Prediction of C-reactive protein dynamics during meropenem treatment in neonates and infants.

AIMS: C-reactive protein (CRP) is used to determine the effect of antibiotic treatment on sepsis in neonates/infants. We aimed to develop pharmacokinetic-pharmacodynamic (PKPD) model of meropenem and CRP in neonates/infants and evaluate its predictive performance of CRP dynamics. METHODS: Data from neonates/infants treated with meropenem in 3 previous studies were analysed. To the previously developed meropenem PK models, the addition of turnover, transit or effect compartment, delay differential equation PD models of CRP as a function of meropenem concentration or its cumulative area under the curve (AUC) were evaluated. The percentage of neonates/infants (P0.1 , P0.2 ) in whom the ratio of the fifth day CRP to its peak value was predicted with an error of <0.1 (<0.2) was calculated. RESULTS: A total of 60 meropenem treatment episodes (median [range] gestational age 27.6 [22.6-40.9] weeks, postnatal age 13 [2-89] days) with a total of 351 CRP concentrations (maximum value 65.5 [13-358.4] mg/L) were included. Turnover model of CRP as a function of meropenem cumulative AUC provided the best fit and included CRP at the start of treatment, use of prior antibiotics, study and causative agent Staphylococcus aureus or enterococci as covariates. Using meropenem population predictions and data available at 0, 24, 48, 72 h after the start of treatment, P0.1 (P0.2 ) was 36.4, 36.4, 60.6 and 66.7% (70.0, 66.7, 72.7 and 78.7%), respectively. CONCLUSION: The developed PKPD model of meropenem and CRP as a function of meropenem cumulative AUC incorporating several patient characteristics predicts CRP dynamics with an error of <0.2 in most neonates/infants.

Pharmacokinetics of Penicillin G in Preterm and Term Neonates.

Group B streptococci are common causative agents of early-onset neonatal sepsis (EOS). Pharmacokinetic (PK) data for penicillin G have been described for extremely preterm neonates but have been poorly described for late-preterm and term neonates. Thus, evidence-based dosing recommendations are lacking. We describe the PK of penicillin G in neonates with a gestational age (GA) of ≥32 weeks and a postnatal age of <72 h. Penicillin G was administered intravenously at a dose of 25,000 or 50,000 IU/kg of body weight every 12 h (q12h). At steady state, PK blood samples were collected prior to and at 5 min, 1 h, 3 h, 8 h, and 12 h after injection. Noncompartmental PK analysis was performed with WinNonlin software. With those data in combination with data from neonates with a GA of ≤28 weeks, we developed a population PK model using NONMEM software and performed probability of target attainment (PTA) simulations. In total, 16 neonates with a GA of ≥32 weeks were included in noncompartmental analysis. The median volume of distribution (V) was 0.50 liters/kg (interquartile range, 0.42 to 0.57 liters/kg), the median clearance (CL) was 0.21 liters/h (interquartile range, 0.16 to 0.29 liters/kg), and the median half-life was 3.6 h (interquartile range, 3.2 to 4.3 h). In the population PK analysis that included 35 neonates, a two-compartment model best described the data. The final parameter estimates were 10.3 liters/70 kg and 29.8 liters/70 kg for V of the central and peripheral compartments, respectively, and 13.2 liters/h/70 kg for CL. Considering the fraction of unbound penicillin G to be 40%, the PTA of an unbound drug concentration that exceeds the MIC for 40% of the dosing interval was >90% for MICs of ≤2 mg/liter with doses of 25,000 IU/kg q12h. In neonates, regardless of GA, the PK parameters of penicillin G were similar. The dose of 25,000 IU/kg q12h is suggested for treatment of group B streptococcal EOS diagnosed within the first 72 h of life. (This study was registered with the EU Clinical Trials Register under EudraCT number 2012-002836-97.).

Coagulase negative staphylococcal sepsis in neonates: do we need to adapt vancomycin dose or target?

BACKGROUND: Despite differences in types of infection and causative organisms, pharmacokinetic-pharmacodynamic (PKPD) targets of vancomycin therapy derived from adult studies are suggested for neonates. We aimed to identify doses needed for the attainment of AUC/MIC > 400 and AUC/MIC > 300 in neonates with sepsis and correlate these targets with recommended doses and treatment outcome. METHODS: Neonates who had Vancomycin therapeutic drug monitoring (TDM) performed between January 1, 2010 and December 31, 2012 were studied. Clinical characteristics, episodes of Gram-positive sepsis with outcomes and all neonatal blood culture isolates in hospital were collected from medical records. To estimate probability of target attainment of AUC/MIC >400 and AUC/MIC >300 a 1000-subject Monte Carlo simulation was performed by calculating AUC using Anderson's (Anderson et al. 2006) and TDM trough concentrations (Ctrough) based population PK models. RESULTS: Final dataset included 76 patients; 57 with confirmed Gram-positive sepsis. TDM was taken after the 1st to 44th dose. 84.1% of Ctrough were within the range 5-15 mg/L. Currently recommended doses achieved probability of the targets (PTA) of AUC/MIC >400 and AUC/MIC >300 in less than 25% and 40% of cases, respectively. Doses required for 80% PTA of AUC/MIC > 400 for MIC ≥2 mg/L resulted in Ctrough values ≥14 mg/L. Mean AUC/MIC values were similar in treatment failure and success groups. CONCLUSION: With currently recommended vancomycin dosing the therapeutic target of AUC/MIC > 400 is achieved only by 25% of neonates. Appropriate PKPD targets and respective dosing regimens need to be defined in prospective clinical studies in this population.

Sudan black poisoning resulted in methemoglobinemia in a baby with congenital chyloperitoneum.

Treatment of congenital chyloperitoneum is a challenge. Conservative methods may be ineffective. Preoperative visualization of the site of lymphatic leakage is crucial, but radiological imaging is technically complicated and may not provide sufficient information, especially in small patients. To ease the detection of lymphatic leakage during surgery, preoperative feeding with fat-rich formula with Sudan Black has been recommended. However, administration of Sudan Black may result in life-threatening methemoglobinemia and liver damage without any advantage of revealing leakage during surgery. We recommend preoperative feeding with pure fat-rich formula.

Short versus long infusion of meropenem in very-low-birth-weight neonates.

Prolonged infusion of meropenem has been suggested in studies with population pharmacokinetic modeling but has not been tested in neonates. We compared the steady-state pharmacokinetics (PK) of meropenem given as a short (30-min) or prolonged (4-h) infusion to very-low-birth-weight (gestational age, <32 weeks; birth weight, <1,200 g) neonates to define the appropriate dosing regimen for a phase 3 efficacy study. Short (n = 9) or prolonged (n = 10) infusions of meropenem were given at a dose of 20 mg/kg every 12 h. Immediately before and 0.5, 1.5, 4, 8, and 12 h after the 4th to 7th doses of meropenem, blood samples were collected. Meropenem concentrations were measured by ultrahigh-performance liquid chromatography. PK analysis was performed with WinNonlin software, and modeling was performed with NONMEM software. A short infusion resulted in a higher mean drug concentration in serum (C(max)) than a prolonged infusion (89 versus 54 mg/liter). In all but two patients in the prolonged-infusion group, the free serum drug concentration was above the MIC (2 mg/liter) 100% of the time. Meropenem clearance (CL) was not influenced by postnatal or postmenstrual age. In population PK analysis, a one-compartment model provided the best fit and the steady-state distribution volume (V(ss)) was scaled with body weight and CL with a published renal maturation function. The covariates serum creatinine and postnatal and gestational ages did not improve the model fit. The final parameter estimates were a V(ss) of 0.301 liter/kg and a CL of 0.061 liter/h/kg. Meropenem infusions of 30 min are acceptable as they balance a reasonably high C(max) with convenience of dosing. In very-low-birth-weight neonates, no dosing adjustment is needed over the first month of life.

Pharmacokinetics of Gentamicin Components C1, C1a, and C2/C2a/C2b and Subsequent Decline in Glomerular Filtration Rate in Neonates.

Gentamicin is a commonly used antibiotic in neonates. Its components C1, C1a, C2, C2a, and C2b may have different nephrotoxic potential. We aimed to describe pharmacokinetics and nephrotoxic potential of gentamicin components in a joint model in neonates. Neonates with gestational age ≥ 32 weeks treated with gentamicin blood samples were collected at a steady state. Pharmacokinetics of C1, C1a, and C2/C2a/C2b were modelled in NONMEM and included competitive uptake into kidney proximal tubular cells and decrease in glomerular filtration rate. The nephrotoxic potential of total gentamicin, C1, C1a, and C2/C2a/C2b was evaluated by simulations. A total of 30 neonates (median (range) gestational age 36.4 (32-42) weeks, postnatal age 3 (1-5) days, creatinine value 47.5 (17-78) µmol/L) were included. Pharmacokinetics of all components was best described by a two-compartment model. Clearance of C1 was smaller than clearances of C1a and C2/C2a/C2b, and other parameters were similar. The model with different Km (concentration for which half-maximal uptake into kidney proximal tubular cells is achieved) for C1, C1a, and C2/C2a/C2b (37.5, 18, 15 mg/L) provided a better fit than the model with equal Km (15 mg/L). According to simulations, decrease in glomerular filtration rate in the case of once-daily dosing of 4 mg/kg/day was the largest for C2/C2a/C2b (median (5th and 95th percentile) 0.22% (0.00-8.12%)), followed by total gentamicin (0.20% (0.00-4.10%)), C1a (0.11% (0.00-7.57%)), and C1 (0.04% (0.00-1.55%)). Different gentamicin components C1, C1a, and C2/C2a/C2b exhibited different pharmacokinetic profiles. Once-daily dosing of 4 mg/kg/day results in low nephrotoxicity in neonates, in line with previous studies.

Ampicillin Pharmacokinetics During First Week of Life in Preterm and Term Neonates.

BACKGROUND AND AIMS: Ampicillin is 1 of the most commonly used antibiotics for treatment of early onset sepsis, but its pharmacokinetics (PK) is poorly characterized. We aimed to define the dose of ampicillin for late preterm and term neonates by evaluating its PK in serum, cerebrospinal (CSF), and epithelial lining fluid. METHODS: A prospective study included neonates receiving ampicillin for suspected or proven early onset sepsis and pneumonia. PK samples were collected at steady state, at predose and 5 minutes, 1 hour, 3 hours, 8 hours, and 12 hours after ampicillin 3-minute infusion. Ampicillin concentrations were measured by ultra-high-performance liquid chromatography. Noncompartmental anaysis (NCA) and population pharmacokinetic (pop-PK) modeling were performed and probability of therapeutic target attainment was simulated. RESULTS: In 14 neonates (GA of 32-42 wks; mean BW 2873 g), PK parameters (mean ± SD) in NCA were the following: half-life 7.21 ± 7.97 hours; volume of distribution (Vd) 1.07 ± 0.51 L; clearance (CL) 0.20 ± 0.13 L/h; 24-hour area under the concentration-time curve 348.92 ± 114.86 mg*h/L. In pop-PK analysis, a 2-compartmental model described the data most adequately with the final parameter estimates of CL 15.15 (CV 40.47%) L/h/70kg; central Vd 24.87 (CV 37.91%) L/70kg; intercompartmental CL 0.39 (CV 868.56) L/h and peripheral Vd 1.039 (CV 69.32%) L. Peutic target attainment simulations demonstrated that a dosage of 50 mg/kg q 12 hours attained 100% fT > MIC 0.25 mg/L, group B streptococcal breakpoint. CONCLUSIONS: We recommend ampicillin dosage 50 mg/kg q 12 hours for neonates with gestational age ≥32 weeks during the first week of life.