Monitoring-based antibiotic dose optimisation

Therapeutic drug monitoring (TDM)-based dose adjustment of piperacillin/tazobactam and meropenem is associated with improved antibiotic exposure in critically ill patients with normal renal function. Level of evidence: 1B (CEBM, RCT of good quality)

Appraised by: B Spooner and T Whitehouse

Citation: De Waele JJ, Carrette S, Carlier M, et al. Therapeutic drug monitoring-based dose optimisation of piperacillin/tazobactam and meropenem: a randomised controlled trial. Intensive Care Med 2014; 40: 380–387.

Lead author: Jan J De Waele, [e-mail]

Three-part clinical question:

Patients: Critical care patients with normal renal function who were receiving piperacillin/tazobactam and/or meropenem.

Intervention: Therapeutic drug monitoring (TDM)-based dose adjustment of piperacillin/tazobactam and meropenem.

Outcomes: The primary outcome was the percentage of time the plasma antibiotic concentration exceeded four times the minimum inhibitory concentration (MIC) of the causative organism (or if unknown, the MIC used was the epidemiological cut-off of wild-type Pseudomonas species of 16 mg/L for piperacillin/tazobactam and 2 mg/L for meropenem) during a dosing interval, over the first 72 h of treatment (% fT_>4MIC). The target was 100%.

Secondary outcomes were the percentage of time the plasma antibiotic concentration exceeded the MIC during a dosing interval over the first 72 h of treatment (% fT_>MIC) and absolute values for the fT_>4MIC and fT_>MIC. Clinical response was also evaluated at day 7. ICU, hospital and 28-day mortality were recorded.

Search terms: B-lactam antibiotics, pharmacokinetics, pharmacodynamics, therapeutic drug monitoring (TDM), critical care

Study design: Single-centre, prospective, partially blinded, randomised controlled trial.

The study patients:

Eligible: Patients over 18 years old, receiving piperacillin/tazobactam and/or meropenem on ICU, with an arterial catheter (for blood sampling).

Included: 41 patients from the ICU at Ghent University Hospital, Belgium between April 2011 and February 2012.

Exclusion criteria: Pregnancy, lactation, allergy to administered drugs, impaired renal function (eGFR < 80), haemoglobin <7 g/dL, do not resuscitate order or if the patient was not expected to survive 48 h.

Control group: (20 patients) Antibiotics were delivered according to standard hospital extended infusion protocols (30 min loading infusion followed by infusion over 3 h). The infusion was then repeated at 6 hourly (piperacillin/tazobactam) or 8 hourly (meropenem) intervals. Antibiotic levels were taken at pre-defined times throughout the study.

	Group		p
	Dose adaptation	Control
Primary outcome
% time when plasma levels above target [target = 100% fT>4MIC]	57.9%	15.8%	0.007
Secondary outcomes
% time when plasma levels above target [target = 100% fT>1MIC]	94.7%	68.4%	0.045
Treatment failure	9.5%	20%	0.41
Bacterial presence on day 7	4.8%	25%	0.09
Death on ICU	4.8%	20%	0.18
Death at 28 days	14.3%	25%	0.45

Therapeutic drug monitoring dose adjustment group: (21 patients) As per control group except the dosing frequency (and dose for meropenem) was increased or decreased according to a pre-defined algorithm based on the actual antibiotic levels.

The evidence:

Key % fT_>4MIC: percentage of time the plasma antibiotic concentration exceeded four times the minimum inhibitory concentration (MIC) of the causative organism over the first 72 h of treatment. % fT_>1MIC: percentage of time the plasma antibiotic concentration exceeded the minimum inhibitory concentration (MIC) of the causative organism over the first 72 h of treatment.

Significantly more patients achieved target antibiotic plasma levels in the intervention group.

The intervention significantly increased the median time the antibiotic levels were more than four times MIC (44.5% to 86% on day 2 and 60% to 90% on day 3; p = 0.012).

There were no adverse events relating to antibiotics in either group.

EBM questions:

Do the methods allow accurate testing of the hypothesis? Yes. This study was well designed to detect whether dose adjustment (based on daily therapeutic drug monitoring) could achieve better pharmacokinetic target attainments than with standard dosing. It was a single-centre, prospective, partially blinded, randomised controlled trial. The main outcomes were blinded. Some of the secondary clinical outcomes (clinical response at day 7) were only partially blinded making observer bias unlikely; however, this does not weaken the main pharmacokinetic outcomes of the study.

Do the statistical tests correctly test the results to allow differentiation of statistically significant results? Yes, although this is the first work of its kind and powering the study was impossible.

Are the conclusions valid in light of the results? Yes. They are that:

TDM-based dose adaptation of beta-lactam antibiotic therapy improves antibiotic exposure in critically ill patients with normal renal function.

Standard dosing does not achieve target concentrations in all patients even with conservative plasma targets.

Whether TDM-based dose adaptation leads to improved patient outcomes remains to be determined.

Did results get omitted and why? Yes.

Three patients did not complete the study protocol and target attainment at day 3 could not be calculated for these patients.

Did they suggest areas of future research? Yes. It suggests TDM could be studied in patients at risk of under-dosing (obese patients and patients on renal replacement therapy). The paper also acknowledges it was not powered to detect clinical outcome differences and this requires further study.

Did they make recommendations based on the results and were they appropriate? No.

Is the study relevant to my clinical practice? Yes. The study shows many (up to 85%) patients with normal renal function may not be receiving adequate doses of piperacillin/tazobactam or meropenem. This could explain treatment failure on ICU and contribute to unnecessary morbidity and mortality; this may also add to selection pressures and compound antibiotic resistance. TDM is a strategy to address this shortfall in antibiotic delivery.

What level of evidence does this study represent? 1B (Well-conducted single-centre, blinded, randomised controlled trial)

What grade of recommendation can I make on this result alone? B.

What grade of recommendation can I make when this study is considered along with other available evidence? B. There are other studies (not randomised controlled trials and with limitations) about TDM with beta-lactams but they mainly highlight the issue of insufficient plasma levels.

Should I change my practice because of these results? No.

Although it is likely that there are patients with normal renal function on critical care who are receiving insufficient levels of meropenem and piperacillin, TDM is not available in most hospitals and therefore wide-scale implementation is currently not possible.

Should I audit my current practice because of these results? Yes, if possible , where TDM is available.

Appraised by:

Brendan Spooner, Core Trainee Year 3, ACCS Anaesthetics

[e-mail]

Tony Whitehouse, Consultant Intensive Care Medicine, Intensive Care Unit, Queen Elizabeth Hospital, Birmingham, UK