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Colistin Dosing Regimens against Pseudomonas aeruginosa in Critically Ill Patients: An Application of Monte Carlo Simulation.

ABSTRACT: Our aims are to assess various colistin dosing regimens against Pseudomonas aeruginosa (P. aeruginosa) infection in critically ill patients and to propose an appropriate regimen based on microbiological data. A Monte Carlo simulation was performed using the published colistin's pharmacokinetic parameters of critically ill patients, the published pharmacodynamic target from a mouse thigh infection model, and the minimum inhibitory concentration (MIC) results from a Vietnamese hospital. The probability of target attainment (PTA) of 80% and cumulative fraction of response (CFR) of 90% were used to evaluate the efficacy of each regimen. Of 121 P. aeruginosa laboratory datasets, the carbapenem-resistant P. aeruginosa (CRPA) and the colistin-resistant P. aeruginosa rates were 29.8% and 0.8%, respectively. MIC_50,90 were both 0.5 mg/L. The simulated results showed that at MIC of 2 mg/L, most regimens could not reach the PTA target, particularly in patients with normal renal function (Creatinine clearance (CrCl) ≥ 80 mL/min). At MIC of 0.5 mg/L and 1 mg/L, current recommendations still worked well. On the basis of these results, aside from lung infection, our study recommends three regimens against P. aeruginosa infection at MIC of 0.5 mg/L, 1 mg/L, and 2 mg/L. In conclusion, higher total daily doses and fractionated colistin dosing regimens could be the strategy for difficult-to-acquire PTA cases, while a less aggressive dose might be appropriate for empirical treatment in settings with low MIC_50/90.

SUBMITTER: Nguyen VTK

PROVIDER: S-EPMC8157232 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Project description:ObjectivesProlonged intermittent renal replacement therapy is an increasingly popular treatment for acute kidney injury in critically ill patients that runs at different flow rates and durations than conventional hemodialysis or continuous renal replacement therapies. Pharmacokinetic studies conducted in patients receiving prolonged intermittent renal replacement therapy are scarce; consequently, clinicians are challenged to dose antibiotics effectively. The purpose of this study was to develop vancomycin dosing recommendations for patients receiving prolonged intermittent renal replacement therapy.MethodsMonte Carlo simulations were performed in thousands of virtual patients derived from previously published demographic, pharmacokinetic, and dialytic information derived from critically ill patients receiving vancomycin and other forms of renal replacement therapy. We conducted "in silico" vancomycin pharmacokinetic/pharmacodynamics analyses in these patients receiving prolonged intermittent renal replacement therapy to determine what vancomycin dose would achieve vancomycin 24-h area under the curve (AUC24h) of 400-700?mg·h/L, a target associated with positive clinical outcomes. Nine different vancomycin dosing regimens were tested using four different, commonly used prolonged intermittent renal replacement therapy modalities. A dosing nomogram based on serum concentration data achieved after the third dose was developed to individualize vancomycin therapy.ResultsAn initial vancomycin dose of 15 or 20?mg/kg immediately followed by 15?mg/kg after subsequent prolonged intermittent renal replacement therapy treatments achieved AUC24h of ?400?mg·h/L for ?90% of patients regardless of prolonged intermittent renal replacement therapy duration, modality, or time of vancomycin dose relative to prolonged intermittent renal replacement therapy. Many patients experienced AUC24h of ?700?mg·h/L, but once the dosing nomogram was applied to serum concentrations obtained after the third vancomycin dose, 67%-88% of patients achieved AUC24h of 400-700?mg·h/L.ConclusionAn initial loading dose of 15-20?mg/kg followed by a maintenance regimen of 15?mg/kg after every prolonged intermittent renal replacement therapy session coupled with serum concentration monitoring should be used to individualize vancomycin dosing. These predictions need clinical verification.

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Colistin Dosing Regimens against Pseudomonas aeruginosa in Critically Ill Patients: An Application of Monte Carlo Simulation.

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