Finding the Dose for Ceftolozane-Tazobactam in Critically Ill Children with and without Acute Kidney Injury

Abstract

Background: Ceftolozane-tazobactam is a new antibiotic against multidrug-resistant pathogens such as Pseudomonas aeruginosas. Ceftolozane-tazobactam dosage is still uncertain in children, especially in those with renal impairment or undergoing continuous renal replacement therapy (CRRT). Methods: Evaluation of different ceftolozane-tazobactam dosing regimens in three critically ill children. Ceftolozane pharmacokinetics (PK) were characterized by obtaining the patient’s specific parameters by Bayesian estimation based on a population PK model. The clearance (CL) in patient C undergoing CRRT was estimated using the prefilter, postfilter, and ultrafiltrate concentrations simultaneously. Variables such as blood, dialysate, replacement, and ultrafiltrate flow rates, and hematocrit were integrated in the model. All PK analyses were performed using NONMEM v.7.4. Results: Patient A (8 months of age, 8.7 kg) with normal renal function received 40 mg/kg every 6 h: renal clearance (CLR) was 0.88 L/h; volume of distribution (Vd) Vd1 = 3.45 L, Vd2 = 0.942 L; terminal halflife (t1/2,β) = 3.51 h, dosing interval area under the drug concentration vs. time curve at steady-state (AUCτ,SS) 397.73 mg × h × L−1. Patient B (19 months of age, 11 kg) with eGFR of 22 mL/min/1.73 m2 received 36 mg/kg every 8 h: CLR = 0.27 L/h; Vd1 = 1.13 L; Vd2 = 1.36; t1/2,β = 6.62 h; AUCSS 1481.48 mg × h × L−1. Patient C (9 months of age, 5.8 kg), with severe renal impairment undergoing CRRT received 30 mg/kg every 8 h: renal replacement therapy clearance (CLRRT) 0.39 L/h; Vd1 = 0.74 L; Vd2= 1.17; t 1/2,β = 3.51 h; AUCτ,SS 448.72 mg × h × L−1. No adverse effects attributable to antibiotic treatment were observed. Conclusions: Our results suggest that a dose of 35 mg/kg every 8 h can be appropriate in critically ill septic children with multi-drug resistance Pseudomonas aeruginosa infections. A lower dose of 10 mg/kg every 8 h could be considered for children with severe AKI. For patients with CRRT and a high effluent rate, a dose of 30 mg/kg every 8 h can be considered.

Antimicrobial Dose Reduction in Continuous Renal Replacement Therapy: Myth or Real Need? A Practical Approach for Guiding Dose Optimization of Novel Antibiotics

“…Overall, the search strategy identified 70 articles that were assessed for eligibility. Fifty-five of these articles did not fulfil the inclusion criteria, resulting in the inclusion of 15 original studies (3 population PK studies and 12 case reports) [24][25][26][27][28][29][30][31][32][33][34][35][36][37][38] assessing the PK behaviour of novel agents in critically septic patients requiring CRRT (Fig. 1).…”

“…One population PK study and seven case reports assessed the PK behaviour of ceftolozane-tazobactam in 13 different critically patients requiring CRRT, including one child [24,[27][28][29][30][31][32][33]. Different dosing schedules (1.5 g or 3 g every 8 h) were administered.…”

Pharmacokinetics of Antibiotics in Pediatric Intensive Care: Fostering Variability to Attain Precision Medicine

“…Finally, a recent case series of three critically ill children with different renal functions (normal, decreased, and CRRT) treated with ceftolozane/tazobactam described the PK differences amongst these three patients [90]. The CL of ceftolozane/tazobactam under CRRT was approximately half of the CL in the child with normal renal function, which has also been described in adult patients.…”

Anti-infective Medicines Use in Children and Neonates With Pre-existing Kidney Dysfunction: A Systematic Review

“…In the study by Butragueño-Laiseca and colleagues, data on dosing regimens of ceftolozane-tazobactam in three critically-ill children, of which two had kidney impairment, were reported ( 42 ). Patient B, of 19 months of age with hypoplastic left heart syndrome at Glenn stage, had pneumonia due to MDR P. aeruginosa and stage II KDIGO AKI with eGFR of 22 mL/min/1.73 m 2 ; he received an adjusted dose of 36 mg/kg every 8 h. Patient C, of 9 months and on CKRT after heart transplantation, had pneumonia due to MDR P. aeruginosa and ESBL E. coli bacteremia, for which he received 30 mg/kg every 8 h. CKRT settings were blood flow 30 mL/min, substitution flow 160 mL/h, dialysis flow 250 mL/h, extraction 60 mL/h, and total effluent flow 470 mL/h.…”

“…Last, inter-individual variabilities must be considered in these complex contexts while defining the most appropriate dosing regimen, ensuring safety and efficacy with therapeutic drug monitoring and adjustments by the development of PK models based on Monte Carlo or Bayesian simulations, whenever possible ( 27 , 28 , 31 , 42 , 49 ).…”