Population Pharmacokinetics of Continuous-Infusion Meropenem in Febrile Neutropenic Patients with Hematologic Malignancies: Dosing Strategies for Optimizing Empirical Treatment against Enterobacterales and P. aeruginosa

Abstract

A population pharmacokinetic analysis of continuous infusion (CI) meropenem was conducted in a prospective cohort of febrile neutropenic (FN) patients with hematologic malignancies. A non-parametric approach with Pmetrics was used for pharmacokinetic analysis and covariate evaluation. Monte Carlo simulations were performed for identifying the most appropriate dosages for empirical treatment against common Enterobacterales and P. aeruginosa. The probability of target attainment (PTA) of steady-state meropenem concentration (Css)-to-minimum inhibitory concentration (MIC) ratio (Css/MIC) ≥1 and ≥4 at the European Committee on Antimicrobial Susceptibility Testing (EUCAST) clinical breakpoint of 2 mg/L were calculated. Cumulative fraction of response (CFR) against Enterobacterales and P. aeruginosa were assessed as well. PTAs and CFRs ≥ 90% were considered optimal. A total of 61 patients with 178 meropenem Css were included. Creatinine clearance (CLCR) was the only covariate associated with meropenem clearance. Monte Carlo simulations showed that dosages of meropenem ranging between 1 g q8h and 1.25 g q6h by CI may grant optimal PTAs of Css/MIC ≥4 at the EUCAST clinical breakpoint. Optimal CFRs may be granted with these dosages against the Enterobacterales at Css/MIC ≥ 4 and against P. aeruginosa at Css/MIC ≥ 1. When dealing against P. aeruginosa at Css/MIC ≥ 4, only a dosage of 1.5 g q6h by CI may grant quasi-optimal CFR (around 80–87%). In conclusion, our findings suggest that dosages of meropenem ranging between 1 g q8h and 1.25 g q6h by CI may maximize empirical treatment against Enterobacterales and P. aeruginosa among FN patients with hematologic malignancies having different degree of renal function.

Continuous versus intermittent infusion of antibiotics in Gram-negative multidrug-resistant infections

“…Recently, Cojutti et al [32] found that CI meropenem at a dosage ranging between 1 g q8 h over 8 h and 1.25 g q6 h over 6 h allowed the achievement of optimal PK/PD target in terms of steady state concentration [C ss ]/MIC ratio ≥ 4 against Enterobacteriaceae among febrile neutropenic patients affected by hematological malignancies. Similarly, a CI dosage of 1.5 g q6 h over 6 h was required to achieve aggressive PK/PD target against P. aeruginosa [32].…”

“…Recently, Cojutti et al [32] found that CI meropenem at a dosage ranging between 1 g q8 h over 8 h and 1.25 g q6 h over 6 h allowed the achievement of optimal PK/PD target in terms of steady state concentration [C ss ]/MIC ratio ≥ 4 against Enterobacteriaceae among febrile neutropenic patients affected by hematological malignancies. Similarly, a CI dosage of 1.5 g q6 h over 6 h was required to achieve aggressive PK/PD target against P. aeruginosa [32]. Notably, the approach of adjusting CI meropenem dosage among oncohematologic patients with febrile neutropenia on the basis of real-time therapeutic drug monitoring (TDM) allowed not only to attain aggressive PK/PD target of Css/MIC of 4–8, but also to prevent the occurrence carbapenem-producing Enterobacteriaceae (CPE), as documented by the lack of CPE isolates at rectal swab during a 3-month follow-up period [33 ▪ ].…”

The Dutch Working Party on Antibiotic Policy (SWAB) Recommendations for the Diagnosis and Management of Febrile Neutropenia in Patients with Cancer

“…It has been advocated that PK/PD targets may be higher in patients without alternative defense mechanisms, such as neutropenic patients [ 42 ], and administration by prolonged infusion may yield the highest chances of reaching the required targets. Moreover, in febrile neutropenic patients with hematological malignancies, certain underlying conditions may alter the PK of hydrophilic antibiotics such as beta-lactams, further compromising PD target attainment for P. aeruginosa and Enterobacterales using standard intermittent infusion regimens [ 43 ]. Administration by prolonged infusion may be imperative to reach the required PK/PD target, with both extended and continuous infusion having proven to be successful dosing strategies in PK studies with antipseudomonal beta-lactams [ 43 – 47 ].…”

“…Moreover, in febrile neutropenic patients with hematological malignancies, certain underlying conditions may alter the PK of hydrophilic antibiotics such as beta-lactams, further compromising PD target attainment for P. aeruginosa and Enterobacterales using standard intermittent infusion regimens [ 43 ]. Administration by prolonged infusion may be imperative to reach the required PK/PD target, with both extended and continuous infusion having proven to be successful dosing strategies in PK studies with antipseudomonal beta-lactams [ 43 – 47 ]. Clinical data on effects of the beta-lactam infusion mode in neutropenic patients, however, are scarce.…”

Does Cytokine-Release Syndrome Induced by CAR T-Cell Treatment Have an Impact on the Pharmacokinetics of Meropenem and Piperacillin/Tazobactam in Patients with Hematological Malignancies? Findings from an Observational Case-Control Study

“…For the treatment of severe infections, high-dosing regimens of meropenem administered by 24-h CI has been advocated in different clinical settings [ 16 , 17 ]. Specifically, in order to maximize empirical treatment of Enterobacterales and Pseudomonas aeruginosa in FN patients with hematologic malignancies, Monte Carlo simulations suggest the use of meropenem dosages ranging from 3 to 5 g daily by 24-h CI in relation to patient renal function.…”