scholarly journals Impact of Maximizing Css/MIC Ratio on Efficacy of Continuous Infusion Meropenem Against Documented Gram-Negative Infections in Critically Ill Patients and Population Pharmacokinetic/Pharmacodynamic Analysis to Support Treatment Optimization

2021 ◽  
Vol 12 ◽  
Author(s):  
Pier Giorgio Cojutti ◽  
Milo Gatti ◽  
Matteo Rinaldi ◽  
Tommaso Tonetti ◽  
Cristiana Laici ◽  
...  
Keyword(s):  
Renal Function ◽  
Critically Ill ◽  
Critically Ill Patients ◽  
Population Pharmacokinetic ◽  
Treatment Optimization ◽  
Gram Negative ◽  
Cart Analysis ◽  
Pharmacodynamic Analysis ◽  
Favorable Clinical Outcome ◽  
Support Treatment

Introduction: optimal treatment of Gram-negative infections in critically ill patients is challenged by changing pathophysiological conditions, reduced antimicrobial susceptibility and limited therapeutic options. The aim of this study was to assess the impact of maximizing Css/MIC ratio on efficacy of continuous infusion (CI) meropenem in treating documented Gram-negative infections in critically ill patients and to perform a population pharmacokinetic/pharmacodynamic analysis to support treatment optimization.Materials and Methods: Classification and regression tree (CART) analysis was used to identify whether a cutoff of steady-state meropenem concentration (Css)-to-minimum inhibitory concentration (MIC) (Css/MIC) ratio correlated with favorable clinical outcome. A non-parametric approach with Pmetrics was used for pharmacokinetic analysis and covariate evaluation. The probability of target attainment (PTA) of the identified Css/MIC ratio was calculated by means of Monte Carlo simulations. Cumulative fraction of response (CFRs) were calculated against common Enterobacterales, P. aeruginosa and A. baumannii as well.Results: a total of 74 patients with 183 meropenem Css were included. CART analysis identified a Css/MIC ratio ≥4.63 as cutoff value significantly associated with favorable clinical outcomes. Multivariate regression analysis confirmed the association [OR (95%CI): 20.440 (2.063–202.522); p < 0.01]. Creatinine clearance (CLCR) was the only covariate associated with meropenem clearance. Monte Carlo simulations showed that, across different classes of renal function, dosages of meropenem ranging between 0.5 and 2 g q6h over 6 h (namely by CI) may grant PTAs of Css/MIC ratios ≥4.63 against susceptible pathogens with an MIC up to the EUCAST clinical breakpoint of 2 mg/L. The CFRs achievable with these dosages were very high (>90%) against Enterobacterales across all the classes of renal function and against P. aeruginosa among patients with CLCR < 30 ml/min/1.73 m2, and quite lower against A. baumannii.Discussion: our findings suggest that Css/MIC ratio ≥4.63 may be considered the pharmacodynamic target useful at maximizing the efficacy of CI meropenem in the treatment of Gram-negative infections in critically ill patients. Dosages ranging between 0.5 g q6h and 2 g q6h by CI may maximize the probability of favorable clinical outcome against meropenem-susceptible Gram-negative pathogens among critically ill patients having different degrees of renal function.

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.

scholarly journals Colistin Population Pharmacokinetics after Application of a Loading Dose of 9 MU Colistin Methanesulfonate in Critically Ill Patients

2015 ◽  
Vol 59 (12) ◽  
pp. 7240-7248 ◽  
Author(s):  
Ilias Karaiskos ◽  
Lena E. Friberg ◽  
Konstantinos Pontikis ◽  
Konstantinos Ioannidis ◽  
Vasiliki Tsagkari ◽  
...  
Keyword(s):  
Critically Ill ◽  
Critically Ill Patients ◽  
Compartment Model ◽  
Population Pharmacokinetic Analysis ◽  
Pharmacokinetic Analysis ◽  
Population Pharmacokinetic ◽  
Loading Dose ◽  
Gram Negative ◽  
Link Type ◽  
Colistin Methanesulfonate

ABSTRACTColistin has been revived, in the era of extensively drug-resistant (XDR) Gram-negative infections, as the last-resort treatment in critically ill patients. Recent studies focusing on the optimal dosing strategy of colistin have demonstrated the necessity of a loading dose at treatment initiation (D. Plachouras, M. Karvanen, L. E. Friberg, E. Papadomichelakis, A. Antoniadou, I. Tsangaris, I. Karaiskos, G. Poulakou, F. Kontopidou, A. Armaganidis, O. Cars, and H. Giamarellou, Antimicrob Agents Chemother 53:3430–3436, 2009,http://dx.doi.org/10.1128/AAC.01361-08; A. F. Mohamed, I. Karaiskos, D. Plachouras, M. Karvanen, K. Pontikis, B. Jansson, E. Papadomichelakis, A. Antoniadou, H. Giamarellou, A. Armaganidis, O. Cars, and L. E. Friberg, Antimicrob Agents Chemother 56:4241– 4249, 2012,http://dx.doi.org/10.1128/AAC.06426-11; S. M. Garonzik, J. Li, V. Thamlikitkul, D. L. Paterson, S. Shoham, J. Jacob, F. P. Silveira, A. Forrest, and R. L. Nation, Antimicrob Agents Chemother 55:3284–3294, 2011,http://dx.doi.org/10.1128/AAC.01733-10). In 19 critically ill patients with suspected or microbiologically documented infections caused by XDR Gram-negative strains, a loading dose of 9 MU colistin methanesulfonate (CMS) (∼270 mg colistin base activity) was administered with a maintenance dose of 4.5 MU every 12 h, commenced after 24 h. Patients on renal replacement were excluded. CMS infusion was given over 30 min or 1 h. Repeated blood sampling was performed after the loading dose and after the 5th or 6th dose. Colistin concentrations and measured CMS, determined after hydrolization to colistin and including the partially sulfomethylated derivatives, were determined with a liquid chromatography-tandem mass spectrometry assay. Population pharmacokinetic analysis was conducted in NONMEM with the new data combined with data from previous studies. Measured colistimethate concentrations were described by 4 compartments for distribution and removal of sulfomethyl groups, while colistin disposition followed a 1-compartment model. The average observed maximum colistin A plus B concentration was 2.65 mg/liter after the loading dose (maximum time was 8 h). A significantly higher availability of the measured A and B forms of colistimethate and colistin explained the higher-than-expected concentrations in the present study compared to those in previous studies. Creatinine clearance was a time-varying covariate of colistimethate clearance. The incidence of acute renal injury was 20%.

scholarly journals Does Critical Illness Change Levofloxacin Pharmacokinetics?

2015 ◽  
Vol 60 (3) ◽  
pp. 1459-1463 ◽  
Author(s):  
Jason A. Roberts ◽  
Menino Osbert Cotta ◽  
Piergiorgio Cojutti ◽  
Manuela Lugano ◽  
Giorgio Della Rocca ◽  
...  
Keyword(s):  
Renal Function ◽  
Critical Illness ◽  
Creatinine Clearance ◽  
Critically Ill ◽  
Critically Ill Patients ◽  
Clinical Indication ◽  
Independent Effect ◽  
Pharmacokinetic Analysis ◽  
Population Pharmacokinetic ◽  
The Mean

Levofloxacin is commonly used in critically ill patients for which existing data suggest nonstandard dosing regimens should be used. The objective of this study was to compare the population pharmacokinetics of levofloxacin in critically ill and in non-critically ill patients. Adult patients with a clinical indication for levofloxacin were eligible for participation in this prospective pharmacokinetic study. Patients were given 500 mg or 750 mg daily by intravenous administration with up to 11 blood samples taken on day 1 or 2 of therapy. Plasma samples were analyzed and population pharmacokinetic analysis was undertaken using Pmetrics. Thirty-five patients (18 critically ill) were included. The mean (standard deviation [SD]) age, weight, and Cockcroft-Gault creatinine clearance for the critically ill and for the non-critically ill patients were 60.3 (16.4) and 72.0 (11.6) years, 78.5 (14.8) and 70.9 (15.8) kg, and 71.9 (65.8) and 68.2 (30.1) ml/min, respectively. A two-compartment linear model best described the data. Increasing creatinine clearance was the only covariate associated with increasing drug clearance. The presence of critical illness did not significantly affect any pharmacokinetic parameter. The mean (SD) parameter estimates were as follows: clearance, 8.66 (3.85) liters/h; volume of the central compartment (Vc), 41.5 (24.5) liters; intercompartmental clearance constants from central to peripheral, 2.58 (3.51) liters/h; and peripheral to central compartments, 0.90 (0.58) liters/h. Monte Carlo dosing simulations demonstrated that achievement of therapeutic exposures was dependent on renal function, pathogen, and MIC. Critical illness appears to have no independent effect on levofloxacin pharmacokinetics that cannot be explained by altered renal function.

scholarly journals Time Above All Else: Pharmacodynamic Analysis of Β-Lactams in Critically Ill Patients

2021 ◽  
Vol 1 (S1) ◽  
pp. s70-s70
Author(s):  
Katherine Landmesser ◽  
David Burgess ◽  
Justin Clark
Keyword(s):  
Critically Ill ◽  
Critically Ill Patients ◽  
Intermittent Infusion ◽  
Healthcare Setting ◽  
Negative Resistance ◽  
Distribution Data ◽  
Parameter Estimates ◽  
Gram Negative ◽  
Development Of Resistance ◽  
Pharmacodynamic Analysis

Background: Despite the development of new β-lactam agents, gram-negative resistance continues to be an increasing concern in the healthcare setting. The understanding and optimizing antimicrobial pharmacokinetics and pharmacodynamics are essential to enhance activity of appropriate therapy, improve clinical outcomes, and reduce the development of resistance. Methods: A pharmacodynamic analysis was performed for 4 β-lactams (aztreonam, cefepime, piperacillin/tazobactam, and meropenem) and 14 dosage regimens as either intermittent bolus (IB) or prolonged infusion (PI) against 7 gram-negative pathogens: Klebsiella pneumoniae, K. oxytoca, Escherichia coli, Enterobacter cloacae, E. aerogenes, Acinetobacter baumannii, and Pseudomonas aeruginosa. Unit-specific minimum inhibitory concentration (MIC) distribution data were generated using antibiogram data over a decade for 4 intensive care units within our institution: medical ICU, cardiovascular ICU, surgical ICU, and neurosurgical ICU. Published pharmacokinetic parameter estimates in critically ill patients, combined with this MIC distribution data, were utilized to perform Monte Carlo simulations for each antimicrobial regimen. The percentage of time for which the unbound concentration of antibiotic remained above the MIC (ƒT>MIC) was utilized as the pharmacodynamic target for each agent: 40% ƒT>MIC for meropenem, 50% ƒT>MIC for piperacillin/tazobactam, 60% ƒT>MIC for aztreonam, and 70% ƒT>MIC for cefepime. Regimens were modeled using Oracle Crystal Ball software to determine the likelihood of achieving >90% probability of target attainment (PTA). Because resistance rates were significantly higher for P. aeruginosa and A. baumannii, cumulative PTAs for K. pneumoniae, K. oxytoca, E. coli, E. cloacae, and E. aerogenes were analyzed separately to determine the relative PTA for Enterobacterales in each ICU. Results: No intermittent infusion regimens of piperacillin/tazobactam, aztreonam, or cefepime achieved >90% PTA for any organism. Piperacillin/tazobactam 4.5 g infused over 4 hours (PI q6h) and aztreonam 2 g PI q6h failed to achieve adequate PTA for Enterobacterales with only 84% and 85% PTA, respectively. For Enterobacterales, the only regimens to achieve >90% PTA included cefepime 2 g infused over 3 hours (PI q8h) and meropenem 1g IB q8h with 95% and 99% PTA, respectively. Meropenem 2 g PI q8h was the only regimen capable of achieving >90% PTA for both A. baumannii and P. aeruginosa with 97% and 92% PTA, respectively. Conclusions: Although utilization of high doses and prolonged infusions dramatically improve the pharmacodynamics of β-lactam therapy, the only regimen capable of achieving adequate PTA for all organisms analyzed was meropenem 2g PI q8h. To reduce carbapenem use, combination therapy may be considered for critically ill patients receiving aztreonam, cefepime, or piperacillin/tazobactam for empiric treatment of gram-negative infections.Funding: NoDisclosures: None

β-Lactam pharmacodynamics in Gram-negative bloodstream infections in the critically ill

2019 ◽  
Author(s):  
Gloria Wong ◽  
Fabio Taccone ◽  
Paola Villois ◽  
Marc H Scheetz ◽  
Nathaniel J Rhodes ◽  
...  
Keyword(s):  
Clinical Outcome ◽  
Critically Ill ◽  
Critically Ill Patients ◽  
Drug Exposure ◽  
Blood Stream Infection ◽  
Bloodstream Infections ◽  
Positive Outcome ◽  
Classification And Regression Tree ◽  
Gram Negative ◽  
Cart Analysis

Abstract Objectives To determine the β-lactam exposure associated with positive clinical outcomes for Gram-negative blood stream infection (BSI) in critically ill patients. Patients and methods Pooled data of critically ill patients with mono-microbial Gram-negative BSI treated with β-lactams were collected from two databases. Free minimum concentrations (fCmin) of aztreonam, cefepime, ceftazidime, ceftriaxone, piperacillin (co-administered with tazobactam) and meropenem were interpreted in relation to the measured MIC for targeted bacteria (fCmin/MIC). A positive clinical outcome was defined as completion of the treatment course or de-escalation, without other change of antibiotic therapy, and with no additional antibiotics commenced within 48 h of cessation. Drug exposure breakpoints associated with positive clinical outcome were determined by classification and regression tree (CART) analysis. Results Data from 98 patients were included. Meropenem (46.9%) and piperacillin/tazobactam (36.7%) were the most commonly prescribed antibiotics. The most common pathogens were Escherichia coli (28.6%), Pseudomonas aeruginosa (19.4%) and Klebsiella pneumoniae (13.3%). In all patients, 87.8% and 71.4% achieved fCmin/MIC ≥1 and fCmin/MIC >5, respectively. Seventy-eight patients (79.6%) achieved positive clinical outcome. Two drug exposure breakpoints were identified: fCmin/MIC >1.3 for all β-lactams (predicted difference in positive outcome 84.5% versus 15.5%, P < 0.05) and fCmin/MIC >4.95 for meropenem, aztreonam or ceftriaxone (predicted difference in positive outcome 97.7% versus 2.3%, P < 0.05). Conclusions A β-lactam fCmin/MIC >1.3 was a significant predictor of a positive clinical outcome in critically ill patients with Gram-negative BSI and could be considered an antibiotic dosing target.

Combination of pharmacokinetic and pathogen susceptibility information to optimize meropenem treatment of gram-negative infections in critically ill patients

2021 ◽  
Author(s):  
Uwe Liebchen ◽  
Ferdinand Weinelt ◽  
Christina Scharf ◽  
Ines Schroeder ◽  
Michael Paal ◽  
...  
Keyword(s):  
Renal Function ◽  
Critically Ill ◽  
Critically Ill Patients ◽  
Tertiary Care ◽  
Stochastic Simulations ◽  
Care Hospital ◽  
Gram Negative ◽  
Susceptibility Data ◽  
Dosing Algorithm ◽  
Dosing Regimens

Background: Meropenem is one of the most frequently used antibiotics to treat life-threatening infections in critically ill patients. This study aimed to develop a meropenem dosing algorithm for the treatment of gram-negative infections based on intensive care unit (ICU)-specific resistance data. Methods: Antimicrobial susceptibility testing of gram-negative bacteria obtained from critically ill patients was carried out from 2016 to 2020 at a tertiary care hospital. Based on the observed minimal inhibitory concentration (MIC) distribution, stochastic simulations (n=1000) of an evaluated pharmacokinetic meropenem model and a defined pharmacokinetic/pharmacodynamic target (100%T >4xMIC while minimum concentrations <44.5 mg/L), dosing recommendations for patients with varying renal function were derived: Pathogen-specific MIC distributions were used to calculate the cumulative fraction of response (CFR) and the overall MIC distribution was used to calculate the local pathogen-independent mean fraction of response (LPIFR) for the investigated dosing regimens. A CFR/LPIFR >90% was considered adequate. Results: The observed MIC distribution significantly differed from the EUCAST database. Based on the 6520 MIC values included, a three-level dosing algorithm was developed. If the pathogen causing the infection is unknown (level 1), known (level 2), known to be neither Pseudomonas aeruginosa nor Acinetobacter baumannii or classified as susceptible (level 3), a continuous infusion of 1.5 g daily reached sufficient target attainment independent of renal function. In all other cases dosing needs to be adjusted based on renal function. Conclusion: ICU-specific susceptibility data should be assessed regularly and integrated into dosing decisions. The presented workflow may serve as a blueprint for other antimicrobial settings. (250 words)

scholarly journals Population Pharmacokinetics of High-Dose, Prolonged-Infusion Cefepime in Adult Critically Ill Patients with Ventilator-Associated Pneumonia

2009 ◽  
Vol 53 (4) ◽  
pp. 1476-1481 ◽  
Author(s):  
Anthony M. Nicasio ◽  
Robert E. Ariano ◽  
Sheryl A. Zelenitsky ◽  
Aryun Kim ◽  
Jared L. Crandon ◽  
...  
Keyword(s):  
Renal Function ◽  
Critically Ill ◽  
Critically Ill Patients ◽  
Pharmacokinetic Model ◽  
Coefficient Of Determination ◽  
Population Pharmacokinetic ◽  
High Dose ◽  
Ventilator Associated Pneumonia ◽  
Initial Model ◽  
Drug Concentrations

ABSTRACT A population pharmacokinetic model of cefepime was constructed from data from adult critical care patients with ventilator-associated pneumonia (VAP). A total of 32 patients treated with high-dose cefepime, 2 g every 8 h (3-h infusion) or a renal function-adjusted equivalent dose, were randomized into two groups—26 for the initial model and 6 for model validation. Serum samples of cefepime were collected at steady state. Nonparametric adaptive grid population modeling was employed using a two-compartment K slope pharmacokinetic model relating the elimination rate constant (K 10) to renal function, as defined by creatinine clearance (CLCR), and central distribution volume (V 1) to total body weight (TBW). The final model was described by the following equations: K 10 = 0.0027 × CLCR + 0.071 h−1 and V 1 = TBW × 0.21 liter/kg. The median intercompartmental transfer constants K 12 and K 21 were 0.780 h−1 and 0.472 h−1, respectively. Using these median parameter estimates, the bias, precision, and coefficient of determination for the initial model were 11.3 μg/ml, 24.0 μg/ml, and 26%, respectively. The independent validation group displayed a bias, precision, and coefficient of determination of −1.64 μg/ml, 17.1 μg/ml, and 62%, respectively. Time-concentration profiles were assessed for various dosing regimens, using 5,000-patient Monte Carlo simulations. Among the regimens, the likelihoods of 2 g every 8 h (3-h infusion) achieving free drug concentrations above the MIC for 50% of the dosing interval were 91.8%, 78.1%, and 50.3% for MICs of 8, 16, and 32 μg/ml, respectively. This study provides a pharmacokinetic model capable of predicting cefepime concentrations in critically ill patients with VAP.

scholarly journals Optimal empiric treatment for KPC-2-producing Klebsiella pneumoniae infections in critically ill patients with normal or decreased renal function using Monte Carlo simulation

2021 ◽  
Vol 21 (1) ◽  
Author(s):  
Guoan Wang ◽  
Wei Yu ◽  
Yushan Cui ◽  
Qingyi Shi ◽  
Chen Huang ◽  
...  
Keyword(s):  
Monte Carlo Simulation ◽  
Monte Carlo ◽  
Renal Function ◽  
Klebsiella Pneumoniae ◽  
Critically Ill ◽  
Normal Renal Function ◽  
Critically Ill Patients ◽  
Population Pharmacokinetic ◽  
Loading Dose ◽  
Daily Dose

Abstract Background Limited clinical studies describe the pharmacodynamics of fosfomycin (FOS), tigecycline (TGC) and colistin methanesulfonate (CMS) in combination against KPC-producing Klebsiella pneumoniae (KPC-Kp). Population pharmacokinetic models were used in our study. Monte Carlo simulation was conducted to calculate probability of target attainment (PTA) and cumulative fraction of response (CFR) of each agent alone and in combination against KPC-Kp in patients with normal or decreased renal function. Results The simulated regimen of FOS 6 g q8h reached ≥90% PTA against a MIC of 64 mg/L in patients with normal renal function. For patients with renal impairment, FOS 4 g q8h could provide sufficient antimicrobial coverage against a MIC of 128 mg/L. And increasing the daily dose could result to the cut-off value to 256 mg/L in decreased renal function. For TGC, conventional dosing regimens failed to reach 90% PTA against a MIC of 2 mg/L. Higher loading and daily doses (TGC 200/400 mg loading doses followed by 100 mg q12h/200 mg q24h) were needed. For CMS, none achieved 90% PTA against a MIC of 2 mg/L in normal renal function. Against KPC-Kp, the regimens of 200/400 mg loading dose followed by 100 q12h /200 mg q24h achieved > 80% CFRs regardless of renal function, followed by CMS 9 million IU loading dose followed by 4.5/3 million IU q12h in combination with FOS 8 g q8h (CFR 75–91%). Conclusions The use of a loading dose and high daily dose of TGC and CMS in combination with FOS can provide sufficient antimicrobial coverage against critically ill patients infected with KPC-Kp.

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