Activity of clindamycin against <i>Staphylococcus aureus</i> and <i>Staphylococcus epidermidis</i> from four UK centres

Reeves, D. S.; Holt, H. A.; Phillips, Ian; King, Anna; Miles, R. S.; Paton, R.; Wise, Robert I.; Andrews, J. M.

doi:10.1093/jac/27.4.469

Cited by 19 publications

(17 citation statements)

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“…Patients who would receive Ͼ900 mg following weight-based dosing (Ͼ75 kg for 12 mg/kg and Ͼ90 kg for 10 mg/kg) received a maximum dose of 900 mg. Unbound, steady-state clindamycin concentrations at half the dosing interval (fC 50,SS ) were calculated assuming a fraction unbound of 6% (7,27). The proportion of virtual participants with an fC 50,SS greater than a MIC of 0.12 g/ml (MIC 90 for Staphylococcus aureus) following optimal dosing was calculated (28).…”

Section: Methodsmentioning

confidence: 99%

Pharmacokinetics of Clindamycin in Obese and Nonobese Children

Smith

González

Goldman

et al. 2017

Antimicrob Agents Chemother

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Although obesity is prevalent among children in the United States, pharmacokinetic (PK) data for obese children are limited. Clindamycin is a commonly used antibiotic that may require dose adjustment in obese children due to its lipophilic properties. We performed a clindamycin population PK analysis using data from three separate trials. A total of 420 samples from 220 children, 76 of whom had a body mass index greater than or equal to the 95th percentile for age, were included in the analysis. Compared to other metrics, total body weight (TBW) was the most robust measure of body size. The final model included TBW and a sigmoidal maturation relationship between postmenstrual age (PMA) and clearance (CL): CL (liters/hour) ϭ 13.8 ϫ (TBW/70) 0.75 ϫ [PMA 2.83 /(39.5 2.83 ϩPMA 2.83 )]; volume of distribution (V) was associated with TBW, albumin (ALB), and alpha-1 acid glycoprotein (AAG): V (liters) ϭ 63.6 ϫ (TBW/70) ϫ (ALB/3.3) Ϫ0.83 ϫ (AAG/2.4) Ϫ0.25 . After accounting for differences in TBW, obesity status did not explain additional interindividual variability in model parameters. Our findings support TBW-based dosing for obese and nonobese children.

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Section: Methodsmentioning

confidence: 99%

Pharmacokinetics of Clindamycin in Obese and Nonobese Children

Smith

González

Goldman

et al. 2017

Antimicrob Agents Chemother

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“…We calculated the area under the concentration versus time curve from 0 to infinity after a single dose (AUC 0-∞ ) to represent the area under the concentration versus time curve from 0 to tau at steady state (AUC 0-8,ss ) using a non-compartmental analysis. We also calculated the percent of participants with simulated clindamycin concentrations in target organs and tissues (bone, lung, and skin) >MRSA MIC (0.5 mg/L) for at least 50% of the dosing interval following the optimized pediatric dosing regimen (7). …”

Section: Methodsmentioning

confidence: 99%

“…Also, the availability of adult literature data and pediatric opportunistic data collected from infants to adolescents provided the necessary in vivo data needed to evaluate model performance. Last, clindamycin has pharmacologic properties that make it ideally suited for PBPK modeling: as a CYP3A4 substrate, its clearance will be affected by developmental changes; and target tissue concentrations for MRSA therapy in the lung, bones, and skin have been established as pharmacodynamic endpoints that can be simulated by the PBPK model (7, 8). …”

Section: Introductionmentioning

confidence: 99%

Development of a Pediatric Physiologically-Based Pharmacokinetic Model of Clindamycin Using Opportunistic Pharmacokinetic Data

Hornik

Edginton

et al. 2017

Clin Pharmacokinet

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Physiologically based pharmacokinetic (PBPK) modeling is a powerful tool used to characterize maturational changes in drug disposition to inform dosing across childhood; however, its use is limited in pediatric drug development. Access to pediatric pharmacokinetic data is a barrier to widespread application of this model, which impedes its development and optimization. To support the development of a pediatric PBPK model, we sought to leverage opportunistically-collected plasma concentrations of the commonly used antibiotic, clindamycin. The pediatric PBPK model was optimized following development of an adult PBPK model that adequately described literature data. We evaluated the predictability of the pediatric population PBPK model across 4 age groups, and found that 63–93% of the observed data where captured within the 90% prediction interval of the model. We then used the pediatric PBPK model to optimize intravenous clindamycin dosing for a future prospective validation trial. The optimal dosing proposed by this model are 9 mg/kg/dose in children ≤5 months of age, 12 mg/kg/dose in children >5 months to 6 years of age, and 10 mg/kg/dose in children 6-18 years of age, all administered every 8 hours. The simulated exposures achieved with the dosing regimen proposed were comparable to adult plasma and tissue exposures for treatment of community acquired methicillin resistant Staphylococcus aureus infections. Our model demonstrated the feasibility of using opportunistic pediatric data to develop pediatric PBPK models, extending the reach of this powerful modeling tool and potentially transforming the pediatric drug development field.

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“…Finally, the simulated unbound, steady-state concentration at half the dosing interval (fC ss,50 ) was calculated for each virtual subject assuming a fraction unbound of 17% (9). The proportion of virtual participants with an fC ss,50 greater than an MIC of 0.12 g/ml (previously reported MIC 90 for S. aureus) after the optimal dosing was calculated (18).…”

Section: Methodsmentioning

confidence: 99%

Clindamycin Pharmacokinetics and Safety in Preterm and Term Infants

González

Paul

Bloom

et al. 2016

Antimicrob Agents Chemother

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i Clindamycin may be active against methicillin-resistant Staphylococcus aureus, a common pathogen causing sepsis in infants, but optimal dosing in this population is unknown. We performed a multicenter, prospective pharmacokinetic (PK) and safety study of clindamycin in infants. We analyzed the data using a population PK analysis approach and included samples from two additional pediatric trials. Intravenous data were collected from 62 infants (135 plasma PK samples) with postnatal ages of <121 days (median [range] gestational age of 28 weeks [23 to 42] and postnatal age of 17 days [1 to 115]). In addition to body weight, postmenstrual age (PMA) and plasma protein concentrations (albumin and alpha-1 acid glycoprotein) were found to be significantly associated with clearance and volume of distribution, respectively. Clearance reached 50% of the adult value at PMA of 39.5 weeks. Simulated PMA-based intravenous dosing regimens administered every 8 h (<32 weeks PMA, 5 mg/kg; 32 to 40 weeks PMA, 7 mg/kg; >40 to 60 weeks PMA, 9 mg/kg) resulted in an unbound, steady-state concentration at half the dosing interval greater than a MIC for S. aureus of 0.12 g/ml in >90% of infants. There were no adverse events related to clindamycin use. (This study has been registered at ClinicalTrials.gov under registration no. NCT01728363.)

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Activity of clindamycin against Staphylococcus aureus and Staphylococcus epidermidis from four UK centres

Cited by 19 publications

References 0 publications

Pharmacokinetics of Clindamycin in Obese and Nonobese Children

Pharmacokinetics of Clindamycin in Obese and Nonobese Children

Development of a Pediatric Physiologically-Based Pharmacokinetic Model of Clindamycin Using Opportunistic Pharmacokinetic Data

Clindamycin Pharmacokinetics and Safety in Preterm and Term Infants

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