Beta-lactam dosing in critically ill patients with septic shock and continuous renal replacement therapy

Abstract

Although early and appropriate antibiotic therapy remains the most important intervention for successful treatment of septic shock, data guiding optimization of beta-lactam prescription in critically ill patients prescribed with continuous renal replacement therapy (CRRT) are still limited. Being small hydrophilic molecules, beta-lactams are likely to be cleared by CRRT to a significant extent. As a result, additional variability may be introduced to the per se variable antibiotic concentrations in critically ill patients. This article aims to describe the current clinical scenario for beta-lactam dosing in critically ill patients with septic shock and CRRT, to highlight the sources of variability among the different studies that reduce extrapolation to clinical practice, and to identify the opportunities for future research and improvement in this field. Three frequently prescribed beta-lactams (meropenem, piperacillin and ceftriaxone) were chosen for review. Our findings showed that present dosing recommendations are based on studies with drawbacks limiting their applicability in the clinical setting. In general, current antibiotic dosing regimens for CRRT follow a one-size-fits-all fashion despite emerging clinical data suggesting that drug clearance is partially dependent on CRRT modality and intensity. Moreover, some studies pool data from heterogeneous populations with CRRT that may exhibit different pharmacokinetics (for example, admission diagnoses different to septic shock, such as trauma), which also limit their extrapolation to critically ill patients with septic shock. Finally, there is still no consensus regarding the %T>MIC (percentage of dosing interval when concentration of the antibiotic is above the minimum inhibitory concentration of the pathogen) value that should be chosen as the pharmacodynamic target for antibiotic therapy in patients with septic shock and CRRT. For empirically optimized dosing, during the first day a loading dose is required to compensate the increased volume of distribution, regardless of impaired organ function. An additional loading dose may be required when CRRT is initiated due to steady-state equilibrium breakage driven by clearance variation. From day 2, dosing must be adjusted to CRRT settings and residual renal function. Therapeutic drug monitoring of beta-lactams may be regarded as a useful tool to daily individualize dosing and to ensure optimal antibiotic exposure.

Meropenem Population Pharmacokinetics in Critically Ill Patients with Septic Shock and Continuous Renal Replacement Therapy: Influence of Residual Diuresis on Dose Requirements

“…In general, antibiotic dose adjustments in critically ill patients are very challenging for the clinician because, unlike other drugs, such as vasopressors or sedatives, among others, the pharmacological effect of antibiotics is not immediately evident but requires a certain period of time, even days, to be visible. For critically ill patients with septic shock and a CRRT requirement, detection of the pharmacological effect of antibiotics is even more challenging due to all the PK changes driven by critical illness and the use of extracorporeal devices (6). In spite of this difficulty, the attainment and maintenance of therapeutic concentrations are crucial, as they have an impact on both clinical outcomes and the development of bacterial resistances.…”

“…For these patients, available guidelines recommend that 500 to 1,000 mg of meropenem every 8 h (q8h) to every 12 h (q12h) be prescribed (7), which is a considerably broad dose range. However, this population is subject to conditions that may significantly influence meropenem pharmacokinetics (PKs) and, consequently, modify the dosing requirements, such as hypoproteinemia, variable urine output, or diverse CRRT settings (6). It follows that while several studies have described meropenem PKs in critically ill patients with continuous venovenous hemofiltration (CVVHF) and continuous venovenous hemodiafiltration (CVVHDF) (8)(9)(10)(11)(12)(13)(14)(15)(16)(17)(18)(19), empirical dosing at the bedside is still challenging in this scenario.…”

“…These characteristics make meropenem a drug mainly eliminated by the kidneys, as only the unbound fraction is available for glomerular filtration (major elimination pathway) (1). This also makes meropenem a dialyzable drug because the main determinants of drug clearance (CL) while a patient is receiving renal replacement therapy (RRT) are a low molecular size, a high affinity for water, a low V, and a large unbound fraction (6).…”

Efficacy of nebulized colistin-based therapy without concurrent intravenous colistin for ventilator-associated pneumonia caused by carbapenem-resistant Acinetobacter baumannii

“…A recent study by Khawcharoenporn et al showed that combination therapy of nebulized colistin and carbapenems was an effective treatment option if carbapenems were given in a prolonged infusion fashion (37). In addition, previous studies indicated that individualized dosing of β-lactam antibiotics should be considered to increase the likelihood of optimal outcomes because of altered pharmacokinetics of β-lactam in critically ill patients (38,39). Because all patients in this study treated with colistin-carbapenem combination therapy received standard dosage regimen for carbapenems with intermittent bolus dosing, the unexpectedly low efficacy of colistincarbapenem combination might occur.…”

The use of liquid chromatography-tandem mass spectrometry for therapeutic drug monitoring of antibiotics in cancer patients

“…Furthermore, patients, presenting dysfunction in vital organs such as kidney and liver that represent the major routes for drug elimination, are at increased risk of the prompt onset of toxic drug concentration [12,23]. On the other hand, patients with augmented renal clearance [24] or prescribed with continuous renal therapy suffer from decreased levels of antibiotics necessary to achieve a positive clinical outcome [25]. It is evident that different antibiotics are differently affected by the pathophysiological changes encountered in ICU patients.…”