Steady‐state pharmacokinetic and pharmacodynamic profiling of colistin in critically ill patients with multi‐drug–resistant gram‐negative bacterial infections, along with differences in clinical, microbiological and safety outcome

2020 ◽  
Vol 128 (1) ◽  
pp. 128-140
Author(s):  
Kishna Ram ◽  
Salim Sheikh ◽  
Rahul Kumar Bhati ◽  
Chakra Dhar Tripathi ◽  
Jagdish Chander Suri ◽  
...  
Keyword(s):  
Steady State ◽  
Critically Ill ◽  
Critically Ill Patients ◽  
Bacterial Infections ◽  
Drug Resistant ◽  
Gram Negative ◽  
Safety Outcome

scholarly journals Population Pharmacokinetic Analysis of Colistin Methanesulfonate and Colistin after Intravenous Administration in Critically Ill Patients with Infections Caused by Gram-Negative Bacteria

2009 ◽  
Vol 53 (8) ◽  
pp. 3430-3436 ◽  
Author(s):  
D. Plachouras ◽  
M. Karvanen ◽  
L. E. Friberg ◽  
E. Papadomichelakis ◽  
A. Antoniadou ◽  
...  
Keyword(s):  
Steady State ◽  
Critically Ill ◽  
Critically Ill Patients ◽  
Compartment Model ◽  
Population Pharmacokinetic Analysis ◽  
Pharmacokinetic Analysis ◽  
Population Pharmacokinetic ◽  
Gram Negative Bacteria ◽  
Gram Negative ◽  
Colistin Methanesulfonate

ABSTRACT Colistin is used to treat infections caused by multidrug-resistant gram-negative bacteria (MDR-GNB). It is administered intravenously in the form of colistin methanesulfonate (CMS), which is hydrolyzed in vivo to the active drug. However, pharmacokinetic data are limited. The aim of the present study was to characterize the pharmacokinetics of CMS and colistin in a population of critically ill patients. Patients receiving colistin for the treatment of infections caused by MDR-GNB were enrolled in the study; however, patients receiving a renal replacement therapy were excluded. CMS was administered at a dose of 3 million units (240 mg) every 8 h. Venous blood was collected immediately before and at multiple occasions after the first and the fourth infusions. Plasma CMS and colistin concentrations were determined by a novel liquid chromatography-tandem mass spectrometry method after a rapid precipitation step that avoids the significant degradation of CMS and colistin. Population pharmacokinetic analysis was performed with the NONMEM program. Eighteen patients (6 females; mean age, 63.6 years; mean creatinine clearance, 82.3 ml/min) were included in the study. For CMS, a two-compartment model best described the pharmacokinetics, and the half-lives of the two phases were estimated to be 0.046 h and 2.3 h, respectively. The clearance of CMS was 13.7 liters/h. For colistin, a one-compartment model was sufficient to describe the data, and the estimated half-life was 14.4 h. The predicted maximum concentrations of drug in plasma were 0.60 mg/liter and 2.3 mg/liter for the first dose and at steady state, respectively. Colistin displayed a half-life that was significantly long in relation to the dosing interval. The implications of these findings are that the plasma colistin concentrations are insufficient before steady state and raise the question of whether the administration of a loading dose would benefit critically ill patients.

Continuous infusion versus intermittent administration of ceftazidime in critically ill patients with suspected gram-negative infections.

1996 ◽  
Vol 40 (3) ◽  
pp. 691-695 ◽  
Author(s):  
A S Benko ◽  
D M Cappelletty ◽  
J A Kruse ◽  
M J Rybak
Keyword(s):  
Steady State ◽  
Continuous Infusion ◽  
Clinical Isolate ◽  
Critically Ill ◽  
Critically Ill Patients ◽  
Apache Ii Score ◽  
Serum Drug Concentration ◽  
Gram Negative ◽  
Intermittent Bolus ◽  
Standard Deviations

The pharmacodynamics and pharmacokinetics of ceftazidime administered by continuous infusion and intermittent bolus over a 4-day period were compared. We conducted a prospective, randomized, crossover study of 12 critically ill patients with suspected gram-negative infections. The patients were randomized to receive ceftazidime either as a 2-g intravenous (i.v.) loading dose followed by a 3-g continuous infusion (CI) over 24 h or as 2 g i.v. every 8 h (q8h), each for 2 days. After 2 days, the patients were crossed over and received the opposite regimen. Each regimen also included tobramycin (4 to 7 mg/kg of body weight, given i.v. q24h). Eighteen blood samples were drawn on study days 2 and 4 to evaluate the pharmacokinetics of ceftazidime and its pharmacodynamics against a clinical isolate of Pseudomonas aeruginosa (R288). The patient demographics (means +/- standard deviations) were as follows: age, 57 +/- 12 years; sex, nine males and three females; APACHE II score, 15 +/- 3; diagnosis, 9 of 12 patients with pneumonia. The mean pharmacokinetic parameters for ceftazidime given as an intermittent bolus (IB) (means +/- standard deviations) were as follows: maximum concentration of drug in serum, 124.4 +/- 52.6 micrograms/ml; minimum concentration in serum, 25.0 +/- 17.5 micrograms/ml; elimination constant, 0.268 +/- 0.205 h-1; half-life, 3.48 +/- 1.61 h; and volume of distribution, 18.9 +/- 9.0 liters. The steady-state ceftazidime concentration for CI was 29.7 +/- 17.4 micrograms/ml, which was not significantly different from the targeted concentrations. The range of mean steady-state ceftazidime concentrations for the 12 patients was 10.6 to 62.4 micrograms/ml. Tobramycin peak concentrations ranged between 7 and 20 micrograms/ml. As expected, the area under the curve for the 2-g q8h regimen was larger than that for CI (P = 0.003). For IB and CI, the times that the serum drug concentration was greater than the MIC were 92 and 100%, respectively, for each regimen against the P. aeruginosa clinical isolate. The 24-h bactericidal titers in serum, at which the tobramycin concentrations were < 1.0 microgram/ml in all patients, were the same for CI and IB (1:4). In the presence of tobramycin, the area under the bactericidal titer-time curve (AUBC) was significantly greater for IB than CI (P = 0.001). After tobramycin was removed from the serum, no significant difference existed between the AUBCs for CI and IB. We conclude that CI of ceftazidime utilizing one-half the IB daily dose was equivalent to the IB treatment as judged by pharmacodynamic analysis of critically ill patients with suspected gram-negative infections. No evaluation comparing the clinical efficacies of these two dosage regimens was performed.

scholarly journals Multi-Drug Resistant Gram-Negative Infections Among Critically Ill Patients: Analysis of Baseline Characteristics and Factors Associated with Mortality

2020 ◽  
Author(s):  
Fadi Aljamaan ◽  
Esraa Altawil ◽  
Mohamad-Hani Temsah ◽  
Ahmad Almeman
Keyword(s):  
Pseudomonas Aeruginosa ◽  
Length Of Stay ◽  
Critically Ill ◽  
Critically Ill Patients ◽  
Drug Resistant ◽  
Gram Negative ◽  
Factors Associated ◽  
Icu Length Of Stay ◽  
Acinetobacter Spp ◽  
Apache Iv

Abstract BackgroundBacterial infections are a frequent cause of hospitalization and a leading cause of death, particularly with the emergence of antibiotics resistance. The emergence of Carbapenem resistance among gram-negative bacteria (GNB) is one of the evolving alerts as its use is considered the last resort of treatment [1]. Therefore, this urged studying the risk factors for the development of multi-drug resistant [2] GNB, identify the clinical outcomes and factors associated with mortality, especially among critically ill patients who are expected to have the worst outcomes.Materials/methodsThis is a retrospective observational study of critically ill patients who had an infection with Carbapenem-resistant Enterobacteriaceae (CRE), or MDR Pseudomonas aeruginosa, or MDR Acinetobacter spp. between May 2016- Nov 2018. Baseline demographics, co-morbidities, and clinical outcomes were collected and were evaluated for association with 28 days mortality. ResultsA total of 255 patients with MDR Gram-negative cultures were screened, 77 patients met the inclusion criteria. Pseudomonas aeruginosa was the most common index organism (53% of patients), followed by Acinetobacter spp. and CRE, respectively. The mortality rate at 28 days was (59.7%). Non-survivors were significantly older (mean age 64 vs. 44 years, P= 0.0001), had significantly worse disease severity scores on ICU admission, higher incidence of chronic kidney disease (CKD) (43% vs. 16%, P= 0.010), required more continuous renal replacement therapy (CRRT) (54% vs. 13% P= 0.0001), had longer hospital length of stay prior to infection (median 34 vs. 13 days, P= 0.018), and required longer inotropic and vasopressors support (median 19 vs. 8 days, P = 0.0001). In multivariate logistic regression the following factors were significantly associated with mortality; requirement of inotropic support [OR 10.01 (95% CI 1.55-64.77); P= 0.015], age [OR 1.05 (95% CI 1.0-1.1); P=0.01], APACHE IV score on ICU admission [OR 1.03 (95% CI 1.0- 1.06); P= 0.04], and ICU length of stay [OR 1.03 (95% CI 1.0- 1.06); P= 0.035].ConclusionMDR Gram-negative infection is associated with significant in-hospital mortality among critically ill patients. Old age, high APACHE IV score, higher ICU length of stay, and higher hemodynamic support are associated with higher mortality.Trial registrationretrospectively registered.

FEATURES

2012 ◽  
Vol 16 (02) ◽  
pp. 15-33
Keyword(s):  
Critically Ill ◽  
Critically Ill Patients ◽  
Susceptibility Testing ◽  
Bacterial Culture ◽  
Drug Resistant ◽  
Gram Negative ◽  
Ocular Infections ◽  
Indian Perspective

A Crisis in the Development of Antibiotics.Bacterial Culture and Anti-microbial Susceptibility Testing – their Use in Guiding Therapy.Epidemiology and Impact of Multi-Drug Resistant Gram Negative Infections in Critically Ill Patients in Asia.Antibiotics and Resistance in Ocular Infections – Indian Perspective.

scholarly journals A Population Pharmacokinetics and Pharmacodynamic Approach To Optimize Tazobactam Activity in Critically Ill Patients

2019 ◽  
Vol 64 (3) ◽  
Author(s):  
Shamir N. Kalaria ◽  
Mathangi Gopalakrishnan ◽  
Emily L. Heil
Keyword(s):  
Critically Ill ◽  
Critically Ill Patients ◽  
Bacterial Infections ◽  
Compartment Model ◽  
Time Profile ◽  
Gram Negative ◽  
Content Type ◽  
Dosing Regimens ◽  
Concentration Threshold

ABSTRACT The percentage of the time that the free drug concentration remains above a concentration threshold (%fT > concentration threshold) has frequently been identified to be the optimal pharmacokinetic (PK)-pharmacodynamic (PD) target of interest for tazobactam using in vitro infection models. Similar in vitro models suggested that an 85% fT > concentration threshold of 2 μg/ml for tazobactam is required to demonstrate a 2-log10-unit decrease in the number of CFU per milliliter from that at the baseline at 24 h for high-level β-lactamase-producing Escherichia coli strains. The objective of this study was to characterize the tazobactam concentrations in a cohort of critically ill patients with Gram-negative bacterial infections, determine if traditional dosing regimens achieve a prespecified PK/PD target of an 80% fT > concentration threshold of 2 μg/ml, and propose alternative dosing regimens. Hospitalized critically ill adult patients receiving piperacillin-tazobactam (TZP) for a culture-positive Gram-negative bacterial infection were eligible to consent for study inclusion. Two blood samples were drawn, one during the midpoint of the dosing interval and one at the time of the trough concentration once the patient achieved PK steady state. A population PK model was developed using Phoenix NLME (v8.1) software to characterize the observed concentration-time profile of tazobactam, explore potential covariates to explain the variability in the clearance and volume parameters, and to simulate potential dosing regimens that would achieve the PK/PD target. The PK of tazobactam were adequately described by a one-compartment model with first-order elimination in 18 patients who provided consent. The final model incorporated creatinine clearance as a covariate on clearance. Simulations demonstrated target attainments of less than 50% for tazobactam using traditional dosing regimens (4/0.5 g over 30 min every 6 h). Target attainments of greater than 75% were achieved when using extended infusion times of 4 to 6 h or when administering TZP as a continuous infusion (16/2 g over 24 h). Traditional tazobactam dosing regimens fail to achieve conservative PK/PD targets in critically ill patients. Increases in the tazobactam dose or prolongation of the infusion rate may be warranted to achieve activity against β-lactamase-producing Gram-negative bacteria.

Sign in / Sign up

Export Citation Format

Share Document