Population Pharmacokinetics of Ceftizoxime Administered by Continuous Infusion in Clinically Ill Adult Patients

ABSTRACT Ceftizoxime is a widely used beta-lactam antimicrobial agent, but pharmacokinetic data for use with clinically ill patients are lacking. We studied the population pharmacokinetics of ceftizoxime in 72 clinically ill patients at a community-based, university-affiliated hospital. A population pharmacokinetic model for ceftizoxime was created by using a prospective observational design. Ceftizoxime was administered by continuous infusion to treat patients with proven or suspected bacterial infections. While the patients were receiving infusions of ceftizoxime, serum samples were collected for pharmacokinetic analysis with the nonlinear mixed-effect modeling program NONMEM. In addition to clearance and volume of distribution, various comorbidities were examined for their influence on the kinetics. All 72 subjects completed the study, and 114 serum samples were collected. Several demographic and comorbidity variables, namely, age, weight, serum creatinine levels, congestive heart failure, and long-term ventilator dependency, had a significant impact on the estimate for ceftizoxime clearance. A mixture model, or two populations for estimation of ceftizoxime clearance, was discovered. One population presented with an additive clearance component of 1.6 liters per h. In addition, a maximizer function for serum creatinine levels was found. In summary, two models for ceftizoxime clearance, mixture and nonmixture, were found and are presented. Clearance for ceftizoxime can be estimated with commonly available clinical information and the models presented. From the clearance estimates, the dose of ceftizoxime to maintain the desired concentration in serum can be determined. Work is needed to validate the model for drug clearance and to evaluate its predictive performance.

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P61 Population pharmacokinetics of vancomycin in chinese ICU neonates: initial dosage recommendations

Archives of Disease in Childhood ◽

10.1136/archdischild-2019-esdppp.99 ◽

2019 ◽

Vol 104 (6) ◽

pp. e42.2-e42

Author(s):

Z Li ◽

Z Jiao

Keyword(s):

Body Weight ◽

Population Pharmacokinetics ◽

Pharmacokinetic Model ◽

Preterm Neonates ◽

Pharmacokinetic Analysis ◽

Population Pharmacokinetic ◽

List Type ◽

Current Guideline ◽

Mixed Effect ◽

Pediatric Cancer Patients

The main goal of our study was to characterize the population pharmacokinetics of vancomycin in critically ill Chinese neonates to develop a pharmacokinetic model and investigate factors that have significant influences on the pharmacokinetics of vancomycin in this population.1 2 The study population consisted of 80neonates in the neonatal intensive care unit (ICU)from which 165 trough and peak concentrations of vancomycin were obtained.Nonlinear mixed effect modeling was used to develop a population pharmacokinetic model for vancomycin.4 The stability and predictive ability of the final model were evaluated based on diagnostic plots, normalized prediction distribution errorsandthe bootstrap method.Serum creatinine (Scr) and body weight were significant covariates on the clearance of vancomycin.5 6 The average clearance was 0.309L/h for a neonate with Scr of 23.3mmol/L and body weight of 2.9 kg. No obvious ethnic differences in the clearance of vancomycin were found relative to the earlier studies of Caucasian neonates. Moreover, the established model indicated that in patients with a greater renal clearance status, especially Scr < 15mmol/L,current guideline recommendationswould likely not achieve therapeuticarea under the concentration-time curve over24 h/minimum inhibitoryconcentration (AUC24h/MIC) ≥ 400.3 The exceptions to this areBritish National Formulary (2016–2017), Blue Book (2016) and Neofax (2017). Recommended dose regimensfor neonates with differentScrlevelsandpostmenstrual ageswere estimatedbased on Monte Carlo simulations andthe established model.These findings will be valuable for developing individualized dosage regimens in the neonatal ICU setting.ReferencesAbdel HO, Al OS, Nazer LH., Mubarak S, Le, J. Vancomycin pharmacokinetics and predicted dosage requirements in pediatric cancer patients. Journal of Oncology Pharmacy Practice 2015;22(3):448–453doi: 10.1177/1078155215591386Anderson, B. J., Allegaert, K., Jn, V. D. A., Cossey, V., &Holford, N. H. ( 2007). Vancomycin pharmacokinetics in preterm neonates and the prediction of adult clearance. British Journal of Clinical Pharmacolog;63(1):75–84. doi: 10.1111/j.1365-2125.2006.02725.xAllegaert K, Anderson BJ, Jn, VDA, Vanhaesebrouck, S., & De, Z. F. ( 2007). Renal drug clearance in preterm neonates: relation to prenatal growth. Therapeutic Drug Monitoring, 29(3), 284–291. doi: 10.1097/FTD.0b013e31806db3f5Byon, W., Smith, M. K., Chan, P., Tortorici, M. A., Riley, S., & Dai, H., et al. ( 2013). Establishing best practices and guidance in population modeling: an experience with an internal population pharmacokinetic analysis guidance. CptPharmacometrics & Systems Pharmacology,2(7), e51. doi: 10.1016/j.cmpb.2010.04.018Capparelli, E. V., Lane, F. R., Romanowski, G. L., Pharm, M. F., Murray, W., & Sousa, P., et al. ( 2001). The influences of renal function and maturation on vancomycin elimination in newborns and infants. Journal of Clinical Pharmacology, 41(9), 927–934.Centers for Disease Control and Prevention. ( 2009). WHO Child Growth Standards. http://www.who.int/childgrowth/en. [EB/OL] 2017-09-12Disclosure(s)Nothing to disclose

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Population Pharmacokinetics of Arbekacin in Patients Infected with Methicillin-Resistant Staphylococcus aureus

Antimicrobial Agents and Chemotherapy ◽

10.1128/aac.00420-05 ◽

2006 ◽

Vol 50 (11) ◽

pp. 3754-3762 ◽

Cited By ~ 26

Author(s):

Yusuke Tanigawara ◽

Reiko Sato ◽

Kunihiko Morita ◽

Mitsuo Kaku ◽

Naoki Aikawa ◽

...

Keyword(s):

Staphylococcus Aureus ◽

Population Pharmacokinetics ◽

Elderly Subjects ◽

Pharmacokinetic Analysis ◽

Pharmacokinetic Parameters ◽

Peripheral Compartment ◽

Population Pharmacokinetic ◽

Time Data ◽

Mixed Effect ◽

Methicillin Resistant

ABSTRACT Arbekacin, a derivative of dibekacin, is an aminoglycoside developed and widely used in Japan for the treatment of patients infected with methicillin-resistant Staphylococcus aureus (MRSA). The population pharmacokinetics of arbekacin was investigated in the Japanese, using 353 patients infected with MRSA and 50 healthy or renally impaired volunteers. The age of the study population ranged from 8 to 95 years, and weight ranged from 10.8 to 107 kg. In total, 1,581 serum arbekacin concentrations were measured (primarily from routine patient care) and used to perform the present pharmacokinetic analysis. Drug concentration-time data were well described by a two-compartment open model. Factors influencing arbekacin pharmacokinetics were investigated using a nonlinear mixed-effect model analysis. The best-developed model showed that drug clearance (CL) was related to creatinine clearance (CLCR), age, and body weight (WT), as expressed by CL (liter/h) = 0.0319CLCR + (26.5/age) (CLCR < 80 ml/min) and CL (liter/h) = 0.0130 CLCR + 0.0342WT + (26.5/age) (CLCR ≥ 80 ml/min). The volume of distribution for the central and peripheral compartments was different in healthy subjects and infected patients, and this difference was more pronounced among disease types. The elderly subjects (aged 80 years or over) exhibited, on average, a 19% greater volume for the central compartment. The volumes for the peripheral compartment were 50.6 liters in patients with pneumonia and 24.3 liters in patients with sepsis. The population pharmacokinetic parameters of arbekacin obtained here are useful for optimal use of this aminoglycoside in the treatment of MRSA-infected patients.

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Population Pharmacokinetics and Dosing Optimization of Ceftazidime in Infants

Antimicrobial Agents and Chemotherapy ◽

10.1128/aac.02486-17 ◽

2018 ◽

Vol 62 (4) ◽

Cited By ~ 7

Author(s):

Zhong-Ren Shi ◽

Xing-Kai Chen ◽

Li-Yuan Tian ◽

Ya-Kun Wang ◽

Gu-Ying Zhang ◽

...

Keyword(s):

Population Pharmacokinetics ◽

High Performance ◽

Compartment Model ◽

Population Pharmacokinetic Analysis ◽

Generation Cephalosporin ◽

Pharmacokinetic Analysis ◽

Population Pharmacokinetic ◽

Pharmacokinetic Data ◽

Dosing Regimen ◽

Age Range

ABSTRACT Ceftazidime, a third-generation cephalosporin, can be used for the treatment of adults and children with infections due to susceptible bacteria. To date, the pediatric pharmacokinetic data are limited in infants, and therefore we aimed to evaluate the population pharmacokinetics of ceftazidime in infants and to define the appropriate dose to optimize ceftazidime treatment. Blood samples were collected from children treated with ceftazidime, and concentrations of the drug were quantified by high-performance liquid chromatography with UV detection (HPLC-UV). A population pharmacokinetic analysis was performed using NONMEM software ( version 7.2.0). Fifty-one infants ( age range, 0.1 to 2.0 years ) were included. Sparse pharmacokinetic samples ( n = 90 ) were available for analysis. A one-compartment model with first-order elimination showed the best fit with the data. A covariate analysis identified that body weight and creatinine clearance (CL CR ) were significant covariates influencing ceftazidime clearance. Monte Carlo simulation demonstrated that the currently used dosing regimen of 50 mg / kg twice daily was associated with a high risk of underdosing in infants. In order to reach the target of 70% of the time that the free antimicrobial drug concentration exceeds the MIC ( fT >MIC ), 25 mg/kg every 8 h (q8h) and 50 mg/kg q8h were required for MICs of 4 and 8 mg/liter, respectively. The population pharmacokinetic characteristics of ceftazidime were evaluated in infants. An evidence-based dosing regimen was established based on simulation.

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P49 A pharmacokinetic evaluation of oral clavulanic acid in term newborns

Archives of Disease in Childhood ◽

10.1136/archdischild-2019-esdppp.87 ◽

2019 ◽

Vol 104 (6) ◽

pp. e37.2-e37

Author(s):

FM Keij ◽

RF Kornelisse ◽

NG Hartwig ◽

J van der Sluijs ◽

A van Driel ◽

...

Keyword(s):

Clavulanic Acid ◽

Intervention Group ◽

Pharmacokinetic Analysis ◽

Population Pharmacokinetic ◽

Time Interval ◽

Antibiotic Administration ◽

List Type ◽

Beta Lactam ◽

Multicenter Rct ◽

Term Newborns

BackgroundClavulanic acid is an irreversible beta-lactamase inhibitor which has a weak antibacterial action. When combined with a beta-lactam antibiotic such as amoxicillin, it is effective against a broad range of bacteria. Despite its widespread use, little is known on the mechanism of action and target levels. A few studies on oral clavulanic acid in adults are available reporting great variance (AUC median 4.99 mg·h/L [0.44–8.31])1 and a short elimination half-time (1.08h).2 Observations in neonates are currently lacking. We therefore evaluated the pharmacokinetics of oral clavulanic acid co-administered with amoxicillin in term newborns.MethodsAs part of a multicenter RCT (Clinicaltrials.gov:NCT03247920) evaluating neonatal intravenous-to-oral switch therapy in probable bacterial infection, we measured serum levels in patients allocated to the intervention group. They switched to amoxicillin/clavulanic acid suspension (25/6.25 mg/kg tid), after 48 hours of intravenous penicillin/gentamicin. Two blood samples from different dosing intervals, were obtained and directly stored at -80°C. Initially, and to ensure that amoxicillin levels were attained as safety marker, levels in the second part of the timeframe (4–8 h after administration) were collected. For the second batch, peak levels (1–2 h after administration) were collected. Analysis was performed using Liquid Chromatography and Mass Spectrometry.ResultsAt submission, samples of the first 15 patients were analysed (first batch). Samples were collected 6.0 ± 1.3 h (mean,S.D.) after antibiotic administration. Clavulanic acid levels were detected in all patients but a great variance was observed (median: 1.4 mg/L; range: 0.20–4.82 mg/L). Extrapolation would lead to an AUC of at least 8.4 mg·h/L.ConclusionsOral clavulanic acid is absorbed in term newborns, but great variance is seen in trough levels (4–8 h after administration). Extrapolation predicts at least an AUC comparable to those of adults. Peak levels in the first part of the time interval (0–4h) are needed to further build confidence on this conclusion.ReferencesDe Velde F, De Winter BCM, Koch BCP, Van Gelder T, Mouton JW, Consortium C-N. Highly variable absorption of clavulanic acid during the day: a population pharmacokinetic analysis. J Antimicrob Chemother. 2018;73(2):469–76.Vree TB, Dammers E, Exler PS. Identical pattern of highly variable absorption of clavulanic acid from four different oral formulations of co-amoxiclav in healthy subjects. J Antimicrob Chemother 2003;51(2):373–8.Disclosure(s)Nothing to disclose

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Population Pharmacokinetics of Continuous-Infusion Meropenem in Febrile Neutropenic Patients with Hematologic Malignancies: Dosing Strategies for Optimizing Empirical Treatment against Enterobacterales and P. aeruginosa

Pharmaceutics ◽

10.3390/pharmaceutics12090785 ◽

2020 ◽

Vol 12 (9) ◽

pp. 785

Author(s):

Pier Giorgio Cojutti ◽

Anna Candoni ◽

Davide Lazzarotto ◽

Carla Filì ◽

Maria Zannier ◽

...

Keyword(s):

Monte Carlo ◽

Monte Carlo Simulations ◽

Continuous Infusion ◽

Hematologic Malignancies ◽

Population Pharmacokinetic Analysis ◽

Empirical Treatment ◽

Pharmacokinetic Analysis ◽

Population Pharmacokinetic ◽

Dosing Strategies ◽

Neutropenic Patients

A population pharmacokinetic analysis of continuous infusion (CI) meropenem was conducted in a prospective cohort of febrile neutropenic (FN) patients with hematologic malignancies. A non-parametric approach with Pmetrics was used for pharmacokinetic analysis and covariate evaluation. Monte Carlo simulations were performed for identifying the most appropriate dosages for empirical treatment against common Enterobacterales and P. aeruginosa. The probability of target attainment (PTA) of steady-state meropenem concentration (Css)-to-minimum inhibitory concentration (MIC) ratio (Css/MIC) ≥1 and ≥4 at the European Committee on Antimicrobial Susceptibility Testing (EUCAST) clinical breakpoint of 2 mg/L were calculated. Cumulative fraction of response (CFR) against Enterobacterales and P. aeruginosa were assessed as well. PTAs and CFRs ≥ 90% were considered optimal. A total of 61 patients with 178 meropenem Css were included. Creatinine clearance (CLCR) was the only covariate associated with meropenem clearance. Monte Carlo simulations showed that dosages of meropenem ranging between 1 g q8h and 1.25 g q6h by CI may grant optimal PTAs of Css/MIC ≥4 at the EUCAST clinical breakpoint. Optimal CFRs may be granted with these dosages against the Enterobacterales at Css/MIC ≥ 4 and against P. aeruginosa at Css/MIC ≥ 1. When dealing against P. aeruginosa at Css/MIC ≥ 4, only a dosage of 1.5 g q6h by CI may grant quasi-optimal CFR (around 80–87%). In conclusion, our findings suggest that dosages of meropenem ranging between 1 g q8h and 1.25 g q6h by CI may maximize empirical treatment against Enterobacterales and P. aeruginosa among FN patients with hematologic malignancies having different degree of renal function.

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Population Pharmacokinetics of Piperacillin following Continuous Infusion in Critically Ill Patients and Impact of Renal Function on Target Attainment

Antimicrobial Agents and Chemotherapy ◽

10.1128/aac.02556-19 ◽

2020 ◽

Vol 64 (7) ◽

Author(s):

Vibeke Klastrup ◽

Anders Thorsted ◽

Merete Storgaard ◽

Steffen Christensen ◽

Lena E. Friberg ◽

...

Keyword(s):

Continuous Infusion ◽

Critically Ill ◽

Critically Ill Patients ◽

Bacterial Infections ◽

Population Pharmacokinetic ◽

Target Attainment ◽

Content Type ◽

Daily Dose ◽

Linear Elimination ◽

Severe Infections

ABSTRACT Pharmacokinetic changes are often seen in patients with severe infections. Administration by continuous infusion has been suggested to optimize antibiotic exposure and pharmacokinetic/pharmacodynamic (PK/PD) target attainment for β-lactams. In an observational study, unbound piperacillin concentrations (n = 196) were assessed in 78 critically ill patients following continuous infusion of piperacillin-tazobactam (ratio 8:1). The initial dose of 8, 12, or 16 g (piperacillin component) was determined by individual creatinine clearance (CRCL). Piperacillin concentrations were compared to the EUCAST clinical breakpoint MIC for Pseudomonas aeruginosa (16 mg/liter), and the following PK/PD targets were evaluated: 100% free time (fT) > 1× MIC and 100% fT > 4× MIC. A population pharmacokinetic model was developed using NONMEM 7.4.3 consisting of a one-compartment disposition model with linear elimination separated into nonrenal and renal (linearly increasing with patient CRCL) clearances. Target attainment was predicted and visualized for all individuals based on the utilized CRCL dosing algorithm. The target of 100% fT > 1× MIC was achieved for all patients based on the administered dose, but few patients achieved the target of 100% fT > 4× MIC. Probability of target attainment for a simulated cohort of patients showed that increasing the daily dose by 4-g increments (piperacillin component) did not result in substantially improved target attainment for the 100% fT > 4× MIC target. To conclude, in patients with high CRCL combined with high-MIC bacterial infections, even a continuous infusion (CI) regimen with a daily dose of 24 g may be insufficient to achieve therapeutic concentrations.

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Population Pharmacokinetics and Dosing Optimization of Linezolid in Pediatric Patients

Antimicrobial Agents and Chemotherapy ◽

10.1128/aac.02387-18 ◽

2019 ◽

Vol 63 (4) ◽

Cited By ~ 2

Author(s):

Si-Chan Li ◽

Qi Ye ◽

Hua Xu ◽

Long Zhang ◽

Yang Wang

Keyword(s):

Body Weight ◽

Population Pharmacokinetics ◽

Population Pharmacokinetic Model ◽

Pharmacokinetic Model ◽

Pediatric Patients ◽

Population Pharmacokinetic ◽

Pharmacokinetic Data ◽

Nonparametric Bootstrap ◽

Bootstrap Analysis ◽

Final Model

ABSTRACT Linezolid is a synthetic antibiotic very effective in the treatment of infections caused by Gram-positive pathogens. Although the clinical application of linezolid in children has increased progressively, data on linezolid pharmacokinetics in pediatric patients are very limited. The aim of this study was to develop a population pharmacokinetic model for linezolid in children and optimize the dosing strategy in order to improve therapeutic efficacy. We performed a prospective pharmacokinetic study of pediatric patients aged 0 to 12 years. The population pharmacokinetic model was developed using the NONMEM program. Goodness-of-fit plots, nonparametric bootstrap analysis, normalized prediction distribution errors, and a visual predictive check were employed to evaluate the final model. The dosing regimen was optimized based on the final model. The pharmacokinetic data from 112 pediatric patients ages 0.03 to 11.9 years were analyzed. The pharmacokinetics could best be described by a one-compartment model with first-order elimination along with body weight and the estimated glomerular filtration rate as significant covariates. Simulations demonstrated that the currently approved dosage of 10 mg/kg of body weight every 8 h (q8h) would lead to a high risk of underdosing for children in the presence of bacteria with MICs of ≥2 mg/liter. To reach the pharmacokinetic target, an elevated dosage of 15 or 20 mg/kg q8h may be required for them. The population pharmacokinetics of linezolid were characterized in pediatric patients, and simulations provide an evidence-based approach for linezolid dosage individualization.

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Optimal Dosing of Ceftriaxone in Infants Based on a Developmental Population Pharmacokinetic-Pharmacodynamic Analysis

Antimicrobial Agents and Chemotherapy ◽

10.1128/aac.01412-20 ◽

2020 ◽

Vol 64 (11) ◽

Author(s):

Ya-Kun Wang ◽

Yue-E Wu ◽

Xue Li ◽

Li-Yuan Tian ◽

Muhammad Wasim Khan ◽

...

Keyword(s):

Population Pharmacokinetics ◽

Sampling Strategy ◽

Optimal Dose ◽

Community Acquired Pneumonia ◽

Pharmacokinetic Analysis ◽

Population Pharmacokinetic ◽

Evidence Based ◽

Open Label ◽

Large Variability ◽

Pharmacodynamic Analysis

ABSTRACT Ceftriaxone is a third-generation cephalosporin used to treat infants with community-acquired pneumonia. Currently, there is a large variability in the amount of ceftriaxone used for this purpose in this particular age group, and an evidence-based optimal dose is still unavailable. Therefore, we investigated the population pharmacokinetics of ceftriaxone in infants and performed a developmental pharmacokinetic-pharmacodynamic analysis to determine the optimal dose of ceftriaxone for the treatment of infants with community-acquired pneumonia. A prospective, open-label pharmacokinetic study of ceftriaxone was conducted in infants (between 1 month and 2 years of age), adopting an opportunistic sampling strategy to collect blood samples and applying high-performance liquid chromatography to quantify ceftriaxone concentrations. Developmental population pharmacokinetic-pharmacodynamic analysis was conducted using nonlinear mixed effects modeling (NONMEM) software. Sixty-six infants were included, and 169 samples were available for pharmacokinetic analysis. A one-compartment model with first-order elimination matched the data best. Covariate analysis elucidated that age and weight significantly affected ceftriaxone pharmacokinetics. According to the results of a Monte Carlo simulation, with a pharmacokinetic-pharmacodynamic target of a free drug concentration above the MIC during 70% of the dosing interval (70% fT>MIC), regimens of 20 mg/kg of body weight twice daily for infants under 1 year of age and 30 mg/kg twice daily for those older than 1 year of age were suggested. The population pharmacokinetics of ceftriaxone were established in infants, and evidence-based dosing regimens for community-acquired pneumonia were suggested based on developmental pharmacokinetics-pharmacodynamics.

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Population Pharmacokinetics of Ciprofloxacin in Neonates and Young Infants Less than Three Months of Age

Antimicrobial Agents and Chemotherapy ◽

10.1128/aac.03568-14 ◽

2014 ◽

Vol 58 (11) ◽

pp. 6572-6580 ◽

Cited By ~ 26

Author(s):

Wei Zhao ◽

Helen Hill ◽

Chantal Le Guellec ◽

Tim Neal ◽

Sarah Mahoney ◽

...

Keyword(s):

Population Pharmacokinetics ◽

Newborn Infants ◽

Compartment Model ◽

Population Pharmacokinetic Analysis ◽

Pharmacokinetic Analysis ◽

Population Pharmacokinetic ◽

Pharmacokinetic Studies ◽

Dosing Regimen ◽

Creatinine Concentration ◽

Young Infants

ABSTRACTCiprofloxacin is used in neonates with suspected or documented Gram-negative serious infections. Currently, its use is off-label partly because of lack of pharmacokinetic studies. Within the FP7 EU project TINN (Treat Infection in NeoNates), our aim was to evaluate the population pharmacokinetics of ciprofloxacin in neonates and young infants <3 months of age and define the appropriate dose in order to optimize ciprofloxacin treatment in this vulnerable population. Blood samples were collected from neonates treated with ciprofloxacin and concentrations were quantified by high-pressure liquid chromatography–mass spectrometry. Population pharmacokinetic analysis was performed using NONMEM software. The data from 60 newborn infants (postmenstrual age [PMA] range, 24.9 to 47.9 weeks) were available for population pharmacokinetic analysis. A two-compartment model with first-order elimination showed the best fit with the data. A covariate analysis identified that gestational age, postnatal age, current weight, serum creatinine concentration, and use of inotropes had a significant impact on ciprofloxacin pharmacokinetics. Monte Carlo simulation demonstrated that 90% of hypothetical newborns with a PMA of <34 weeks treated with 7.5 mg/kg twice daily and 84% of newborns with a PMA ≥34 weeks and young infants receiving 12.5 mg/kg twice daily would reach the AUC/MIC target of 125, using the standard EUCAST MIC susceptibility breakpoint of 0.5 mg/liter. The associated risks of overdose for the proposed dosing regimen were <8%. The population pharmacokinetics of ciprofloxacin was evaluated in neonates and young infants <3 months old, and a dosing regimen was established based on simulation.

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Bone Penetration of Amoxicillin and Clavulanic Acid Evaluated by Population Pharmacokinetics and Monte Carlo Simulation

Antimicrobial Agents and Chemotherapy ◽

10.1128/aac.01119-08 ◽

2009 ◽

Vol 53 (6) ◽

pp. 2569-2578 ◽

Cited By ~ 18

Author(s):

Cornelia B. Landersdorfer ◽

Martina Kinzig ◽

Jürgen B. Bulitta ◽

Friedrich F. Hennig ◽

Ulrike Holzgrabe ◽

...

Keyword(s):

Monte Carlo ◽

Cortical Bone ◽

Population Pharmacokinetics ◽

Clavulanic Acid ◽

Cancellous Bone ◽

Pharmacokinetic Analysis ◽

Population Pharmacokinetic ◽

Bone Infections ◽

Drug Concentrations ◽

Amoxicillin Clavulanic Acid

ABSTRACT Amoxicillin (amoxicilline)-clavulanic acid has promising activity against pathogens that cause bone infections. We present the first evaluation of the bone penetration of a beta-lactam by population pharmacokinetics and pharmacodynamic profiling via Monte Carlo simulations. Twenty uninfected patients undergoing total hip replacement received a single intravenous infusion of 2,000 mg/200 mg amoxicillin-clavulanic acid before surgery. Blood and bone specimens were collected. Bone samples were pulverized under liquid nitrogen with a cryogenic mill, including an internal standard. The drug concentrations in serum and total bone were analyzed by liquid chromatography-tandem mass spectrometry. We used NONMEM and S-ADAPT for population pharmacokinetic analysis and a target time of the non-protein-bound drug concentration above the MIC for ≥50% of the dosing interval for near-maximal bactericidal activity in serum. The median of the ratio of the area under the curve (AUC) for bone/AUC for serum was 20% (10th to 90th percentile for between-subject variability [variability], 16 to 25%) in cortical bone and 18% (variability, 11 to 29%) in cancellous bone for amoxicillin and 15% (variability, 11 to 21%) in cortical bone and 10% (variability, 5.1 to 21%) in cancellous bone for clavulanic acid. Analysis in S-ADAPT yielded similar results. The equilibration half-lives between serum and bone were 12 min for amoxicillin and 14 min for clavulanic acid. For a 30-min infusion of 2,000 mg/200 mg amoxicillin-clavulanic acid every 4 h, amoxicillin achieved robust (≥90%) probabilities of target attainment (PTAs) for MICs of ≤12 mg/liter in serum and 2 to 3 mg/liter in bone and population PTAs above 95% against methicillin-susceptible Staphylococcus aureus in bone and serum. The AUC of amoxicillin-clavulanic acid was 5 to 10 times lower in bone than in serum, and amoxicillin-clavulanic acid achieved a rapid equilibrium and favorable population PTAs against pathogens commonly encountered in bone infections.

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