Optimizing Antimicrobial Drug Dosing in Critically Ill Patients

A fundamental step in the successful management of sepsis and septic shock is early empiric antimicrobial therapy. However, for this to be effective, several decisions must be addressed simultaneously: (1) antimicrobial choices should be adequate, covering the most probable pathogens; (2) they should be administered in the appropriate dose, (3) by the correct route, and (4) using the correct mode of administration to achieve successful concentration at the infection site. In critically ill patients, antimicrobial dosing is a common challenge and a frequent source of errors, since these patients present deranged pharmacokinetics, namely increased volume of distribution and altered drug clearance, which either increased or decreased. Moreover, the clinical condition of these patients changes markedly over time, either improving or deteriorating. The consequent impact on drug pharmacokinetics further complicates the selection of correct drug schedules and dosing during the course of therapy. In recent years, the knowledge of pharmacokinetics and pharmacodynamics, drug dosing, therapeutic drug monitoring, and antimicrobial resistance in the critically ill patients has greatly improved, fostering strategies to optimize therapeutic efficacy and to reduce toxicity and adverse events. Nonetheless, delivering adequate and appropriate antimicrobial therapy is still a challenge, since pathogen resistance continues to rise, and new therapeutic agents remain scarce. We aim to review the available literature to assess the challenges, impact, and tools to optimize individualization of antimicrobial dosing to maximize exposure and effectiveness in critically ill patients.

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Evaluation of Intravenous Phenobarbital Pharmacokinetics in Critically Ill Patients With Brain Injury

ACTA MEDICA IRANICA ◽

10.18502/acta.v60i1.8323 ◽

2022 ◽

Author(s):

Seyedeh Sana Khezrnia ◽

Bita Shahrami ◽

Mohammad Reza Rouini ◽

Atabak Najafi ◽

Hamid Reza Sharifnia ◽

...

Keyword(s):

Brain Injury ◽

Critically Ill ◽

Critically Ill Patients ◽

Normal Population ◽

Volume Of Distribution ◽

Pharmacokinetic Parameters ◽

Therapeutic Drug ◽

Uv Detector ◽

Therapeutic Goals ◽

The Impact

Phenobarbital is still one of the drugs of choice in managing patients with brain injury in the intensive care unit (ICU). However, the impact of acute physiological changes on phenobarbital pharmacokinetic parameters is not well studied. This study aimed to evaluate the pharmacokinetic parameters of parenteral phenobarbital in critically ill patients with brain injury. Patients with severe traumatic or non-traumatic brain injury at high risk of seizure were included and followed for seven days. All patients initially received phenobarbital as a loading dose of 15 mg/kg over 30-minutes infusion, followed by 2 mg/kg/day divided into three doses. Blood samples were obtained on the first and fourth day of study at 1, 2, 5, 8, and 10 hours after the end of the infusion. Serum concentrations of phenobarbital were measured by high-pressure liquid chromatography (HPLC) with an ultraviolet (UV) detector. Pharmacokinetic parameters, including the volume of distribution (Vd), half-life (t1/2), and the drug clearance (CL), were provided by MonolixSuite 2019R1 software using stochastic approximation expectation-maximization (SAEM) algorithm and compared with previously reported parameters in healthy volunteers. Data from seventeen patients were analyzed. The mean value±standard deviation of pharmacokinetic parameters was calculated as follows: Vd: 0.81±0.15 L/kg; t1/2: 6.16±2.66 days; CL: 4.23±1.51 ml/kg/h. CL and Vd were significantly lower and higher than the normal population with the value of 5.6 ml/kg/h (P=0.002) and 0.7 L/kg (P=0.01), respectively. Pharmacokinetic behavior of phenobarbital may change significantly in critically ill brain-injured patients. This study affirms the value of early phenobarbital therapeutic drug monitoring (TDM) to achieve therapeutic goals.

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Population Pharmacokinetics and Monte Carlo Dosing Simulations of Meropenem during the Early Phase of Severe Sepsis and Septic Shock in Critically Ill Patients in Intensive Care Units

Antimicrobial Agents and Chemotherapy ◽

10.1128/aac.04166-14 ◽

2015 ◽

Vol 59 (6) ◽

pp. 2995-3001 ◽

Cited By ~ 30

Author(s):

Sutep Jaruratanasirikul ◽

Suriyan Thengyai ◽

Wibul Wongpoowarak ◽

Thitima Wattanavijitkul ◽

Kanyawisa Tangkitwanitjaroen ◽

...

Keyword(s):

Septic Shock ◽

Monte Carlo ◽

Severe Sepsis ◽

Critically Ill ◽

Critically Ill Patients ◽

Early Phase ◽

Volume Of Distribution ◽

Therapeutic Success ◽

Altered Pharmacokinetic ◽

Sepsis And Septic Shock

ABSTRACTPathophysiological changes during the early phase of severe sepsis and septic shock in critically ill patients, resulting in altered pharmacokinetic (PK) patterns for antibiotics, are important factors influencing therapeutic success. The aims of this study were (i) to reveal the population PK parameters and (ii) to assess the probability of target attainment (PTA) for meropenem. The PK studies were carried out following administration of 1 g of meropenem every 8 h during the first 24 h of severe sepsis and septic shock in nine patients, and a Monte Carlo simulation was performed to determine the PTA of achieving 40% exposure time during which the free plasma drug concentration remains above the MIC (fT>MIC) and 80%fT>MIC. The volume of distribution (V) and total clearance (CL) of meropenem in these patients were 23.7 liters and 7.82 liters/h, respectively. For pathogens with MICs of 4 μg/ml, the PTAs of 40%fT>MICfollowing administration of meropenem as a 1-h infusion of 1 g every 8 h and a 4-h infusion of 0.5 g every 8 h were 92.52% and 90.29%, respectively. For pathogens with MICs of 2 μg/ml in immunocompromised hosts, the PTAs of 80%fT>MICfollowing administration of 1-h and 4-h infusions of 2 g of meropenem every 8 h were 84.32% and 94.72%, respectively. These findings indicated that theVof meropenem was greater and the CL of meropenem was lower than the values obtained in a previous study with healthy subjects. The maximum recommended dose, i.e., 2 g of meropenem every 8 h, may be required for treatment of life-threatening infections in this patient population.

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Drug Dosing Considerations in Critically Ill Patients Receiving Continuous Renal Replacement Therapy

Pharmacy ◽

10.3390/pharmacy8010018 ◽

2020 ◽

Vol 8 (1) ◽

pp. 18 ◽

Cited By ~ 1

Author(s):

Soo Min Jang ◽

Sergio Infante ◽

Amir Abdi Pour

Keyword(s):

Renal Replacement Therapy ◽

Continuous Renal Replacement Therapy ◽

Replacement Therapy ◽

Critically Ill ◽

Critically Ill Patients ◽

Patient Specific ◽

Therapeutic Drug ◽

Intermittent Hemodialysis ◽

Drug Dosing ◽

Low Efficiency

Acute kidney injury is very common in critically ill patients requiring renal replacement therapy. Despite the advancement in medicine, the mortality rate from septic shock can be as high as 60%. This manuscript describes drug-dosing considerations and challenges for clinicians. For instance, drugs’ pharmacokinetic changes (e.g., decreased protein binding and increased volume of distribution) and drug property changes in critical illness affecting solute or drug clearance during renal replacement therapy. Moreover, different types of renal replacement therapy (intermittent hemodialysis, prolonged intermittent renal replacement therapy or sustained low-efficiency dialysis, and continuous renal replacement therapy) are discussed to describe how to optimize the drug administration strategies. With updated literature, pharmacodynamic targets and empirical dosing recommendations for commonly used antibiotics in critically ill patients receiving continuous renal replacement therapy are outlined. It is vital to utilize local epidemiology and resistance patterns to select appropriate antibiotics to optimize clinical outcomes. Therapeutic drug monitoring should be used, when possible. This review should be used as a guide to develop a patient-specific antibiotic therapy plan.

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Individualization of Piperacillin Dosing for Critically Ill Patients: Dosing Software To Optimize Antimicrobial Therapy

Antimicrobial Agents and Chemotherapy ◽

10.1128/aac.02664-14 ◽

2014 ◽

Vol 58 (7) ◽

pp. 4094-4102 ◽

Cited By ~ 38

Author(s):

T. W. Felton ◽

J. A. Roberts ◽

T. P. Lodise ◽

M. Van Guilder ◽

E. Boselli ◽

...

Keyword(s):

Linear Regression ◽

Creatinine Clearance ◽

Critically Ill ◽

Critically Ill Patients ◽

Drug Exposure ◽

Volume Of Distribution ◽

Drug Clearance ◽

Dose Optimization ◽

Optimization Software ◽

The Impact

ABSTRACTPiperacillin-tazobactam is frequently used for empirical and targeted therapy of infections in critically ill patients. Considerable pharmacokinetic (PK) variability is observed in critically ill patients. By estimating an individual's PK, dosage optimization Bayesian estimation techniques can be used to calculate the appropriate piperacillin regimen to achieve desired drug exposure targets. The aim of this study was to establish a population PK model for piperacillin in critically ill patients and then analyze the performance of the model in the dose optimization software program BestDose. Linear, with estimated creatinine clearance and weight as covariates, Michaelis-Menten (MM) and parallel linear/MM structural models were fitted to the data from 146 critically ill patients with nosocomial infection. Piperacillin concentrations measured in the first dosing interval, from each of 8 additional individuals, combined with the population model were embedded into the dose optimization software. The impact of the number of observations was assessed. Precision was assessed by (i) the predicted piperacillin dosage and by (ii) linear regression of the observed-versus-predicted piperacillin concentrations from the second 24 h of treatment. We found that a linear clearance model with creatinine clearance and weight as covariates for drug clearance and volume of distribution, respectively, best described the observed data. When there were at least two observed piperacillin concentrations, the dose optimization software predicted a mean piperacillin dosage of 4.02 g in the 8 patients administered piperacillin doses of 4.00 g. Linear regression of the observed-versus-predicted piperacillin concentrations for 8 individuals after 24 h of piperacillin dosing demonstrated anr2of >0.89. In conclusion, for most critically ill patients, individualized piperacillin regimens delivering a target serum piperacillin concentration is achievable. Further validation of the dosage optimization software in a clinical trial is required.

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Personalized Piperacillin Dosing for the Critically Ill: A Retrospective Analysis of Clinical Experience with Dosing Software and Therapeutic Drug Monitoring to Optimize Antimicrobial Dosing

Antibiotics ◽

10.3390/antibiotics10060667 ◽

2021 ◽

Vol 10 (6) ◽

pp. 667

Author(s):

Ute Chiriac ◽

Daniel C. Richter ◽

Otto R. Frey ◽

Anka C. Röhr ◽

Sophia Helbig ◽

...

Keyword(s):

Septic Shock ◽

Therapeutic Drug Monitoring ◽

Critically Ill ◽

Drug Monitoring ◽

Critically Ill Patients ◽

Drug Exposure ◽

Therapeutic Drug ◽

Serum Concentrations ◽

Severe Infections ◽

Sepsis And Septic Shock

Optimization of antibiotic dosing is a treatment intervention that is likely to improve outcomes in severe infections. The aim of this retrospective study was to describe the therapeutic exposure of steady state piperacillin concentrations (cPIP) and clinical outcome in critically ill patients with sepsis or septic shock who received continuous infusion of piperacillin with dosing personalized through software-guided empiric dosing and therapeutic drug monitoring (TDM). Therapeutic drug exposure was defined as cPIP of 32–64 mg/L (2–4× the ‘MIC breakpoint’ of Pseudomonas aeruginosa). Of the 1544 patients screened, we included 179 patients (335 serum concentrations), of whom 89% achieved the minimum therapeutic exposure of >32 mg/L and 12% achieved potentially harmful cPIP > 96 mg/L within the first 48 h. Therapeutic exposure was achieved in 40% of the patients. Subsequent TDM-guided dose adjustments significantly enhanced therapeutic exposure to 65%, and significantly reduced cPIP > 96 mg/L to 5%. Mortality in patients with cPIP > 96 mg/L (13/21; 62%) (OR 5.257, 95% CI 1.867–14.802, p = 0.001) or 64–96 mg/L (30/76; 45%) (OR 2.696, 95% CI 1.301–5.586, p = 0.007) was significantly higher compared to patients with therapeutic exposure (17/72; 24%). Given the observed variability in critically ill patients, combining the application of dosing software and consecutive TDM increases therapeutic drug exposure of piperacillin in patients with sepsis and septic shock.

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Meropenem Dosing in Critically Ill Patients with Sepsis Receiving High-Volume Continuous Venovenous Hemofiltration

Antimicrobial Agents and Chemotherapy ◽

10.1128/aac.01582-09 ◽

2010 ◽

Vol 54 (7) ◽

pp. 2974-2978 ◽

Cited By ~ 49

Author(s):

I. Bilgrami ◽

J. A. Roberts ◽

S. C. Wallis ◽

J. Thomas ◽

J. Davis ◽

...

Keyword(s):

Critically Ill ◽

Critically Ill Patients ◽

High Volume ◽

Volume Of Distribution ◽

Continuous Venovenous Hemofiltration ◽

Drug Dosing ◽

Elimination Half ◽

Lower Volume ◽

Dosing Regimens ◽

Few Data

ABSTRACT Use of high ultrafiltrate flow rates with continuous venovenous hemofiltration (CVVHF) in critically ill patients is an emerging setting, for which there are few data to guide drug dosing. The objectives of this study were, firstly, to investigate the pharmacokinetics of meropenem in critically ill patients with severe sepsis who are receiving high-volume CVVHF with high-volume exchanges (≥4 liters/h); secondly, to determine whether standard dosing regimens (1,000 mg intravenously [i.v.] every 8 h) are sufficient for treatment of less susceptible organisms such as Burkholderia pseudomallei (MIC, 4 mg/liter); and, finally, to compare the clearances observed in this study with data from previous studies using lower-volume exchanges (1 to 2 liters/h). We recruited 10 eligible patients and collected serial pre- and postfilter blood samples and ultrafiltrate and urine samples. A noncompartmental method was used to determine meropenem pharmacokinetics. The cohort had a median age of 56.6 years, a median weight of 70 kg, and a median APACHE II (acute physiology and chronic health evaluation) score of 25. The median (interquartile range) values for meropenem were as follows: terminal elimination half-life, 4.3 h (2.9 to 6.0); terminal volume of distribution, 0.2 liters/kg (0.2 to 0.3); trough concentration, 7.7 mg/liter (6.2 to 12.9); total clearance, 6.0 liters/h (5.2 to 6.2); hemofiltration clearance, 3.5 liters/h (3.4 to 3.9). In comparing the meropenem clearance here with those in previous studies, ultrafiltration flow rate was found to be the parameter that accounted for the differences in clearance of meropenem (R 2 = 0.89). In conclusion, high-volume CVVHF causes significant clearance of meropenem, necessitating steady-state doses of 1,000 mg every 8 h to maintain sufficient concentrations to treat less susceptible organisms such as B. pseudomallei.

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Appropriate antibiotic therapy in critically ill patients

Italian Journal of Medicine ◽

10.4081/itjm.2016.792 ◽

2016 ◽

Vol 10 (4) ◽

pp. 275

Author(s):

Filippo Pieralli ◽

Antonio Mancini ◽

Andrea Crociani

Keyword(s):

Antibiotic Therapy ◽

Critically Ill ◽

Antimicrobial Therapy ◽

Critically Ill Patients ◽

Management Strategies ◽

Source Control ◽

Clinical Settings ◽

Clinical Scenario ◽

Initial Antimicrobial Therapy ◽

Sepsis And Septic Shock

Severe sepsis and septic shock are leading causes of morbidity and mortality in critically ill patients in and outside Intensive Care Units. Early hemodynamic and respiratory support, along with prompt appropriate antimicrobial therapy and source control of the infectious process are cornerstone management strategies to improve survival. Antimicrobial therapy should be as much appropriate as possible, since inappropriate initial antimicrobial therapy is associated with poorer outcome in different clinical settings. When prescribing antibiotic therapy, drug’s characteristics, along with dosing, pharmacokinetics, and pharmacodynamic properties related to the drug and to the clinical scenario should be well kept in mind in order to achieve maximal success.

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