers’ recommendations fail to reach the pharmacokinetic/pharmacodynamic (PK/PD) target to kill or inhibit the growth of a pathogen. Sometimes, even if the β-lactam is given as a continuous or extended infusion, it still doesn’t reach the desired antibiotic exposure. An additional option to further optimise PK/PD target attainment of β-lactam antibiotics is therapeutic drug monitoring (TDM)-guided therapy.

To address this issue, Hagel et al. conducted a randomised controlled trial on 254 adult patients with severe sepsis or septic shock treated with piperacillin/tazobactam. They tested the hypothesis that TDM-based dose optimisation compared to fixed dosing would improve clinical outcomes in patients with sepsis treated with piperacillin/tazobactam continuous infusion.

In all patients on day 0, a continuous infusion of piperacillin/tazobactam, corresponding to a total daily dose of 13.5 g (9 g in patients with renal dysfunction), was started immediately after administration of a loading dose of 4.5 g piperacillin/tazobactam. On the next day, day 1, in the intervention group, dosing of piperacillin/ tazobactam was guided by daily TDM of piperacillin (target plasma concentration of free piperacillin should be four times the minimal inhibitory concentration (MIC) of the causative pathogen). In the control group, the same continuous infusion rate from day 0 was maintained.

Regarding the primary outcome of the study (namely sepsis-related organ dysfunction), there was no statistical significance between the two groups: the mean SOFA score was 7.9 points in the TDM group and 8.2 points in the control group. There was also no statistical significance reached in any of the study’s secondary endpoints. Still, a decrease in 28-day mortality and a higher rate of clinical and microbiological cure should be noted in the TDM group. In addition, when adjusting for APACHE II score, patients achieving the individual piperacillin target within the first two days showed a better resolution of organ dysfunction compared to patients who did not achieve target attainment.

STUDY STRENGTHS & LIMITATIONS

Strengths

• It is a randomised controlled trial;
• The study was adequately powered regarding the primary outcome;
• Both study groups are treated with continuous infusion eliminating the bias of changing antibiotic concentration with bolus administration and extended infusion.

Limitations

• The caregivers were not blinded to the study groups;
• Antibiotic combination therapy was allowed at any time, which might have biased the study results;
• Only serum piperacillin concentrations were obtained, and these concentrations do not always reflect concentrations at the site of infection;
• The study was performed in a single country with a low prevalence of resistant gram-negative bacteria, which limits the generalisability of the results;
• The majority of bacteria identified within the study displayed a low MIC within the susceptible range; therefore, supposedly insufficient piperacillin concentrations, designated as “underdosed”, were still adequate for successful antimicrobial therapy;
• No dosage algorithm or dosing software was used to support consistent dosing adjustments in patients with TDM-guided therapy.

TAKE-HOME MESSAGES

• In this trial, a significant benefit for TDM-guided therapy in adult patients with sepsis and continuous infusion of piperacillin/tazobactam concerning the primary endpoint, namely, the mean total SOFA score was not observed;
• There was a decrease in the 28-day mortality, as well as a clinical and microbiological cure, but it didn’t reach statistical significance;
• Further studies are necessary to confirm the observed benefit in the secondary endpoints, for which the current study was not powered;
• Further studies are necessary to identify patients who might benefit most from a TDM-guided β-lactam antibiotic therapy.

This article review was prepared and submitted by Viktoria Ilieva, MD, PhD, Anesthesiologist and Intensive Care Physician at University Hospital “St. Ivan Rilski”, Sofia (Bulgaria), on behalf of ESICM Journal Review Club.