Hiie Soeorg, Helgi Padari, Mari-Liis Ilmoja, Koit Herodes, Karin Kipper, Irja Lutsar, Tuuli Metsvaht
University of Tartu, Estonia
Objectives. Sepsis is major cause of mortality in neonates. Blood cultures are often negative and therefore antibiotic (AB) dosing cannot be based on minimum inhibitory concentration (MIC) of infecting pathogen. Alternatively, C-reactive protein (CRP) guided treatment has been proposed as this is a routinely measured inflammatory marker. CRP pharmacokinetic-pharmacodynamic (PKPD) models of glycopeptides or beta-lactams in adults have shown that area under the curve of AB (AUC) to AB concentration inducing half maximal AB effect (EC50) ratio is correlated with CRP decline during treatment. Thus, individualized dosing based on such PKPD index could lead to earlier resolution of infection.
We aimed to describe CRP dynamics in neonates receiving meropenem (MER) in joint PKPD model and relationship between CRP concentration changes during treatment and MER AUC, MER peak or MER trough concentration ratio to EC50 and time above EC50.
Methods. Daily CRP concentrations were collected from very-low-birth-weight (gestational age <32 weeks, birth weight <1200 g) neonates receiving MER 20 mg/kg every 12 h for late-onset sepsis or pneumonia. Previously developed one-compartment MER pharmacokinetic model [1] was used to derive empirical Bayes parameter estimates from fixed population parameters based on MER concentrations measured in each neonate immediately before and 0.5, 1.5, 4, 8, and 12 h after one of the 4th to 7th dose of MER [1]. After fixing individual PK parameter estimates, PD model was used to describe change in CRP concentration: KCRPprod*CCRP*(1- CCRP/POPmax)-(KCRPinh* CCRP *(CMER)**H/(EC50**H+(CMER)**H)) (CCRP – CRP concentration (mg/L); CMER – MER concentration (mg/L); KCRPprod – maximum rate of CRP production (mg*h/L); POPmax – maximum value of CRP (mg/L); KCRPinh – maximum rate of CRP inhibition (mg*h/L); H – slope function for CRP inhibition; EC50 – MER concentration (mg/L) that produces half maximum CRP inhibition) [2]. Relationship of PKPD indices daily average MER AUC to EC50 ratio (AUC24:EC50), percentage of time of MER concentration above EC50 (TEC50), mean ratio of MER peak concentration to EC50 (Cmax:EC50), mean ratio of MER trough concentration to EC50 (Cmin:EC50) with inhibition of CRP synthesis at various time periods (ratio of CRP concentration within time periods 72-96, 96-120 or 120-144 h to CRP concentration within 0-24 h after start of treatment) at log10-log10 scale was described by linear regression. Regression tree was used to find PKPD index value in which case patients achieve significantly smaller CRP ratio for a given time interval.
Results. From 18 neonates (mean (range) gestational age 26.6 (24.6-30.1) w; postnatal age 16 (2-31) d; 15 (83.3%) had sepsis, 3 (16.7%) pneumonia) 180 CRP concentrations were collected. Mean (range) CRP concentrations 0-24, 72-96, 96-120 or 120-144 h after start of treatment were 67 (4-193), 36 (2-186), 25 (4-153) and 11 (5-32) mg/L, respectively.
PD model parameter estimates (standard errors) were KCRPprod 0.046 (0.0548) mg*h/L, KCRPinh 0.124 (0.0036) mg*h/L, EC50 24.5 (0.184) mg/L, H 14.7 (0.23). POPmax was fixed to maximum CRP value in the dataset (305 mg/L). Interindividual variability was retained only in KCRPprod (85.6%) and EC50 (96.7%). Proportional residual variability was 47.9%.
Relationship between PKPD indices and inhibition of CRP synthesis at 72-96, 96-120 and 120-144 h was linear at log10-log10 scale and strongest (in terms of coefficient of determination) at 96-120 h compared with other times after start of treatment. At 96-120 h after start of treatment median (range) AUC24:EC50 was 22 (11-316), TEC50 37 (10-100), Cmax:EC50 1.9 (1.2-44.1), Cmin:EC50 0.2 (0.04-1.3), coefficients of determination (p-value of linear regression coefficient) with inhibition of CRP synthesis at 96-120 h 0.55 (0.002), 0.73 (<0.001), 0.23 (0.09), 0.55 (0.002), respectively. According to regression tree TEC50 >32.3% was associated with smaller inhibition of CRP synthesis at 96-120 h compared with TEC50 <32.3% (ratio of CRP concentrations within 96-120 h to 0-24 h after start of treatment 0.22 vs 0.92).
Conclusions. Use of PKPD indices based on CRP dynamics early in the treatment, particularly time above EC50, can predict treatment response (CRP decline) in neonates with late-onset sepsis or pneumonia. These indices could guide AB treatment through individualized dosing based on routinely collected clinical data. This approach may have potential to overcome the lack of pathogen MIC data, but warrant further larger and prospective studies.
References:
[1] Padari, H., T. Metsvaht, L. T. Kõrgvee, E. Germovsek, M. L. Ilmoja, K. Kipper, K. Herodes, J. F. Standing, K. Oselin & I. Lutsar (2012) Short versus long infusion of meropenem in very-low-birth-weight neonates. Antimicrob Agents Chemother, 56, 4760-4.
[2] Ramos-Martin, V., M. N. Neely, P. McGowan, S. Siner, K. Padmore, M. Peak, M. W. Beresford, M. A. Turner, S. Paulus & W. W. Hope (2016) Population pharmacokinetics and pharmacodynamics of teicoplanin in neonates: making better use of C-reactive protein to deliver individualized therapy. J Antimicrob Chemother, 71, 3168-3178.
Reference: PAGE () Abstr 9429 [www.page-meeting.org/?abstract=9429]
Poster: Drug/Disease Modelling - Infection