Xin Liu1, Adela Benitez-Cano Martinez2, Sònia Luque Pardos2, Xiao Zhu1
1School of Pharmacy, Fudan University, 2Institut Hospital del Mar d’Investigacions Mèdiques (IMIM)
Introduction: Nosocomial urinary tract infections (UTIs) caused by Gram-positive bacteria, mainly Staphylococcus and Enterococcus species, pose significant clinical challenges[1,2]. Many important antibiotics like cephalosporins and aminopenicillins are rendered suboptimal due to intrinsic resistance[3]. Linezolid (LNZ) is a promising alternative for resistant infections, especially in patients with renal impairment and intolerant to nephrotoxic drugs, since it only has approximately 30% renal excretion[4,5].However, the pharmacokinetics (PK) and pharmacodynamics (PD) of LNZ in renal impairment remain unclear, requiring further investigation. Objectives: The aim is to investigate the urinary PK and PD characteristics of LNZ in patients with renal impairment and to explore potential dosing strategies for these patients. Methods: This observational study was conducted at the Surgical Intensive Care Unit of Hospital del Mar, Spain. Critically ill patients with acute/chronic renal impairment receiving intravenous LNZ (600 mg, BID) for at least 72 hours were included. TDM measurements of LNZ concentrations in plasma and urine were taken during routine clinical practice. Both samples were collected at steady-state: immediately before dosing, 1.5h, 4h, 8h, 12h post-infusion. Hourly urine volume was recorded for 12h. One compartment model was developed to describe the plasma PK with two separated clearance paths: renal clearance (CLR) and non-renal clearance(CLNR). Then the plasma PK model was mechanistically linked to the bladder compartment via CLR to capture the urine PK. To improve model identifiability, the urinary clearance (CLU) was assumed equal to urine flow, estimated from hourly urine volume records. FOCE-I algorithm in NONMEM was used for parameter estimation. The interindividual variability was described via an exponential model, except for CLU where the Box-Cox transformation was used. The eGFR on CLR and CLU, weight on CL and distribution volumes, were a priori tested. Other covariates were screened by SCM (forward inclusion: p<0.05, backward elimination: p<0.01). The final model was evaluated by GOF, VPC plots and SIR. PK/PD target attainment (AUC/MIC=80) across different CKD stages and various dosing regimens (300, 400, 500, and 600 mg BID) was assessed using Monte-Carlo simulations. Results: Twenty patients (age: 63–93 years, eGFR: 9–54 mL/min/1.73 m²) were included. The GOF and VPC plots showed the developed model could simultaneously describe the plasma PK, urine PK and urine volume over time. Model parameters were precisely estimated (RSE <50%) with satisfactory SIR results. The estimates of clearance parameters were: CLNR 4.9 L/h, CLR 0.261 L/h, and CLU 0.062 L/h. Approximately 5% (CLR/(CLNR+CLR)) of the administered LNZ dose was excreted via urine in renal impairment patients. The estimates of volume parameters were: VC 45.4 L and Vbladder 0.0647 L, respectively. Weight was incorporated via allometric scaling (CL: 0.75; V: 1, ?OFV= -2.11) and eGFR was added on CLR and CLU with exponential scaling factors of 1.34 and 0.709, respectively (?OFV= -24.263). Age was negatively associated with both CLNR and CLR (-0.0364 per year, ?OFV= – 23.088). The simulations indicated that increasing eGFR significantly increased urinary exposure, and advancing age significantly elevated plasma exposure. While weight was negatively associated with both plasma and urinary exposure. Dosing simulations indicated that, with an AUC24/MIC target of =80, no dosage regimen achieved sufficient drug concentrations to effectively treat UTIs in patients with eGFR <15 mL/min/1.73 m². For patients with eGFR between 15 and 60 mL/min/1.73 m², a dosage of 300 mg BID achieved =90% PTA for Staphylococcus UTIs (MIC = 2 mg/L), while 600 mg BID was necessary to achieve =90% PTA for Enterococcus UTIs (MIC = 4 mg/L). For patients with eGFR over 60 mL/min/1.73 m², 300 mg BID was adequate, achieving =90% PTA for both Staphylococcus (MIC = 2 mg/L) and Enterococcus (MIC = 4 mg/L) UTIs. Conclusion: This study highlights that eGFR was positively associated with LNZ urinary exposure. A regular regimen of LNZ 600 mg BID was effective in treating UTIs in renal impairment patients, except for those with kidney failure (eGFR <15 mL/min/1.73 m²).
[1] Kline KA. Physiol Behav. 2016;176(3):139–48. [2] Hidron AI, et al. Infect Cont Hosp Ep. 2008;29(11):996–1011. [3] Hollenbeck BL, et al. Virulence. 2012;3(5):421–569. [4] Wagenlehner FME, et al. Int. J. Antimicrob. Agents 2004;24:39–43. [5] Florian ME, et al. Antimicrob. Agents Chemother. 2003;47(12):3789–94.
Reference: PAGE 33 (2025) Abstr 11772 [www.page-meeting.org/?abstract=11772]
Poster: Clinical Applications