Pharmacokinetic Evaluation of Cefazolin in the Cerebrospinal Fluid of Critically Ill Patients

Abstract: Background The relative distribution of cefazolin into the cerebrospinal fluid (CSF) remains debated. Determining the distribution of cefazolin to the CSF in non-infected adults may allow for further treatment applications of cefazolin. This prospective pharmacokinetic study aimed to determine the pharmacokinetic parameters of cefazolin in serum and CSF from external ventricular drains (EVD) in neurologically injured adults. Methods Blood and CSF was collected, using a biologic waste protocol, for cefazolin quantification and trapezoidal rule based pharmacokinetic analysis in a total of 15 critically ill adults receiving 2000mg IV every 8 hours or the renal dose equivalent for EVD prophylaxis. Results A median of 3 blood (range 2-4) and 3 CSF (range 2-5) samples were collected in each patient. The most common admitting diagnosis was subarachnoid hemorrhage (66.7%). Median calculated cefazolin CSF Cmax and Cmin (IQR) were 2.97mg/L (1.76-8.56) and 1.59mg/L (0.77-2.17), respectively. Median (IQR) CSF to serum area under-the-curve ratio was 6.7% (3.7%-10.6%), with time matched estimates providing a similar estimate (8.4%). Of those receiving cefazolin every 8 hours, the median and minimum directly measured CSF cefazolin concentration 4 hours or greater following administration were 1.87 and 0.78 mg/L, respectively. Conclusion Cefazolin dosed for EVD prophylaxis achieved CSF concentrations suggesting viability as a therapeutic option for patients with meningitis or ventriculitis due to susceptible bacteria such as methicillin-susceptible Staphylococcus aureus. Further clinical trials are required to confirm a role in therapy for cefazolin. Population-based pharmacokinetic-pharmacodynamic modeling may suggest an optimal cefazolin regimen for the treatment of central nervous system infections.

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Pharmacokinetics of Ganciclovir during Continuous Venovenous Hemodiafiltration in Critically Ill Patients

Antimicrobial Agents and Chemotherapy ◽

10.1128/aac.00892-13 ◽

2013 ◽

Vol 58 (1) ◽

pp. 94-101 ◽

Cited By ~ 8

Author(s):

Thomas Horvatits ◽

Reinhard Kitzberger ◽

Andreas Drolz ◽

Christian Zauner ◽

Walter Jäger ◽

...

Keyword(s):

Critically Ill ◽

Critically Ill Patients ◽

High Performance ◽

Area Under The Curve ◽

Antiviral Agent ◽

Pharmacokinetic Analysis ◽

Pharmacokinetic Parameters ◽

Population Pharmacokinetic ◽

Target Area ◽

Continuous Venovenous Hemodiafiltration

ABSTRACTGanciclovir is an antiviral agent that is frequently used in critically ill patients with cytomegalovirus (CMV) infections. Continuous venovenous hemodiafiltration (CVVHDF) is a common extracorporeal renal replacement therapy in intensive care unit patients. The aim of this study was to investigate the pharmacokinetics of ganciclovir in anuric patients undergoing CVVHDF. Population pharmacokinetic analysis was performed for nine critically ill patients with proven or suspected CMV infection who were undergoing CVVHDF. All patients received a single dose of ganciclovir at 5 mg/kg of body weight intravenously. Serum and ultradiafiltrate concentrations were assessed by high-performance liquid chromatography, and these data were used for pharmacokinetic analysis. Mean peak and trough prefilter ganciclovir concentrations were 11.8 ± 3.5 mg/liter and 2.4 ± 0.7 mg/liter, respectively. The pharmacokinetic parameters elimination half-life (24.2 ± 7.6 h), volume of distribution (81.2 ± 38.3 liters), sieving coefficient (0.76 ± 0.1), total clearance (2.7 ± 1.2 liters/h), and clearance of CVVHDF (1.5 ± 0.2 liters/h) were determined. Based on population pharmacokinetic simulations with respect to a target area under the curve (AUC) of 50 mg · h/liter and a trough level of 2 mg/liter, a ganciclovir dose of 2.5 mg/kg once daily seems to be adequate for anuric critically ill patients during CVVHDF.

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A Systematic Review of Studies Reporting Antibiotic Pharmacokinetic Data in the Cerebrospinal Fluid of Critically Ill Patients with Uninflamed Meninges

Antimicrobial Agents and Chemotherapy ◽

10.1128/aac.01998-20 ◽

2020 ◽

Vol 65 (1) ◽

pp. e01998-20

Author(s):

Nilesh Kumta ◽

Jason A. Roberts ◽

Jeffrey Lipman ◽

Wai Tat Wong ◽

Gavin M. Joynt ◽

...

Keyword(s):

Cerebrospinal Fluid ◽

Critically Ill ◽

Critically Ill Patients ◽

Pharmacokinetic Analysis ◽

Pharmacokinetic Parameters ◽

Therapeutic Drug ◽

Pharmacokinetic Data ◽

Significant Heterogeneity ◽

Related Factors ◽

Meningeal Inflammation

ABSTRACTVentriculostomy-associated infections in critically ill patients remain therapeutically challenging because of drug- and disease-related factors that contribute to suboptimal antibiotic concentrations in cerebrospinal fluid. Optimal antibiotic dosing for the treatment and prevention of such infections should be based on robust and contextually specific pharmacokinetic data. The objects of this study were to describe and critically appraise studies with reported antibiotic concentrations or pharmacokinetic data in cerebrospinal fluid of critically ill patients without meningeal inflammation. We systematically reviewed the literature to identify published reports and studies describing antibiotic concentrations, pharmacokinetics, and pharmacokinetics/pharmacodynamics in cerebrospinal fluid of critically ill patients with uninflamed meninges. Fifty-eight articles met the inclusion criteria. There was significant heterogeneity in methodologies and results. When available, antibiotic pharmacokinetic parameters displayed large intersubject variability. Intraventricular dosing achieved substantially higher antibiotic concentrations in cerebrospinal fluid than did intravenous doses. Few studies conducted a robust pharmacokinetic analysis and described relevant clinical pharmacokinetic/pharmacodynamic indices and exposure targets in cerebrospinal fluid. Robust and clinically relevant antibiotic pharmacokinetic data describing antibiotic disposition in cerebrospinal fluid are necessary. Such studies should use a standardized approach to accurately describe pharmacokinetic variability. These data should ideally be tied to clinical outcomes whereby therapeutic targets in the cerebrospinal fluid can be better defined. Altered dosing strategies, in conjunction with exploring the utility of therapeutic drug monitoring, can then be developed to optimize antibiotic exposure with the goal of improving outcomes in this difficult-to-treat patient group.

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Comparative Pharmacokinetic of Three Sulfadiazine Suspensions by Oral Administration in Chickens

Journal of Agricultural Science ◽

10.5539/jas.v8n2p122 ◽

2016 ◽

Vol 8 (2) ◽

pp. 122

Author(s):

Zhi-Qiang Wang ◽

Han-Song Li ◽

Xia Xiao ◽

Jian-Bing Wang

Keyword(s):

Plasma Concentration ◽

Broiler Chickens ◽

High Performance ◽

Area Under The Curve ◽

Pharmacokinetic Analysis ◽

Pharmacokinetic Parameters ◽

Peak Time ◽

Comparative Pharmacokinetic ◽

Elimination Half ◽

Maximal Plasma

The chemotherapeutics, sulfadiazine (SDA) and trimethoprim (TMP), are extensively used in a variety of animal species. In this study, a pharmacokinetic analysis was performed to compare the bioequivalence of a combined SDA and TMP product against existing licensed SDA and TMP formulations in broiler chickens. Three groups of 15 birds were administered a single dose of either the test formulation or a reference oral suspension. The plasma concentration of SDA and TMP were determined by reverse-phase high performance liquid chromatography (HPLC), and the maximal plasma concentration (Cmax), area under the curve (AUC), the peak time (Tmax), mean residence time (MRT) and elimination half-life (T1/2), were calculated for SDA. The combined formulation I and II reference suspension exhibited almost identical concentration-time curves, and ANOVA analyses of the pharmacokinetic parameters identified no significant differences between the reference preparations and the test one. Furthermore the AUC and Cmax values of the SDA active ingredient were not significantly different. The I formulation was bioequivalent with both II and III (80-125% and 70–143%, respectively, at the 90% confidence interval). In conclusion, the combined SDA and TMP product was bioequivalent with both existing commercially available SDA suspensions and can be used interchangeably in veterinary medical practice.

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Area under the Curve-Based Dosing of Vancomycin in Critically Ill Patients Using 6-Hour Urine Creatinine Clearance Measurement

Critical Care Research and Practice ◽

10.1155/2020/8831138 ◽

2020 ◽

Vol 2020 ◽

pp. 1-6

Author(s):

Bita Shahrami ◽

Farhad Najmeddin ◽

Saeideh Ghaffari ◽

Atabak Najafi ◽

Mohammad Reza Rouini ◽

...

Keyword(s):

Renal Function ◽

Creatinine Clearance ◽

Critically Ill ◽

Normal Renal Function ◽

Critically Ill Patients ◽

Area Under The Curve ◽

Total Daily Dose ◽

Pharmacokinetic Parameters ◽

Concentration Data ◽

Urine Creatinine

Background. The area under the curve- (AUC-) guided vancomycin dosing is the best strategy for individualized therapy in critical illnesses. Since AUC can be calculated directly using drug clearance (CLvan), any parameter estimating CLvan will be able to achieve the goal of 24-hour AUC (AUC24 h). The present study was aimed to determine CLvan based on 6-hour urine creatinine clearance measurement in critically ill patients with normal renal function. Method. 23 adult critically ill patients with an estimated glomerular filtration rate (eGFR) ≥60 mL/min who received vancomycin infusion were enrolled in this pilot study. Vancomycin pharmacokinetic parameters were determined for each patient using serum concentration data and a one-compartment model provided by MONOLIX software using stochastic approximation expectation-maximization (SAEM) algorithm. Correlation of CLvan with the measured creatinine clearance in 6-hour urine collection (CL6 h) and estimated creatinine clearance by the Cockcroft–Gault formula (CLCG) was investigated. Results. Data analysis revealed that CL6 h had a stronger correlation with CLvan rather than CLCG (r = 0.823 vs. 0.594; p < 0.001 vs. 0.003). The relationship between CLvan and CL6 h was utilized to develop the following equation for estimating CLvan: CLvan (mL/min) = ─137.4 + CL6 h (mL/min) + 2.5 IBW (kg) (R2 = 0.826, p < 0.001 ). Regarding the described model, the following equation can be used to calculate the empirical dose of vancomycin for achieving the therapeutic goals in critically ill patients without renal impairment: total daily dose of vancomycin (mg) = (─137.4CL6-h (mL/min) + 2.5 IBW (kg)) × 0.06 AUC24 h (mg.hr/L). Conclusion. For AUC estimation, CLvan can be obtained by collecting urine in a 6-hour period with good approximation in critically ill patients with normal renal function.

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Pharmacokinetics of trimethoprim/sulfametrole in critically ill patients on continuous renal replacement therapy

Journal of Antimicrobial Chemotherapy ◽

10.1093/jac/dkz556 ◽

2020 ◽

Vol 75 (5) ◽

pp. 1237-1241

Author(s):

René Welte ◽

Rudolph Beyer ◽

Johannes Hotter ◽

Astrid Broeker ◽

Sebastian G Wicha ◽

...

Keyword(s):

Renal Replacement Therapy ◽

Continuous Renal Replacement Therapy ◽

Replacement Therapy ◽

Critically Ill ◽

Pharmacokinetic Analysis ◽

Control Group ◽

Population Pharmacokinetic ◽

Significant Difference ◽

Critically Ill Adults ◽

Ill Adults

Abstract Objectives We investigated the effect of continuous renal replacement therapy (CRRT) on the pharmacokinetics of trimethoprim and sulfametrole. Patients and methods We enrolled critically ill adults undergoing CRRT and critically ill adults with normal or slightly impaired renal function (plasma creatinine concentration <1.5 mg/dL, control group). All patients received trimethoprim/sulfametrole at standard doses. Pharmacokinetics were determined after the first dose and at steady-state. In addition, a population pharmacokinetic model using plasma data was built. We also assessed the renal clearance (CLR) and the extracorporeal clearance in patients undergoing CRRT. Results Twelve patients were enrolled in the CRRT group and 12 patients in the control group. There was no statistically significant difference in trimethoprim pharmacokinetics between the two groups. In patients on CRRT, total plasma clearance (CLtot) and V of sulfametrole were significantly higher than in the control group. However, sulfametrole exposure was not significantly altered during CRRT. The population pharmacokinetic analysis indicated that neither CRRT intensity nor residual diuresis were significant covariates on trimethoprim or sulfametrole CL. Median CL by continuous venovenous haemofiltration accounted for about one-third of CLtot of trimethoprim and for about one-half of CLtot of sulfametrole. In patients on CRRT, CLR of trimethoprim and sulfametrole were <5% of CLtot. Conclusions During CRRT, standard doses of trimethoprim/sulfametrole appear to be adequate.

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Bloodstream Infection-Associated Sepsis and Septic Shock in Critically Ill Adults: A Population-Based Study

Infection ◽

10.1007/s15010-004-3064-6 ◽

2004 ◽

Vol 32 (2) ◽

pp. 59-64 ◽

Cited By ~ 46

Author(s):

K. B. Laupland ◽

H. D. Davies ◽

D. L. Church ◽

T. J. Louie ◽

J. S. Dool ◽

...

Keyword(s):

Septic Shock ◽

Bloodstream Infection ◽

Critically Ill ◽

Population Based ◽

Population Based Study ◽

Critically Ill Adults ◽

Sepsis And Septic Shock ◽

Ill Adults

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Evaluation of The Pharmacokinetic Interaction Between Cemetidine or Famotidine and Cyclosporine in Healthy Men

Annals of Pharmacotherapy ◽

10.1177/106002809502901102 ◽

1995 ◽

Vol 29 (11) ◽

pp. 1088-1091 ◽

Cited By ~ 4

Author(s):

Mark S Shaefer ◽

Stephen J Rossi ◽

Timothy R Mcguire ◽

Larry J Schaaf ◽

Dean S Collier ◽

...

Keyword(s):

Area Under The Curve ◽

Pharmacokinetic Interaction ◽

Potential Interaction ◽

University Teaching ◽

Pharmacokinetic Analysis ◽

Pharmacokinetic Parameters ◽

Fluorescence Polarization Immunoassay ◽

Healthy Men ◽

Dose Oral ◽

Study Population

Objective: To investigate the potential interaction between cimetidine or famotidine and cyclosporine in healthy men. Design: All subjects received oral cyclosporine at baseline, after the first week of 1 histamine2 (H2)-blocker, and a third time after a 1-week washout plus 1 week of the second H2-blocker. Blood samples were collected just before each dose of cyclosporine and for up to 36 hours afterward for pharmacokinetic analysis. Setting: A college of pharmacy in a university teaching hospital. Participants: The study population consisted of 8 healthy men at least 19 years of age. Main Outcome Measures: Cyclosporine concentrations in whole blood were measured using a polyclonal fluorescence polarization immunoassay. Cyclosporine pharmacokinetic parameters during each of the 3 treatment periods were compared. Results: The average times to maximum cyclosporine concentrations were similar between baseline (3.2 h), cimetidine (2.9 h), and famotidine (3.6 h) dosing periods. There were no significant differences in area under the curve, half-life, or maximum concentration during the 3 dosing periods. Conclusions: Neither cimetidine or famotidine produced a significant change in the pharmacokinetics of single-dose oral cyclosporine in healthy men.

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Vancomycin Area under the Curve and Pharmacokinetic Parameters during the First 24 Hours of Treatment in Critically Ill Patients using Bayesian Forecasting

Infection and Chemotherapy ◽

10.3947/ic.2020.52.4.573 ◽

2020 ◽

Vol 52 (4) ◽

pp. 573

Author(s):

Manat Pongchaidecha ◽

Dhitiwat Changpradub ◽

Kanjana Bannalung ◽

Kajeewan Seejuntra ◽

Sutthanuch Thongmee ◽

...

Keyword(s):

Critically Ill ◽

Critically Ill Patients ◽

Area Under The Curve ◽

Pharmacokinetic Parameters ◽

Bayesian Forecasting

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Anidulafungin and Micafungin Concentrations in Cerebrospinal Fluid and in Cerebral Cortex

Antimicrobial Agents and Chemotherapy ◽

10.1128/aac.00275-20 ◽

2020 ◽

Vol 64 (7) ◽

Author(s):

Jana Marx ◽

René Welte ◽

Tiziana Gasperetti ◽

Patrizia Moser ◽

Ronny Beer ◽

...

Keyword(s):

Cerebrospinal Fluid ◽

Cerebral Cortex ◽

Critically Ill ◽

Plasma Concentrations ◽

Critically Ill Adults ◽

Ill Adults

ABSTRACT Anidulafungin and micafungin were quantified in cerebrospinal fluid (CSF) of critically ill adults and in cerebral cortex of deceased patients. In CSF, anidulafungin levels (<0.01 to 0.66 μg/ml) and micafungin levels (<0.01 to 0.16 μg/ml) were lower than those in plasma concentrations (0.77 to 5.07 and 1.21 to 8.70 μg/ml, respectively) drawn simultaneously. In cerebral cortex, anidulafungin and micafungin levels were 0.21 to 2.34 and 0.18 to 2.88 μg/g, respectively. Thus, MIC values of several pathogenic Candida strains exceed concentrations in CSF and in brain.

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