Relationship between continuous infusion meropenem PK/PD target attainment and C‐reactive protein dynamics in onco‐haematologic patients with febrile neutropenia

Aim: Meropenem is a second-line antimicrobial agent in the treatment of febrile neutropenia in onco-haematological patients. A population pharmacokinetic/pharmacodynamic (PK/PD) analysis for assessing the relationship between meropenem exposure and C-reactive protein (C-RP) over time was conducted. Methods: Non-linear mixed-effect modelling was used to fit meropenem and C-RP concentrations. Monte Carlo simulations were conducted to assess median percentage reduction of C-RP from baseline associated with continuous infusion meropenem dosing, ensuring optimal PK/PD target attainment against Pseudomonas aeruginosa and Enterobacterales, namely, 100%t>4 × MIC. Clinical outcome was assessed at the end of antimicrobial treatment. Results: A total of 141 patients were included in the analysis. A one-compartment model with estimated glomerular filtration rate as a covariate on drug clearance well-described meropenem pharmacokinetics. An indirect turnover maximum inhibition model was used to capture C-RP dynamics. Patients with C-RP Day 4/baseline ratio of <0.4 (fast response), between 0.4 and 0.8 (slow response) and >0.8 (no response) were 8.5%, 15.6% and 75.9%, respectively. Regression analysis showed that patients with fast and slow response patterns were associated with favourable clinical outcomes. Simulations showed that rapid and slow pattern patients reached C-RP reduction >90% from baseline at Days 6 and 10, respectively. No response pattern had C-RP peaking at Day 3 and eventually gradually reducing within 2 weeks. Conclusion: Despite optimal meropenem PK/PD target attainment, C-RP decreases in no more than one-fourth of onco-haematological patients during the first 2 weeks of treatment. Among no-response patients, C-RP should be associated with other biomarkers to discriminate subjects with favourable clinical outcome.