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

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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Penetration of Moxifloxacin into Bone Evaluated by Monte Carlo Simulation

Antimicrobial Agents and Chemotherapy ◽

10.1128/aac.01056-08 ◽

2009 ◽

Vol 53 (5) ◽

pp. 2074-2081 ◽

Cited By ~ 18

Author(s):

Cornelia B. Landersdorfer ◽

Martina Kinzig ◽

Friedrich F. Hennig ◽

Jürgen B. Bulitta ◽

Ulrike Holzgrabe ◽

...

Keyword(s):

Monte Carlo Simulation ◽

Monte Carlo ◽

Cortical Bone ◽

Cancellous Bone ◽

Internal Standard ◽

Pharmacokinetic Analysis ◽

Free Concentration ◽

Standard Drug ◽

Drug Concentrations ◽

Pharmacodynamic Profile

ABSTRACT Moxifloxacin is a fluoroquinolone with a broad spectrum of activity and good penetration into many tissues, including bone. Penetration of moxifloxacin into bone has not yet been studied using compartmental modeling techniques. Therefore, we determined the rate and extent of bone penetration by moxifloxacin and evaluated its pharmacodynamic profile in bone via Monte Carlo simulation. Twenty-four patients (10 males, 14 females) undergoing total hip replacement received 400 mg moxifloxacin orally 2 to 7 h prior to surgery. Blood and bone specimens were collected. Bone samples were pulverized under liquid nitrogen by a cryogenic mill, including an internal standard. Drug concentrations were analyzed by high-performance liquid chromatography. We used ADAPT II (results reported), NONMEM, and WinBUGS for pharmacokinetic analysis. Monte Carlo simulation was performed to reverse engineer the necessary area under the free concentration-time curve fAUCSERUM/MIC in serum and total AUCBONE/MIC in bone for a successful clinical or microbiological outcome. The median (10% to 90% percentile for between-subject variability) of the AUC in bone divided by the AUC in serum (AUCBONE/AUCSERUM) was 80% (51 to 126%) for cortical bone and 78% (42 to 144%) for cancellous bone. Equilibration between serum and bone was rapid. Moxifloxacin achieved robust (≥90%) probabilities of target attainment (PTAs) in serum, cortical bone, and cancellous bone up to MICs of ≤0.375 mg/liter based on the targets fAUCSERUM/MIC ≥ 40 and AUCBONE/MIC ≥ 33. Moxifloxacin showed high bone concentrations and a rapid equilibrium between bone and serum. The favorable PTAs compared to the 90%-inhibitory MIC of Staphylococcus aureus warrant future clinical trials on the effectiveness of moxifloxacin in the treatment of bone infections.

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Population Pharmacokinetics of Doripenem in Critically Ill Patients with Sepsis in a Malaysian Intensive Care Unit

Antimicrobial Agents and Chemotherapy ◽

10.1128/aac.01543-15 ◽

2015 ◽

Vol 60 (1) ◽

pp. 206-214 ◽

Cited By ~ 11

Author(s):

Mohd H. Abdul-Aziz ◽

Azrin N. Abd Rahman ◽

Mohd-Basri Mat-Nor ◽

Helmi Sulaiman ◽

Steven C. Wallis ◽

...

Keyword(s):

Intensive Care Unit ◽

Monte Carlo ◽

Intensive Care ◽

Population Pharmacokinetics ◽

Critically Ill ◽

Critically Ill Patients ◽

Population Pharmacokinetic Analysis ◽

Volume Of Distribution ◽

Pharmacokinetic Analysis ◽

Population Pharmacokinetic

ABSTRACTDoripenem has been recently introduced in Malaysia and is used for severe infections in the intensive care unit. However, limited data currently exist to guide optimal dosing in this scenario. We aimed to describe the population pharmacokinetics of doripenem in Malaysian critically ill patients with sepsis and use Monte Carlo dosing simulations to develop clinically relevant dosing guidelines for these patients. In this pharmacokinetic study, 12 critically ill adult patients with sepsis receiving 500 mg of doripenem every 8 h as a 1-hour infusion were enrolled. Serial blood samples were collected on 2 different days, and population pharmacokinetic analysis was performed using a nonlinear mixed-effects modeling approach. A two-compartment linear model with between-subject and between-occasion variability on clearance was adequate in describing the data. The typical volume of distribution and clearance of doripenem in this cohort were 0.47 liters/kg and 0.14 liters/kg/h, respectively. Doripenem clearance was significantly influenced by patients' creatinine clearance (CLCR), such that a 30-ml/min increase in the estimated CLCRwould increase doripenem CL by 52%. Monte Carlo dosing simulations suggested that, for pathogens with a MIC of 8 mg/liter, a dose of 1,000 mg every 8 h as a 4-h infusion is optimal for patients with a CLCRof 30 to 100 ml/min, while a dose of 2,000 mg every 8 h as a 4-h infusion is best for patients manifesting a CLCRof >100 ml/min. Findings from this study suggest that, for doripenem usage in Malaysian critically ill patients, an alternative dosing approach may be meritorious, particularly when multidrug resistance pathogens are involved.

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P109 Optimal dosing regimen of caspofungin in children: milligram per kilogram or milligram per square meter?

Archives of Disease in Childhood ◽

10.1136/archdischild-2019-esdppp.147 ◽

2019 ◽

Vol 104 (6) ◽

pp. e63.2-e63

Author(s):

X-M Yang ◽

S Leroux ◽

T Storme ◽

D-L Zhang ◽

T Adam de Beaumais ◽

...

Keyword(s):

Monte Carlo Simulation ◽

Monte Carlo ◽

Population Pharmacokinetics ◽

Surface Area ◽

Body Surface ◽

Population Pharmacokinetic Analysis ◽

Pharmacokinetic Analysis ◽

Population Pharmacokinetic ◽

Candida Spp ◽

Optimal Dosing

BackgroundCaspofungin is the first echinocandin to be used as a first-line antifungal agent for Candida spp. infections in febrile, neutropenic adult and paediatric patients. To date, the optimal dosing of capofungin in children has not been determined. We evaluated the population pharmacokinetics of caspofungin in children (2–12 years old) and defined an appropriate dose in order to optimize caspofungin treatment in this vulnerable population.MethodsBlood samples were collected from 48 children treated with caspofungin and drug concentrations were quantified by HPLC-MS. Population pharmacokinetic analysis and Monte-Carlo simulation were performed using NONMEM softwareResultsData from 48 children was available for population pharmacokinetic analysis. A two-compartment model with first-order elimination had the best fit with the data. Subsequent covariate analysis demonstrated that body surface area had a significant correlation with caspofungin pharmacokinetics compared to body weight. Monte Carlo simulation demonstrated that >90% of a simulated paediatric population (age range, 2–12 years) treated with a loading dose of 70 mg/m2 followed by a 50 mg/m2 maintenance dose once daily would reach a minimum inhibitory concentration of 1 µg/mL, the proposed susceptibility breakpoint for caspofungin against Candida spp.ConclusionThe population pharmacokinetics of caspofungin was evaluated and revealed that adjustment of caspofungin based on body surface area is most appropriate for paediatric use.Disclosure(s)Nothing to disclose

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Methodological Approaches to Evaluate Fetal Drug Exposure

Current Pharmaceutical Design ◽

10.2174/1381612825666190319102812 ◽

2019 ◽

Vol 25 (5) ◽

pp. 496-504 ◽

Cited By ~ 7

Author(s):

Naïm Bouazza ◽

Frantz Foissac ◽

Déborah Hirt ◽

Saïk Urien ◽

Sihem Benaboud ◽

...

Keyword(s):

Cord Blood ◽

Drug Exposure ◽

Placental Transfer ◽

Ex Vivo ◽

Pharmacokinetic Analysis ◽

Population Pharmacokinetic ◽

Pbpk Models ◽

Drug Concentrations ◽

Fetal Drug Exposure

Background: Drug prescriptions are usual during pregnancy, however, women and their fetuses still remain an orphan population with regard to drugs efficacy and safety. Most xenobiotics diffuse through the placenta and some of them can alter fetus development resulting in structural abnormalities, growth or functional deficiencies. Methods: To summarize the different methodologies developed towards the prediction of fetal drug exposure. Results: Neonatal cord blood concentration is the most specific measurement of the transplacental drug transfer at the end of pregnancy. Using the cord blood and mother drug concentrations altogether, drug exchanges between the mother and fetus can be modeled and quantified via a population pharmacokinetic analysis. Thereafter, it is possible to estimate the fetus exposure and the fetus-to-mother exposure ratio. However, the prediction of placental transfer before any administration to pregnant women is desirable. Animal studies remain difficult to interpret due to structural and functional inter-species placenta differences. The ex-vivo perfusion of the human placental cotyledon is the method of reference to study the human placental transfer of drugs because it is thought to mimic the functional placental tissue. However, extrapolation of data to in vivo situation remains difficult. Some research groups have extensively worked on physiologically based models (PBPK) to predict fetal drug exposure and showed very encouraging results. Conclusion: PBPK models appeared to be a very promising tool in order to predict fetal drug exposure in-silico. However, these models mainly picture the end of pregnancy and knowledge regarding both, development of the placental permeability and transporters is strongly needed.

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Population Pharmacokinetics of Intravenous Amoxicillin Combined With Clavulanic Acid in Healthy and Critically Ill Dogs

Frontiers in Veterinary Science ◽

10.3389/fvets.2021.770202 ◽

2021 ◽

Vol 8 ◽

Author(s):

Maria D. Vegas Cómitre ◽

Stefano Cortellini ◽

Marc Cherlet ◽

Mathias Devreese ◽

Beatrice B. Roques ◽

...

Keyword(s):

Monte Carlo ◽

Monte Carlo Simulations ◽

Clavulanic Acid ◽

Critically Ill ◽

Drug Exposure ◽

De Novo ◽

Clinical Failure ◽

Clinical Covariates ◽

Amoxicillin Clavulanic Acid ◽

Healthy Dogs

Background: Data regarding antimicrobial pharmacokinetics (PK) in critically ill dogs are lacking and likely differ from those of healthy dogs. The aim of this work is to describe a population PK model for intravenous (IV) amoxicillin–clavulanic acid (AMC) in both healthy and sick dogs and to simulate a range of clinical dosing scenarios to compute PK/PD cutoffs for both populations.Methods: This study used a prospective clinical trial in normal and critically ill dogs. Twelve client-owned dogs hospitalized in the intensive care unit (ICU) received IV AMC 20 mg/kg every 8 h (0.5-h infusion) during at least 48 h. Eight blood samples were collected at predetermined times, including four trough samples before the next administration. Clinical covariates and outcome were recorded, including survival to discharge and bacteriologic clinical failure. Satellite PK data were obtained de novo from a group of 12 healthy research dogs that were dosed with a single AMC 20 mg/kg IV. Non-linear mixed-effects model was used to estimate the PK parameters (and the effect of health upon them) together with variability within and between subjects. Monte Carlo simulations were performed with seven dosage regimens (standard and increased doses). The correlation between model-derived drug exposure and clinical covariates was tested with Spearman's non-parametric correlation analysis. Outcome was recorded including survival to discharge and bacteriologic clinical failure.Results: A total of 218 amoxicillin concentrations in plasma were available for healthy and sick dogs. A tricompartmental model best described the data. Amoxicillin clearance was reduced by 56% in sick dogs (0.147 L/kg/h) compared with healthy dogs (0.336 L/kg/h); intercompartmental clearance was also decreased (p <0.01). None of the clinical data covariates were significantly correlated with individual exposure. Monte Carlo simulations showed that higher PK/PD cutoff values of 8 mg/L could be reached in sick dogs by extending the infusion to 3 h or doubling the dose.Conclusions: The PK of AMC is profoundly different in critically ill dogs compared with normal dogs, with much higher interindividual variability and a lower systemic clearance. Our study allows to generate hypotheses with regard to higher AMC exposure in clinical dogs and provides supporting data to revise current AMC clinical breakpoint for IV administration.

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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 Ceftizoxime Administered by Continuous Infusion in Clinically Ill Adult Patients

Antimicrobial Agents and Chemotherapy ◽

10.1128/aac.42.7.1783 ◽

1998 ◽

Vol 42 (7) ◽

pp. 1783-1787 ◽

Cited By ~ 17

Author(s):

Bryan Facca ◽

Bill Frame ◽

Steve Triesenberg

Keyword(s):

Serum Creatinine ◽

Continuous Infusion ◽

Population Pharmacokinetics ◽

Bacterial Infections ◽

Pharmacokinetic Analysis ◽

Population Pharmacokinetic ◽

Pharmacokinetic Data ◽

Beta Lactam ◽

Serum Samples ◽

Mixed Effect

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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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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