Substantial Impact of Altered Pharmacokinetics in Critically Ill Patients on the Antibacterial Effects of Meropenem Evaluated via the Dynamic Hollow-Fiber Infection Model

Abstract

Critically ill patients frequently have substantially altered pharmacokinetics compared to non-critically ill patients. We investigated the impact of pharmacokinetic alterations on bacterial killing and resistance for commonly used meropenem dosing regimens. A Pseudomonas aeruginosa isolate (MIC meropenem 0.25 mg/ liter) was studied in the hollow-fiber infection model (inoculum ϳ10 7.5 CFU/ml; 10 days). Pharmacokinetic profiles representing critically ill patients with augmented renal clearance (ARC), normal, or impaired renal function (creatinine clearances of 285, 120, or ϳ10 ml/min, respectively) were generated for three meropenem regimens (2, 1, and 0.5 g administered as 8-hourly 30-min infusions), plus 1 g given 12 hourly with impaired renal function. The time course of total and less-susceptible populations and MICs were determined. Mechanism-based modeling (MBM) was performed using S-ADAPT. All dosing regimens across all renal functions produced similar initial bacterial killing (Յϳ2.5 log 10 ). For all regimens subjected to ARC, regrowth occurred after 7 h. For normal and impaired renal function, bacterial killing continued until 23 to 47 h; regrowth then occurred with 0.5-and 1-g regimens with normal renal function (fT Ͼ5ϫMIC ϭ 56 and 69%, fC min /MIC Ͻ 2); the emergence of less-susceptible populations (Ն32-fold increases in MIC) accompanied all regrowth. Bacterial counts remained suppressed across 10 days with normal (2-g 8-hourly regimen) and impaired (all regimens) renal function (fT Ͼ5ϫMIC Ն 82%, fC min /MIC Ն 2). The MBM successfully described bacterial killing and regrowth for all renal functions and regimens simultaneously. Optimized dosing regimens, including extended infusions and/or combinations, supported by MBM and Monte Carlo simulations, should be evaluated in the context of ARC to maximize bacterial killing and suppress resistance emergence.

Intrapulmonary concentrations of meropenem administered by continuous infusion in critically ill patients with nosocomial pneumonia: a randomized pharmacokinetic trial

“…In pneumonia, a PK/PD target at the site of the infection of fT>MIC of 50% in ELF has been associated with bacterial killing and suppression of resistant subpopulation amplification in a murine model of pneumonia [14]. Unlike other PK/PD targets calculated in the plasma [45,46], this has been more precisely defined at the site of the infection. This was the pharmacodynamic target used in this analysis and is higher than that often cited for the efficacy of the carbapenem class.…”

Meropenem Combined with Ciprofloxacin Combats Hypermutable Pseudomonas aeruginosa from Respiratory Infections of Cystic Fibrosis Patients

“…Presently, the complex and costly attributes of the set up and operation of the dynamic HFIM hinders the incorporation of numerous different strains. Thus, recently published HFIM studies mostly entail one strain and replicate (41)(42)(43)(44)(45)(46). We are not aware of any previous dynamic studies that have evaluated the antibacterial effects of the meropenem with ciprofloxacin combination for CF patients with hypermutable P. aeruginosa in the HFIM.…”

Levofloxacin-ceftazidime administration regimens combat Pseudomonas aeruginosa in the hollow-fiber infection model simulating abnormal renal function in critically ill patients

“…When AUC 0-24h /MIC≥100 and/or C max / MIC> 8, the bactericidal effect was good for fluoroquinolones, and when T > MIC is more than 50%, it showed a good bactericidal effect for β-lactams. However, as observed in some studies [21][22][23], treatment failure and rapid resistance emergence happened even when T > MIC reached or approached 100% for meropenem, or AUC 0-24h /MIC was 168 for tobramycin which was 4 times of the suggested breakpoint. So it is necessary in order to find effective ways to inhibit drug resistance.…”