***TASK*** the task is to summarize an input biomedical literature in six sentences 
    ***INPUT*** the input is a biomedical literature 
    ***OUTPUT*** the output is the summary of an input biomedical literature in six sentences 
    ***DOCUMENTATION*** 
    ***EXAMPLES*** 
    Input: Background Meropenem is a carbapenem antibiotic commonly used in critically ill patients to treat severe infections . The available pharmacokinetic ( PK ) data has been mostly obtained from healthy volunteers as well as from clinical studies addressing selected population s , often excluding the elderly and also patients with renal failure . Our aim was to study PK of meropenem in a broader population of septic critically ill patients . Methods We characterized the PK of meropenem  in 15 critically ill patients during the first 36 hrs of therapy . Aditionally , whenever possible , we collected a second set of late plasma sample s after 5 days of therapy to evaluate PK intra-patient variability and its correlation with clinical course . Patients received  meropenem ( 1 g every 8 hrs IV ) . Drug plasma profiles were determined by high-performance liquid chromatography . The PK of meropenem was characterized and compared with clinical parameters . Results Fifteen septic critically ill patients ( 8 male , median age 73 yrs ) were included . The geometric mean of the volume of distribution at the steady state (Vss)/weight was 0.20 ( 0.15 - 0.27 ) L/kg . No correlation of Vss/weight with severity or comorbidity scores was found . However the Sequential Organ Failure Assessment score correlated with the Vss/weight of the peripheral compartment ( r2 = 0.55 , p = 0.021 ) . The median meropenem clearance ( Cl ) was 73.3 ( 45–120 ) mL/min correlated with the creatinine ( Cr ) Cl ( r2 = 0.35 , p = 0.033).After 5 days ( N = 7 ) although Vss remained stable , a decrease in the proportion of the peripheral compartment ( Vss2 ) was found , from 61.3 (42.5 - 88.5)% to 51.7 (36.6 - 73.1)% . No drug accumulation was noted . Conclusions In this cohort of septic , unselected , critically ill patients , large meropenem PK heterogeneity was noted , although neither underdosing nor accumulation was found . However , Cr Cl correlated to meropenem Cl and the Vss2 decreased with patient ’s improvement The pharmacokinetics of apalcillin and piperacillin , each administered intravenously as a single 2-g dose , were compared in 10 volunteers in a r and omized study of crossover design using bioassay and high-pressure liquid chromatographic procedures . The concentrations of both penicillins in serum were determined over a period of 12 h and in urine over 24 h. Concentrations of apalcillin and piperacillin  at the end of the 15-min infusion were similar ; however , at 8 h , concentrations of piperacillin were below measurable levels , whereas concentrations of apalcillin were still measurable at 10 h. Pharmacokinetic parameters were calculated according to a two-compartment open model . The area under the curve and the half-life for apalcillin were larger than for piperacillin . On the other h and , renal clearance of piperacillin  was substantially greater than that of apalcillin . Of the apalcillin excreted via the kidneys , approximately one-fifth was eliminated as two microbiologically inactive penicilloic acid derivatives . The nonrenal clearance of apalcillin was 79 % of total clearance . Binding of apalcillin to serum protein was almost twice that of piperacillin STUDY OBJECTIVE To determine the appropriate compartmental and noncompartmental pharmacokinetic parameters for intravenous piperacillin and tazobactam . DESIGN Sequential selection of patients entered into a r and omized , open-label clinical efficacy trial . SETTING Los Angeles County-University of Southern California Medical Center . PARTICIPANTS Sequential sample of 18 patients admitted for intraabdominal infections and consented into a comparative antibiotic trial . INTERVENTIONS Patients received piperacillin 4 g plus tazobactam 500 mg by intravenous intermittent infusion every 8 hours . MEASUREMENTS AND MAIN RESULTS The estimated noncompartmental pharmacokinetic parameters ( mean + /- SD ) for piperacillin and tazobactam , respectively , were as follows : maximum concentration in plasma 218.7 + /- 48.9 micrograms/ml and 27.8 + /- 9.1 micrograms/ml ; half-life 1.07 + /- 0.22 hours and 1.00 + /- 0.27 hours ; elimination rate constant 0.67 + /- 0.13 hr-1 and 0.73 + /- 0.18 hr-1 ; area under the concentration-time curve from zero hour to infinity 288.5 + /- 71.25 mg.hr/L and 36.3 + /- 9.55 mg.hr/L ; total plasma clearance 14.75 + /- 3.93 L/hour and 14.78 + /- 4.39 L/hour ; renal clearance 5.69 + /- 1.94 L/hour and 7.85 + /- 3.37 L/hour ; volume of distribution at steady state 21.00 + /- 4.18 L and 22.47 + /- 8.27 L ; and mean residence time 1.72 + /- 0.29 hours and 1.79 + /- 0.35 hours . CONCLUSION Our findings were similar to those in other surgical patient models . The two-compartmental model best described piperacillin and tazobactam disposition in our patients . Bayesian analyses of the two-compartment models of piperacillin and tazobactam were able to predict trough , peak , and 2-hour postadministration levels without bias The pharmacokinetics of piperacillin and tazobactam were assessed after single-dose administration to 47 infants and children . Study subjects ranging in age from 2 months to 12 years were r and omized to receive one of two different doses of a piperacillin-tazobactam combination ( 8:1 ) : a low dose ( n = 23 ) of 50 and 6.25 mg of piperacillin and tazobactam per kg of body weight , respectively , or a high dose ( n = 24 ) of 100 and 12.5 mg , respectively . The pharmacokinetic behavior of tazobactam was very similar to that observed for piperacillin , supporting the use of these two agents in a fixed-dose combination . No differences in the pharmacokinetics of piperacillin or tazobactam were observed between the two doses administered . The elimination parameters half-life and total body clearance decreased and increased , respectively , with increasing age , whereas volume parameters ( volume of distribution and steady-state volume of distribution ) remained relatively constant for both compounds . The primary metabolite of tazobactam , metabolite M1 , was measurable in the plasma of 18 of the 47 study subjects ; 17 of these 18 subjects received the high doses . More than 70 % of the administered piperacillin and tazobactam doses were excreted unchanged in the urine over a 6-h collection period . These data combined with the known in vitro susceptibilities of a broad range of pediatric bacterial pathogens indicate that a dose of 100 mg of piperacillin and 12.5 of mg tazobactam per kg of body weight administered as a fixed-dose combination every 6 to 8 h would be appropriate to initiate clinical efficacy studies in infants and children for the treatment of systemic infections arising outside of the central nervous system . ABSTRACT Meropenem is used to manage postneurosurgical meningitis , but its population pharmacokinetics ( PPK ) in plasma and cerebrospinal fluid ( CSF ) in this patient group are not well-known . Our aims were to ( i ) characterize meropenem PPK in plasma and CSF and ( ii ) recommend favorable dosing regimens in postneurosurgical meningitis patients . Eighty-two patients were enrolled to receive meropenem infusions of 2 g every 8 h  ( q8h ) , 1 g q8h , or 1 g q6h  for at least 3 days . Serial blood and CSF sample s were collected , and concentrations were determined and analyzed via population modeling . Probabilities of target attainment ( PTA ) were predicted via Monte Carlo simulations , using the target of unbound meropenem concentrations above the MICs for at least 40 % of dosing intervals in plasma and at least of 50 % or 100 % of dosing intervals in CSF . A two-compartment model plus another CSF compartment best described the data . The central , inter central /peripheral , and inter central /CSF compartment clearances were 22.2 liters/h , 1.79 liters/h , and 0.01 liter/h , respectively . Distribution volumes of the central and peripheral compartments were 17.9 liters and 3.84 liters , respectively . The CSF compartment volume was fixed at 0.13 liter , with its clearance calculated by the observed drainage amount . The multiplier for the transfer from the central to the CSF compartment was 0.172 . Simulation results show that the PTAs increase as infusion is prolonged and as the daily CSF drainage volume decreases . A 4-hour infusion of 2 g q8h with CSF drainage of less than 150 ml/day , which provides a PTA of > 90 % for MICs of ≤8 mg/liter in blood and of ≤0.5 mg/liter or 0.25 mg/liter in CSF , is recommended . ( This study has been registered at Clinical Trials.gov under identifier NCT02506686 . Objectives To develop population pharmacokinetic ( PK ) models for piperacillin/tazobactam in neonates and infants of less than 2 months of age in order to determine the appropriate dosing regimen and provide a rational basis for the development of preliminary dosing guidelines suitable for this population . Methods A two-stage , open-label study was conducted in neonates and infants less than 2 months of age in the neonatal intensive care unit ( NICU ) . A total of 207 piperacillin and 204 tazobactam concentration – time data sets from 71 patients were analyzed using a nonlinear mixed-effect modeling approach ( NONMEM VII ) . PK models were developed for piperacillin and tazobactam . The final models were evaluated using both bootstrap and visual predictive checks . External model evaluations were made in 20 additional patients . Results For neonates and young infants less than 2 months of age , the median central clearance was 0.133 and 0.149 L/h/kg for piperacillin and tazobactam , respectively . Postmenstrual age ( PMA ) was identified as the most significant covariate on central clearance of piperacillin and tazobactam . However , the combination of current bodyweight ( BW ) and postnatal age proved to be superior to PMA alone . BW was the most important covariate for apparent central volume of distribution . Both internal and external evaluations supported the prediction of the final piperacillin and tazobactam PK models . The dosing strategy 44.44/5.56 mg/kg/dose piperacillin/tazobactam every 8 or 12 h evaluated in this study achieved the pharmacodynamic target ( free piperacillin concentrations > 4 mg/L for more than 50 % of the dosing interval ) in about 67 % of infants . Conclusions Population PK models accurately described the PK profiles of piperacillin/tazobactam in infants less than 2 months of age . The results indicated that higher doses or more frequent dosing regimens may be required for controlling infection in this population in NICU Background : The antibiotic meropenem is commonly administered in patients with severe sepsis and septic shock . We compared the pharmacokinetic , clinical , and bacteriological efficacies of continuous infusion of meropenem versus intermittent administration in such patients . Methods : Patients admitted to the Intensive Care Unit ( ICU ) with severe sepsis or septic shock who received meropenem  were r and omly assigned to either the continuous ( n = 25 ) or intermittent groups ( n = 25 ) . The continuous group received a loading dose of 0.5 g of meropenem followed by a continuous infusion of 3 g/day ; the intermittent group received an initial dose of 1.5 g followed by 1 g for every 8 h. Clinical success , microbiological eradication , superinfection , ICU mortality , length of ICU stay , and duration of meropenem treatment were assessed . Serial plasma meropenem concentrations for the first and third dosing periods ( steady state ) were also measured . Results : Clinical success was similar in both the continuous ( 64 % ) and intermittent ( 56 % ) groups ( P = 0.564 ) ; the rates of microbiological eradication and superinfection ( 81.8 % vs. 66.7 % [ P = 0.255 ] and 4 % vs. 16 % [ P = 0.157 ] , respectively ) showed improvement in the continuous group . The duration of meropenem treatment was significantly shorter in the continuous group ( 7.6 vs. 9.4 days ; P = 0.035 ) , where a better steady-state concentration was also achieved . Peak and trough concentrations were significantly different between the continuous and intermitt 
    Output:
    
PK parameters from critically ill population s were reported with wider confidence intervals than those in healthy volunteers , indicating greater PK variability in critical illness .
The st and ard allometric size and sigmoidal maturation model adequately described increasing clearance in neonates , and a sigmoidal model was also used to describe decline in older age .
Changes in volume of distribution were well described by the st and ard allometric model , although amoxicillin data suggested a relatively higher volume of distribution in neonates .
Critical illness is associated with greater PK variability than in healthy volunteers .