Evaluation of Meropenem‐Ciprofloxacin Combination Dosage Regimens for the Pharmacokinetics of Critically Ill Patients With Augmented Renal Clearance

Abstract

Augmented renal clearance (ARC, creatinine clearance > 130 mL/minute) makes difficult achievement of effective concentrations of renally cleared antibiotics in critically ill patients. This study examined the synergistic killing and resistance suppression for meropenem-ciprofloxacin combination dosage regimens against Pseudomonas aeruginosa isolates within the context of ARC. Clinically relevant meropenem and ciprofloxacin concentrations, alone and in combinations, were studied against three clinical isolates with a range of susceptibilities to each of the antibiotics. Isolate Pa1280 was susceptible to both meropenem and ciprofloxacin, Pa1284 had intermediate susceptibility to meropenem and was susceptible to ciprofloxacin, and CR380 was resistant to meropenem and had intermediate susceptibility to ciprofloxacin. Initially, isolates were studied in 72-hour static-concentration time-kill (SCTK) studies. Subsequently, the pharmacokinetic profiles expected in patients with ARC receiving dosage regimens, including at the highest approved daily doses (meropenem 6 g daily divided and administered as 0.5-hour infusions every 8 hours, or as a continuous infusion; ciprofloxacin 0.4 g as 1-hour infusions every 8 hours), were examined in a dynamic hollow-fiber infection model (HFIM) over 7-10 days. In both SCTK and HFIM, combination regimens were generally synergistic and suppressed growth of less-susceptible subpopulations, these effects being smaller for isolate CR380. The time-courses of total and less-susceptible bacterial populations in the HFIM were well-described by mechanismbased models, which enabled conduct of Monte Carlo simulations to predict likely effectiveness of approved dosage regimens at different creatinine clearances. Optimized meropenem-ciprofloxacin combination dosage regimens may be a viable consideration for P. aeruginosa infections in critically ill patients with ARC.

Are Antibiotics Appropriately Dosed in Critically Ill Patients with Augmented Renal Clearance? A Narrative Review

“…In addition to doses and strategy of infusion, Agyeman A. A. et al recommended combination therapy with meropenem and ciprofloxacin against P. aeruginosa isolates to increase synergistic killing and decrease resistance in patients with ARC [ 22 ].…”

The selection of antibiotic- and bacteriophage-resistant Pseudomonas aeruginosa is prevented by their combination

“…In this study, we developed an innovative use of the HFIM to evaluate the potential benefit of combining ciprofloxacin with phages. The HFIM allows the simulation of a clinically relevant ciprofloxacin concentration profile obtained with oral treatment that leads in monotherapy to the selection of clones with increasing resistance as previously reported [9][10][11]. The combination of ciprofloxacin and meropenem in the HFIM suppressed the growth of resistant P. aeruginosa isolates, including hypermutable strains [10,11].…”

“…Next, multiple mutations lead to a higher MIC, clinical resistance [4], and ultimately require ciprofloxacin to be associated with other antibiotics, upscaling drug use [7,8]. Interestingly, the gradual increase of MIC is reproduced in vitro by mimicking the clinical regimens of ciprofloxacin, providing a mean to study the efficacy of combined treatments [9][10][11].…”

Augmented Renal Clearance: What Have We Known and What Will We Do?

“…It was found that under ARC conditions, the intermittent dosing regimen of meropenem and ciprofloxacin as monotherapy is not effective against Pseudomonas aeruginosa , even at the maximum approved daily dose for sensitive strains. However, the combination of the intermittent dosing regimen could effectively suppress organisms ( Agyeman et al, 2021 ).…”