Pharmacokinetics of meropenem and piperacillin in critically ill patients with indwelling surgical drains

doi:10.1016/j.ijantimicag.2013.02.023

International Journal of Antimicrobial Agents

Volume 42, Issue 1, July 2013, Pages 90-93

https://doi.org/10.1016/j.ijantimicag.2013.02.023 Get rights and content

Abstract

Meropenem and piperacillin are two commonly prescribed antibiotics in critically ill surgical patients. To date, the pharmacokinetics of these antibiotics in the presence of indwelling abdominal surgical drains is poorly defined. This was a prospective pharmacokinetic study of meropenem and piperacillin. Serial plasma, urine and surgical drain fluid samples were collected over one dosing interval of antibiotic treatment in ten patients (meropenem, n = 5; piperacillin n = 5). Drug concentrations were measured using a validated high-performance liquid chromatography assay. Median (interquartile range) pharmacokinetic parameter estimates for meropenem were as follows: area under concentration–time curve (AUC), 128.7 mg h/L (95.3–176.7 mg h/L); clearance (CL), 5.7 L/h (5.1–10.5 L/h); volume of distribution (V_d), 0.41 L/kg (0.35–0.56 L/kg); AUC ratio (drain:plasma), 0.2 (0.1–0.2); and calculated antibiotic clearance via surgical drain, 3.8% (2.8–5.4%). For piperacillin, unbound pharmacokinetic results were as follows; AUC, 344.3 mg h/L (341.1–348.4 mg h/L); CL, 13.1 L/h (12.9–13.2 L/h); V_d, 0.63 L/kg (0.38–1.28 L/kg); AUC ratio (drain:plasma), 0.2 (0.2–0.3); and calculated antibiotic clearance via surgical drain 8.2% (3.3–14.0%). A linear correlation was present between the percentage of antibiotic cleared through the drain and the volume of surgical drain fluid output for meropenem (r² = 0.89; P = 0.05) and piperacillin (r² = 0.63; P = 0.20). Meropenem and piperacillin have altered pharmacokinetics in critically ill patients with indwelling surgical drains. We propose that only when very high drain fluid output is present (>1000 mL/day) would an additional dose of antibiotic be necessary.

Introduction

Meropenem and piperacillin/tazobactam (TZP) are commonly prescribed for post-operative infections in critically ill patients. Surgical drains may be inserted for either therapeutic, prophylactic or decompressive drainage of excess air or fluid or to monitor production of wound exudate post surgery [1].

During clinical practice at our tertiary referral intensive care unit (ICU), we have observed that critically ill patients with indwelling surgical drains have lower plasma concentrations of antibiotics than other comparable patients [2]. There are few data available to suggest whether these surgical drains are associated with subtherapeutic concentrations, which may lead to impaired antibiotic efficacy. Most of the studies documenting the concentrations of antibiotics in intra-abdominal and pleural fluid primarily describe antibiotic penetration and do not examine whether these surgical drains are a mechanism for increased drug clearance. There are also limited data on the time course profile of both meropenem and piperacillin in patients with surgical drains. This lack of data limits the ability to predict dosing requirements for such patients [3], [4], [5].

The importance of achieving adequate antibiotic concentrations at the site of infection is well recognised, with subtherapeutic concentrations hypothesised to be associated with therapeutic failure [6]. However, measurement of drug concentrations at the site of infection is often not feasible, and plasma drug concentrations remain an important surrogate.

The target exposure for antibiotics is guided by the minimum inhibitory concentration (MIC) of the target bacterial pathogen. For β-lactam antibiotics, bacterial killing depends largely on the time the free (or unbound) antibiotic concentration remains above the MIC, i.e. fT_>MIC. The specific percentage of the dosing interval differs between β-lactam classes, i.e. 40% for carbapenems, 50% for cephalosporins and 60–70% for penicillins [7]. The primary aim of this project was to describe the pharmacokinetics of both meropenem and piperacillin in critically ill patients with indwelling surgical drains with a focus on describing drug clearance through the drains.

Section snippets

Materials and methods

This was a prospective, open-labelled, pharmacokinetic study conducted at the ICU of Royal Brisbane and Women's Hospital (Brisbane, Australia). Critically ill patients who met the following criteria were eligible for inclusion: (a) written informed consent had been obtained from the patient or his/her substitute decision-maker; (b) presence of at least one indwelling surgical drain actively producing fluid (defined as > 10 mL in the preceding 6 h); (c) clinical indication for meropenem or TZP

Results

Ten patients were included in this study (meropenem, n = 5; TZP, n = 5). The mean ± standard deviation patient age was 69 ± 15 years, weight 75 ± 23 kg, Acute Physiology and Chronic Health Evaluation (APACHE) II score 11 ± 2 and Sequential Organ Failure Assessment (SOFA) score 3 ± 2. Five (50%) of the patients were male; nine patients had intra-abdominal drains, whilst the other patient had a left leg drain because of severe lower limb trauma.

Fig. 1 displays the concentration–time profiles for meropenem and

Discussion

The present study describes the pharmacokinetics of meropenem and piperacillin in critically ill patients with indwelling surgical drains. The AUC in plasma for both drugs was found to be larger than that reported in healthy volunteers [10], [11]. For the comparative AUC in drain fluid, a lower AUC was shown than in plasma (78% and 75% lower for meropenem and piperacillin, respectively). Rapid clearance through the surgical drain could explain this difference. Similar trends have been observed

Conclusion

This study has shown that patients with indwelling surgical drains receiving either meropenem or TZP have a greatly increased V_d compared with healthy volunteers. This increased V_d is likely to be due to the inflammatory pathology at the site of the drain as well as other pathophysiological changes commonly seen in critically ill patients. Therefore, these data appear to support the need for larger initial antibiotic doses in these patients, although the magnitude of such increased doses is yet

Acknowledgments

The authors would like to acknowledge Suzanne Parker-Scott, Gregory A. Medley and Lu Jin from the Burns, Trauma and Critical Care Centre, School of Medicine, The University of Queensland (Brisbane, Australia) for their technical assistance with the HPLC assays.

Funding: This research has received funding from Royal Brisbane and Women's Hospital Research Foundation. JAR is funded in part by a National Health and Medical Research Council of Australia Research Fellowship (NHMRC APP1048652).

References (15)

J.A. Roberts et al.
Therapeutic drug monitoring of β-lactams in critically ill patients: proof of concept
Int J Antimicrob Agents
(2010)
P.R. Rhomberg et al.
Antimicrobial susceptibility pattern comparisons among intensive care unit and general ward Gram-negative isolates from the Meropenem Yearly Susceptibility Test Information Collection Program (USA)
Diagn Microbiol Infect Dis
(2006)
Q.D. Ngo et al.
Drowning in drainage? The Liverpool Hospital survival guide to drains and tubes
(2004)
J. Karjagin et al.
Pharmacokinetics of meropenem determined by microdialysis in the peritoneal fluid of patients with severe peritonitis associated with septic shock
Clin Pharmacol Ther
(2008)
A. Bedikian et al.
Pharmacokinetics of meropenem in patients with intra-abdominal infections
Antimicrob Agents Chemother
(1994)
C. Li et al.
Population pharmacokinetics and pharmacodynamics of piperacillin/tazobactam in patients with complicated intra-abdominal infection
J Antimicrob Chemother
(2005)
C. Joukhadar et al.
Impaired target site penetration of β-lactams may account for therapeutic failure in patients with septic shock
Crit Care Med
(2001)

There are more references available in the full text version of this article.

Cited by (24)

Pharmacokinetics and pharmacodynamics of beta-lactam antibiotics in critically ill patients
2022, Farmacia Hospitalaria
Optimal antibiotic therapy for critically ill patients can be complicated by the altered physiology associated with critical illness. Antibiotic pharmacokinetics and exposures can be altered driven by the underlying critical illness and medical interventions that critically ill patients receive in the intensive care unit. Furthermore, pathogens that are usually isolated in the intensive care unit are commonly less susceptible and “resistant” to common antibiotics. Indeed, antibiotic dosing that does not consider these unique differences will likely fail leading to poor clinical outcomes and the emergence of antibiotic resistance in the intensive care unit. The aims of this narrative review were to describe the pharmacokinetics of beta-lactam antibiotics in critically ill patients, to highlight pharmacokinetic/pharmacodynamic targets for both non-critically ill and critically ill patients, and to discuss important strategies that can be undertaken to optimize beta-lactam antibiotic dosing for critically ill patients in the intensive care unit.
La terapia antibiótica óptima en los pacientes en estado crítico puede complicarse por la alteración de la fisiología asociada a esta etapa de la enfermedad. La farmacocinética y la exposición a los antibióticos pueden verse alteradas por la enfermedad crítica subyacente y las intervenciones médicas que reciben estos pacientes en la unidad de cuidados intensivos. Además, las cepas que suelen encontrarse en la unidad de cuidados intensivos suelen ser menos susceptibles y “resistentes” a los antibióticos más habituales. De hecho, una dosificación de antibióticos que no tenga en cuenta estas diferencias únicas, probablemente fracasará y dará lugar a resultados clínicos deficientes y a la aparición de resistencia a los antibióticos en la unidad de cuidados intensivos. Los objetivos de esta revisión son describir la farmacocinética de los antibióticos betalactámicos en pacientes críticos, destacar los objetivos farmacocinéticos/farmacodinámicos para los pacientes y exponer algunas estrategias importantes que pueden optimizar la dosificación de los antibióticos betalactámicos en pacientes críticos en la unidad de cuidados intensivos.
Pharmacokinetic modifications and pharmacokinetic/pharmacodynamic optimization of beta-lactams in ICU
2021, Annales Pharmaceutiques Francaises
Les modifications pharmacocinétiques des patients de réanimation et celles induites par les thérapeutiques réanimatoires soulèvent de nombreuses questions concernant les adaptations posologiques d’antibiotiques. Les bêta-lactamines sont des anti-infectieux largement utilisés en réanimation. Les fréquents sous-dosages engendrent un risque d’échec thérapeutique potentiellement létal et d’émergence de résistances bactériennes. Les surdosages exposent quant à eux à un risque de neurotoxicité et de néphrotoxicité. Une compréhension des mécanismes pharmacocinétiques à l’origine de ces problématiques apparait alors comme indispensable. Une approche pharmacocinétique/pharmacodynamique globale est requise, intégrant l’utilisation de perfusions prolongées et continues de bêta-lactamines de façon à optimiser les probabilités d’atteinte des objectifs pharmacocinétiques et pharmacodynamiques. Le Suivi Thérapeutique Pharmacologique des bêta-lactamines doit également être considéré. Les experts s’accordent pour cibler une concentration sérique libre de bêta-lactamine d’au moins 4 fois la CMI de la bactérie concernée pendant 100 % du temps. Les méthodes bayésiennes pourraient permettre une adaptation individualisée des posologies.
Pharmacokinetic modifications in critically ill patients and those induced by ICU therapeutics raise a lot of issues about antibiotic dose adaptation. Beta-lactams are anti-infectious widely used in ICU. Frequent beta-lactam underdoses induce a risk of therapeutic failure potentially lethal and of emergence of bacterial resistance. Overdoses expose to a neurotoxic and nephrotoxic risk. Therefore, an understanding of pharmacokinetics modifications appears to be essential. A global pharmacokinetic/pharmacodynamic approach is required, including use of prolonged or continued beta-lactam infusions to optimise probability of pharmacokinetic/pharmacodynamic target attainment. Beta-lactam therapeutic drug monitoring should also be considered. Experts agree to target a free plasma betalactam concentration above four times the MIC of the causative bacteria for 100 % of the dosing interval. Bayesian methods could permit individualized doses adaptations.
The role of antibiotic pharmacokinetic studies performed post-licensing
2020, International Journal of Antimicrobial Agents
Citation Excerpt :
These patients may manifest extreme physiological derangements due to (1) the natural underlying disease process (e.g. severe sepsis or septic shock) and/or the interventions provided to reverse the condition (e.g. aggressive intravenous fluid and vasoactive drug infusions) [10]. These patients may also require medical interventions during their hospital stay, including mechanical ventilation [25], extracorporeal circuits [26], total parenteral nutrition [27], and the presence of surgical drains [28], all of which can greatly expand the volume of distribution of hydrophilic antimicrobials and lead to sub-optimal drug concentrations. Most of the studies evaluating these patient groups have reported at least a two-fold increase in this PK parameter compared with the non-critically ill patient populations [29].
Post-licensing pharmacometric studies can provide a better understanding of the pharmacokinetic (PK) alterations in special patient populations and may lead to better clinical outcomes. Some patient populations exhibit markedly different pathophysiology to general ward patients or healthy individuals. This may be developmental (paediatric patients), a manifestation of an underlying disease pathology (patients with obesity or haematological malignancies) or due to medical interventions (critically ill patients receiving extracorporeal therapies). This paper outlines the factors that affect the PK of special patient populations and describes some novel methods of antimicrobial administration that may increase antimicrobial concentrations at the site of infection and improve treatment of severe infection.
Pharmacokinetics of meropenem in burn patients with infections caused by Gram-negative bacteria: Are we getting close to the right treatment?
2020, Journal of Global Antimicrobial Resistance
Citation Excerpt :
This was further confirmed by the absence of significant differences in terms of drug concentrations between different dosing regimens (Fig. 1). The mean Cmin and Cmax values were found to be similar to those reported in the literature in 65% and 59% of patients, respectively [3,6,9–14]. Of note, for TBSA ≥ 50%, only two patients had a Cmin ≥ 3.3 mg/L and only one patient had a Cmax > 28.4 mg/L, suggesting that the percentage TBSA might strongly affect the Vd and other physiological parameters, although in the current study no statistically significant correlation was found, possibly due to the small number of patients enrolled.
Infections caused by multidrug-resistant Gram-negative bacteria are associated with high mortality. A relevant concern is the efficacy of antibiotic therapy in burn patients in whom pathophysiological changes strongly influence pharmacokinetic (PK) parameters. This study aimed to describe the PK parameters of meropenem in a population of burn patients.
Blood samples were collected immediately before and 2 h and 5 h after the start of intravenous drug administration. Plasma meropenem concentrations were determined using an ultra-performance liquid chromatography–photodiode array method.
Seventeen burn patients were enrolled in the study. Thirteen patients (76%) were treated with meropenem for infections byPseudomonas aeruginosa or Acinetobacter baumannii isolated from blood or wounds. Mean C_max, C_min, AUC_0–24, half-life, drug clearance and volume of distribution were 28.9 mg/L, 3.7 mg/L, 280.2 mg h/L, 2.0 h, 19.0 L/h and 44.4 L, respectively. Six patients (35%) achieved a C_min ≥3.3 mg/L and seven patients (41%) achieved a C_max ≥ 28.4 mg/L, whilst nine patients (53%) achieved an AUC_0–24 of >226 mg h/L. Given a minimum inhibitory concentration (MIC) of 0.5 mg/L, all patients satisfied the target AUC/MIC of >125, but when the MIC rises to 2 mg/L (the ECOFF), only five patients reached the desired AUC/MIC. Regarding fT_>MIC at an MIC of 2 mg/L with a 2-h infusion time, 13 patients (76%) achieved the PK target (>75%).
These data suggest that a combined 2-h infusion with a higher dosage of meropenem, including a loading dose, may be successful to achieve effective PK parameters.
The effects of major burn related pathophysiological changes on the pharmacokinetics and pharmacodynamics of drug use: An appraisal utilizing antibiotics
2018, Advanced Drug Delivery Reviews
Patients suffering major burn injury represent a unique population of critically ill patients. Widespread skin and tissue damage causes release of systemic inflammatory mediators that promote endothelial leak, extravascular fluid shifts, and cardiovascular derangement. This phase is characterized by relative intra-vascular hypovolaemia and poor peripheral perfusion. Large volume intravenous fluid resuscitation is generally required. The patients' clinical course is then typically complicated by ongoing inflammation, protein catabolism, and marked haemodynamic perturbation. At all times, drug distribution, metabolism, and elimination are grossly distorted. For hydrophilic agents, changes in volume of distribution and clearance are marked, resulting in potentially sub-optimal drug exposure. In the case of antibiotics, this may then promote treatment failure, or the development of bacterial drug resistance. As such, empirical dose selection and pharmaceutical development must consider these features, with the application of strategies that attempt to counter the unique pharmacokinetic changes encountered in this setting.
Optimization of dosing regimens and dosing in special populations
2015, Clinical Microbiology and Infection
Citation Excerpt :
SIRS can also lead to a spectrum of organ-system failure which may necessitate extracorporeal membrane oxygenation or renal replacement therapy [12]. Surgical drainage may play a similar role of providing extra route of loss of inflammatory fluids and even antibiotics [13]. In addition, most of these patients have altered body water volumes associated with either extensive fluid resuscitation or altered cardiovascular and renal function [14–16].
Treatment of infectious diseases is becoming increasingly challenging with the emergence of less-susceptible organisms that are poorly responsive to existing antibiotic therapies, and the unpredictable pharmacokinetic alterations arising from complex pathophysiologic changes in some patient populations. In view of this fact, there has been a progressive work on novel dose optimization strategies to renew the utility of forgotten old antibiotics and to improve the efficacy of those currently in use. This review summarizes the different approaches of optimization of antibiotic dosing regimens and the special patient populations which may benefit most from these approaches. The existing methods are based on monitoring of antibiotic concentrations and/or use of clinical covariates. Measured concentrations can be correlated with predefined pharmacokinetic/pharmacodynamic targets to guide clinicians in predicting the necessary dose adjustment. Dosing nomograms are also available to relate observed concentrations or clinical covariates (e.g. creatinine clearance) with optimal dosing. More precise dose prediction based on observed covariates is possible through the application of population pharmacokinetic models. However, the most accurate estimation of individualized dosing requirements is achieved through Bayesian forecasting which utilizes both measured concentration and clinical covariates. Various software programs are emerging to ease clinical application. Whilst more studies are warranted to clarify the clinical outcomes associated with the different dose optimization approaches, severely ill patients in the course of marked infections and/or inflammation including those with sepsis, septic shock, severe trauma, burns injury, major surgery, febrile neutropenia, cystic fibrosis, organ dysfunction and obesity are those groups which may benefit most from individualized dosing.

View all citing articles on Scopus

View full text

Short communicationPharmacokinetics of meropenem and piperacillin in critically ill patients with indwelling surgical drains

Abstract

Introduction

Section snippets

Materials and methods

Results

Discussion

Conclusion

Acknowledgments

Int J Antimicrob Agents

Diagn Microbiol Infect Dis

Drowning in drainage? The Liverpool Hospital survival guide to drains and tubes

Pharmacokinetics of meropenem determined by microdialysis in the peritoneal fluid of patients with severe peritonitis associated with septic shock

Clin Pharmacol Ther

Pharmacokinetics of meropenem in patients with intra-abdominal infections

Antimicrob Agents Chemother

Population pharmacokinetics and pharmacodynamics of piperacillin/tazobactam in patients with complicated intra-abdominal infection

J Antimicrob Chemother

Impaired target site penetration of β-lactams may account for therapeutic failure in patients with septic shock

Crit Care Med

Short communication
Pharmacokinetics of meropenem and piperacillin in critically ill patients with indwelling surgical drains