scholarly journals Beta-Lactams Dosing in Critically Ill Patients with Gram-Negative Bacterial Infections: A PK/PD Approach

Antibiotics ◽  
2021 ◽  
Vol 10 (10) ◽  
pp. 1154
Author(s):  
Kelly L. Maguigan ◽  
Mohammad H. Al-Shaer ◽  
Charles A. Peloquin
Keyword(s):  
Critically Ill ◽  
Critically Ill Patients ◽  
Bacterial Infections ◽  
Kidney Injury ◽  
Volume Of Distribution ◽  
Beta Lactam ◽  
Beta Lactams ◽  
Icu Patients ◽  
Gram Negative ◽  
Dosing Strategies

Beta-lactam antibiotics are often the backbone of treatment for Gram-negative infections in the critically ill. Beta-lactams exhibit time-dependent killing, and their efficacy depends on the percentage of dosing interval that the concentration remains above the minimum inhibitory concentration. The Gram-negative resistance rates of pathogens are increasing in the intensive care unit (ICU), and critically ill patients often possess physiology that makes dosing more challenging. The volume of distribution is usually increased, and drug clearance is variable. Augmented renal clearance and hypermetabolic states increase the clearance of beta-lactams, while acute kidney injury reduces the clearance. To overcome the factors affecting ICU patients and decreasing susceptibilities, dosing strategies involving higher doses, and extended or continuous infusions may be required. In this review, we specifically examined pharmacokinetic models in ICU patients, to determine the desired beta-lactam regimens for clinical breakpoints of Enterobacterales and Pseudomonas aeruginosa, as determined by the European Committee on Antimicrobial Susceptibility Testing. The beta-lactams evaluated included penicillins, cephalosporins, carbapenems, and monobactams. We found that when treating less-susceptible pathogens, especially P. aeruginosa, continuous infusions are frequently needed to achieve the desired pharmacokinetic/pharmacodynamic targets. More studies are needed to determine optimal dosing strategies in the novel beta-lactams.

scholarly journals Assessment of a PK/PD Target of Continuous Infusion Beta-Lactams Useful for Preventing Microbiological Failure and/or Resistance Development in Critically Ill Patients Affected by Documented Gram-Negative Infections

Antibiotics ◽  
2021 ◽  
Vol 10 (11) ◽  
pp. 1311
Author(s):  
Milo Gatti ◽  
Pier Giorgio Cojutti ◽  
Renato Pascale ◽  
Tommaso Tonetti ◽  
Cristiana Laici ◽  
...  
Keyword(s):  
Continuous Infusion ◽  
Critically Ill ◽  
Critically Ill Patients ◽  
Area Under The Curve ◽  
Therapeutic Drug ◽  
Beta Lactam ◽  
Beta Lactams ◽  
Roc Curve Analysis ◽  
Resistance Development ◽  
Gram Negative

Background: Emerging data suggest that more aggressive beta-lactam PK/PD targets could minimize the occurrence of microbiological failure and/or resistance development. This study aims to assess whether a PK/PD target threshold of continuous infusion (CI) beta-lactams may be useful in preventing microbiological failure and/or resistance development in critically ill patients affected by documented Gram-negative infections. Methods: Patients admitted to intensive care units from December 2020 to July 2021 receiving continuous infusion beta-lactams for documented Gram-negative infections and having at least one therapeutic drug monitoring in the first 72 h of treatment were included. A receiver operating characteristic (ROC) curve analysis was performed using the ratio between steady-state concentration and minimum inhibitory concentration (Css/MIC) ratio as the test variable and occurrence of microbiological failure as the state variable. Area under the curve (AUC) and 95% confidence interval (CI) were calculated. Independent risk factors for the occurrence of microbiological failure were investigated using logistic regression. Results: Overall, 116 patients were included. Microbiological failure occurred in 26 cases (22.4%). A Css/MIC ratio ≤ 5 was identified as PK/PD target cut-off with sensitivity of 80.8% (CI 60.6–93.4%) and specificity of 90.5% (CI 74.2–94.4%), and with an AUC of 0.868 (95%CI 0.793–0.924; p < 0.001). At multivariate regression, independent predictors of microbiological failure were Css/MIC ratio ≤ 5 (odds ratio [OR] 34.54; 95%CI 7.45–160.11; p < 0.001) and Pseudomonas aeruginosa infection (OR 4.79; 95%CI 1.11–20.79; p = 0.036). Conclusions: Early targeting of CI beta-lactams at Css/MIC ratio > 5 during the treatment of documented Gram-negative infections may be helpful in preventing microbiological failure and/or resistance development in critically ill patients.

scholarly journals Low Caspofungin Exposure in Patients in Intensive Care Units

2016 ◽  
Vol 61 (2) ◽  
Author(s):  
Kim C. M. van der Elst ◽  
Anette Veringa ◽  
Jan G. Zijlstra ◽  
Albertus Beishuizen ◽  
Rob Klont ◽  
...  
Keyword(s):  
Intensive Care ◽  
Critically Ill ◽  
Critically Ill Patients ◽  
Drug Exposure ◽  
Standard Dose ◽  
Drug Distribution ◽  
Volume Of Distribution ◽  
Primary Objective ◽  
Time Curve ◽  
Icu Patients

ABSTRACT In critically ill patients, drug exposure may be influenced by altered drug distribution and clearance. Earlier studies showed that the variability in caspofungin exposure was high in intensive care unit (ICU) patients. The primary objective of this study was to determine if the standard dose of caspofungin resulted in adequate exposure in critically ill patients. A multicenter prospective study in ICU patients with (suspected) invasive candidiasis was conducted in the Netherlands from November 2013 to October 2015. Patients received standard caspofungin treatment, and the exposure was determined on day 3 of treatment. An area under the concentration-time curve from 0 to 24 h (AUC0–24) of 98 mg · h/liter was considered adequate exposure. In case of low exposure (i.e., <79 mg · h/liter, a ≥20% lower AUC0–24), the caspofungin dose was increased and the exposure reevaluated. Twenty patients were included in the study, of whom 5 had a positive blood culture. The median caspofungin AUC0–24 at day 3 was 78 mg · h/liter (interquartile range [IQR], 69 to 97 mg · h/liter). A low AUC0–24 (<79 mg · h/liter) was seen in 10 patients. The AUC0–24 was significantly and positively correlated with the caspofungin dose in mg/kg/day (P = 0.011). The median AUC0–24 with a caspofungin dose of 1 mg/kg was estimated using a pharmacokinetic model and was 114.9 mg · h/liter (IQR, 103.2 to 143.5 mg · h/liter). In conclusion, the caspofungin exposure in ICU patients in this study was low compared with that in healthy volunteers and other (non)critically ill patients, most likely due to a larger volume of distribution. A weight-based dose regimen is probably more suitable for patients with substantially altered drug distribution. (This study has been registered at ClinicalTrials.gov under registration no. NCT01994096.)

Efficacy and Safety of a Colistin Loading Dose, High-Dose Maintenance Regimen in Critically Ill Patients With Multidrug-Resistant Gram-Negative Pneumonia

2016 ◽  
Vol 32 (8) ◽  
pp. 487-493 ◽  
Author(s):  
Jessica L. Elefritz ◽  
Karri A. Bauer ◽  
Christian Jones ◽  
Julie E. Mangino ◽  
Kyle Porter ◽  
...  
Keyword(s):  
Critically Ill ◽  
Critically Ill Patients ◽  
Clinical Cure ◽  
Statistical Significance ◽  
Cohort Analysis ◽  
Kidney Injury ◽  
Multidrug Resistant ◽  
High Dose ◽  
Loading Dose ◽  
Gram Negative

Introduction: Emergence of multidrug-resistant (MDR) gram-negative (GN) pathogens and lack of novel antibiotics have increased the use of colistin, despite unknown optimal dosing. This study aimed to evaluate the safety and efficacy of a colistin loading dose, high-dose (LDHD) maintenance regimen in patients with MDR-GN pneumonia. Methods: A retrospective cohort analysis was performed comparing critically ill patients with MDR-GN pneumonia pre- and postimplementation of a colistin LDHD guideline with a primary outcome of clinical cure. Safety was assessed using incidence of acute kidney injury (AKI) based on RIFLE (risk, injury, failure, loss, end-stage renal disease) criteria. Results: Seventy-two patients met the inclusion criteria (42 preimplementation and 30 postimplementation). Clinical cure was achieved in 23 (55%) patients in the preimplementation group and 20 (67%) patients in the postimplementation group ( P = .31). AKI occurred in 50% of the patients during the preimplementation period and 58% during the postimplementation period ( P = .59) with no difference in initiation rates of renal replacement therapy. Conclusion: The increased clinical cure rate after implementation of the colistin LDHD guideline did not reach statistical significance. The LDHD guideline, however, was not associated with an increased incidence of AKI, despite higher intravenous colistin doses. Opportunity exists to optimize colistin dosage while balancing toxicity, but larger studies are warranted.

scholarly journals Methadone Pharmacokinetics in Geriatric Critically Ill Patients Following Intramuscular and Intravenous Administration: A Pilot Stud

2020 ◽  
Author(s):  
Safoura Beik Rassouli ◽  
Mohammad Reza Rouini ◽  
Farhad Najmeddin ◽  
Azin Gheimati ◽  
Ali A Golabchifar ◽  
...  
Keyword(s):  
Pain Management ◽  
Critically Ill ◽  
Intravenous Administration ◽  
Critically Ill Patients ◽  
Half Life ◽  
Serum Levels ◽  
Volume Of Distribution ◽  
Icu Patients ◽  
Potential Alternative ◽  
Pharmacokinetic Behavior

Background: Methadone is used for the pain management worldwide. Its special characteristics make it a potential alternative for pain management in critically ill and geriatric patients. Due to lack of studies in this population, we aimed to compare the pharmacokinetic behavior of Methadone following intramuscular and intravenous administration in geriatric ICU patients and with previously reports in healthy volunteers. Methods: According to the limitations in ICU setting, we could include 11 patients over 65 years old, who required opioid for pain relief in this study. Patients were randomized to receive 5 mg of Methadone IM or IV injection every 8 hours for 6 days. The Methadone plasma level detected with LC-mass tandem mass spectrometry, and pharmacokinetics parameters were evaluated for each subject in both 1st and 6th days of treatment. Results: Based on our results, bioavailability of intramuscular Methadone in geriatric ICU patients was low and less than 40% of the dose was absorbed within first 12 hours. The volume of distribution of Methadone in the first day was significantly lower than the previously reported values in healthy subjects and significantly increased during these 6 days. The Methadone half-life in this population also significantly increased through this period. Conclusion: Pharmacokinetic behavior of Methadone in geriatric ICU patients is unpredictable. Reduced volume of distribution and half-life may be observed initially, following with an increase to the normal range. It seems that IM administration of Methadone in geriatric critically ill patients may not provide target analgesic Methadone serum levels.

Survival in Critically Ill Patients with Acute Kidney Injury Treated with Early Hemodiafiltration

2012 ◽  
Vol 35 (12) ◽  
pp. 1039-1046 ◽  
Author(s):  
Nicolas Boussekey ◽  
Benoit Capron ◽  
Pierre-Yves Delannoy ◽  
Patrick Devos ◽  
Serge Alfandari ◽  
...  
Keyword(s):  
Risk Factors ◽  
Acute Kidney Injury ◽  
Critically Ill ◽  
Mortality Risk ◽  
Critically Ill Patients ◽  
Kidney Injury ◽  
Icu Patients ◽  
Impact On Survival ◽  
Baseline Characteristics ◽  
The Moment

Purpose Early renal replacement therapy (RRT) initiation should theoretically influence many physiological disorders related to acute kidney injury (AKI). Currently, there is no consensus about RRT timing in intensive care unit (ICU) patients. Methods We performed a retrospective analysis of all critically ill patients who received RRT in our ICU during a 3 year-period. Our goal was to identify mortality risk factors and if RRT initiation timing had an impact on survival. RRT timing was calculated from the moment the patient was classified as having acute kidney injury in the RIFLE classification. Results A hundred and ten patients received RRT. We identified four independent mortality risk factors: need for mechanical ventilation (OR = 12.82 (1.305 - 125.868, p = 0.0286); RRT initiation timing >16 h (OR = 5.66 (1.954 - 16.351), p = 0.0014); urine output on admission <500 ml/day (OR = 4.52 (1.666 - 12.251), p = 0.003); and SAPS II on admission >70 (OR = 3.45 (1.216 - 9.815), p = 0.02). The RRT initiation <16 h and RRT initiation >16 h groups presented the same baseline characteristics, except for more severe gravity scores and kidney failure in the early RRT group. Conclusions Early RRT in ICU patients with acute kidney injury or failure was associated with increased survival.

scholarly journals Continuous Infusion Compared with Intermittent Intravenous Infusion of Beta-Lactam Antibiotics for Critically Ill Patients: A Systematic Review and Meta-Analysis of Randomized Trials

2020 ◽  
Author(s):  
Chien-Huei Huang ◽  
Ching-Yao Shih ◽  
Meng Keng Tsay ◽  
Shen-Pei Hsuan ◽  
Yung-Hsin Tseng ◽  
...  
Keyword(s):  
Continuous Infusion ◽  
Critically Ill ◽  
Critically Ill Patients ◽  
Eradication Rate ◽  
Cochrane Library ◽  
Secondary Outcome ◽  
Bacterial Eradication ◽  
Beta Lactam ◽  
Beta Lactams ◽  
Beta Lactam Antibiotics

Abstract Background: The pathophysiologic changes during critical illness and high minimal inhibitory concentration (MIC) pathogens are important risk factors of mortality and bacterial eradication in critical care. Beta-lactam antibiotics have a time-dependent effect on bactericidal activity. The continuous infusion (CIF) of beta-lactam antibiotics achieves sufficient drug concentration above the MIC, especially for critically ill patients. However, the superiority of CIF over intermittent infusion (IIF) of beta-lactam antibiotics is yet to be clearly established. Thus, we aimed to investigate the effects on mortality of CIF of beta-lactams antibiotics in comparison to those of IIF of beta-lactams antibiotics in patients with sepsis admitted to the intensive care unit (ICU).Methods: We systematically searched PUBMED, MEDLINE, Cochrane Library, EMBASE, Web of Science, and ICTRP for randomized controlled trials (RCTs) comparing CIF with IIF of beta-lactam antibiotics in critically ill populations. All RCTs published until October 2019 were eligible. The primary outcome measure was the relative risk (RR) of mortality, while the secondary outcome measures were bacterial eradication rate, length of ICU stay, and length of admission. Results: In total, 6 RCTs comprising 974 patients were analyzed. We found a significantly lower mortality for critically ill patients on CIF (RR: 0.79; 95% CI: 0.63, 0.98) compared with those on IIF of beta-lactam antibiotics. The pooled RR for the bacterial eradication rate was 1.16 (95% CI: 1.03, 1.29) for CIF compared with IIF administration. Conclusion: CIF of beta-lactam antibiotics for critically ill patients significantly reduces mortality and yields a better bacterial eradication rate than IIF. These findings support the clinical and bacterial eradication benefits in adult critically ill patients, and may guide clinical discussions and decisions.

Conservative Management of Acute Kidney Injury

2018 ◽  
Author(s):  
Rolando Claure-Del Granado ◽  
Etienne Macedo ◽  
Ravindra L. Mehta
Keyword(s):  
Acute Kidney Injury ◽  
Critically Ill ◽  
Fluid Resuscitation ◽  
Critically Ill Patients ◽  
Multiorgan Failure ◽  
Kidney Injury ◽  
Care Environment ◽  
Icu Patients ◽  
Fluid Removal ◽  
Risk Of Mortality

Acute kidney injury (AKI) is one of the most common complications occurring among intensive care unit (ICU) patients and is independently associated with a higher risk of mortality. In critically ill patients, AKI presentation is heterogeneous, varying from asymptomatic elevations in serum creatinine to the need for dialysis in the context of multiorgan failure. Within this range of clinical presentation, the kidney is often overlooked because improving and maintaining cardiac performance are the focus. In addition, aggressive fluid resuscitation may impose significant demands on the kidney wherein the normal excretory capacity may be overwhelmed. ICU patients often have underlying comorbidities, including chronic kidney disease and heart failure, which further limit the range of renal capacity. Drug and nutritional administration contribute to the demand for fluid removal to maintain fluid balance. The dissimilarities of the critical care environment and the extra demand kidney capacity highlight the need for different strategies for management and treatment of AKI in the critically ill patients. We focus this review on the general and nondialytic therapy of AKI. This reference contains 5 figures, 3 tables and 90 references Key words: Acute kidney injury, fluid resuscitation, loop diuretics, vasoactive agents, fluid overload, hiperkalemia, and metabolic acidosis.  

Evaluation of studies on extended versus standard infusion of beta-lactam antibiotics

2019 ◽  
Vol 76 (18) ◽  
pp. 1383-1394 ◽  
Author(s):  
Melanie Chen ◽  
Valerie Buurma ◽  
Monica Shah ◽  
Germin Fahim
Keyword(s):  
Pseudomonas Aeruginosa ◽  
Clinical Outcomes ◽  
Critically Ill ◽  
Critically Ill Patients ◽  
Clinical Success ◽  
Beta Lactam ◽  
Therapeutic Success ◽  
Gram Negative ◽  
Beta Lactam Antibiotics ◽  
Drug Concentrations

AbstractPurposeTo summarize the current literature on the use and clinical efficacy of extended-infusion (EI) beta-lactam antibiotics, including piperacillin–tazobactam, meropenem, and cefepime.SummaryGram-negative infections are a serious concern among hospitalized patients and require innovative pharmacokinetic dosing strategies to achieve clinical success, especially as the emergence of resistant gram-negative pathogens has outpaced the development of new antibiotics. Beta-lactam antibiotics exhibit time-dependent activity, which means that optimal efficacy is achieved when free drug concentrations stay above the minimum inhibitory concentration for an extended duration of the recommended dosage interval. EI piperacillin–tazobactam therapy has demonstrated improved clinical outcomes and decrease mortality in critically ill patients with gram-negative infections, particularly Pseudomonas aeruginosa infections. EI meropenem has shown higher therapeutic success rates for patients with febrile neutropenia and shorter intensive care unit (ICU) length of stay (LOS) with a reduction in ventilator days in patients with multidrug-resistant ventilator-associated pneumonia. However, a larger study showed no difference in clinical outcomes between standard-infusion and EI meropenem. EI cefepime has been associated with decreased mortality and shorter ICU LOS in patients with Pseudomonas aeruginosa infections. Common challenges associated with EI beta-lactam antibiotics include Y-site incompatibilities, lack of intravenous access, and tubing residuals. It is important to note that factors such as diverse patient populations and study methodology, along with various antibiotic dose regimens, may have contributed to conflicting data on EI beta-lactam therapy.ConclusionBased on most published literature, there appears to be a favorable trend toward use of EI beta-lactam therapy in clinical practice, particularly in critically ill patients with gram-negative infections.

scholarly journals Renal Replacement Therapy in Critically Ill: Current Trend and New Direction

2015 ◽  
Vol 3 (1) ◽  
pp. 17-21
Author(s):  
Sarwar Iqbal ◽  
Mohammad Omar Faruq
Keyword(s):  
Acute Kidney Injury ◽  
Renal Replacement Therapy ◽  
Serum Creatinine ◽  
Critically Ill ◽  
Critically Ill Patients ◽  
Early Identification ◽  
Kidney Injury ◽  
Hemodynamic Instability ◽  
Acid Base ◽  
Icu Patients

Critically ill patients often present with renal dysfunction. Acute kidney injury (AKI) is common in intensive care unit (ICU) patients and is often a component of multiple organ dysfunction syndrome (MODS). Renal replacement therapy (RRT) plays a significant role in management of acute and chronic renal failure in ICU. During the last decade RRT has made remarkable progress in management of renal dysfunction of critically ill. The Acute Dialysis Quality Initiative conceived in 2002 proposed RIFLE classification for AKI (risk, injury, failure, loss, end-stage kidney disease) using serum creatinine and urine output in critically ill patients. More recently, the Acute Kidney Injury Network (AKIN) has been introduced for staging AKI. Studies have shown that mortality increases proportionately with increasing severity of AKI. In patients with severe AKI requiring RRT mortality is approximately 50% to 70% according to one study and even a small changes in serum creatinine are associated with increased mortality. The most common causes of AKI in ICU are sepsis, hypovolemia, low cardiac output and drugs. The various techniques of RRT used in ICU include intermittent hemodialysis (IHD), continuous RRT (CRRT), sustained low efficiency dialysis (SLED) and peritoneal dialysis (PD). It is preferable to use RRT at either RIFLE injury type or at AKIN stage II in critically ill patients. IHD is commonly used in hemodynamically stable ICU patients. Because of high dialysate (500ml/min) IHD may cause hypotension in some patients. Solute removal may be episodic and often result in inferior uraemic control and acid base control. CRRT is usually initiated with a blood flow of 100 to 200 ml/min. and thus hemodynamic instability associated with IHD is avoided. Major advantages of CRRT include continuous control of fluid status, hemodynamic stability and control of acid base status. It is expensive and there is high risk of bleeding because of use of high dose of IV heparin. SLED has been found to be safe and effective in critically ill patients with hemodynamic instability. It uses the same dialysis machine of IHD and combines the effectiveness of CRRT in unstable patients and easy operability of IHD. It is also cost effective. PD is initiated in ICU for AKI patients when bedside IHD is not available. It is good for hemodynamically unstable patients when IHD or CRRT is difficult. In patients on mechanical ventilator, PD interferes with function of diaphragm causing decrease in lung compliance. Early identification of AKI with bio markers is an important step in improving outcomes of AKI. These bio markers help early detection of AKI before the onset of rise in serum creatinine. Serum cystatin C is one of the sensitive bio markers of small changes in Glomerular filtration rate (GFR) and has been found to be useful. AKI in the ICU most commonly results from multiple insults. Therefore appropriate and early identification of patients at risk of AKI provides an opportunity to prevent subsequent renal insults. This strategy will influence overall ICU morbidity and mortality.Bangladesh Crit Care J March 2015; 3 (1): 17-21

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