Pharmacokinetics Of Meropenem In Critically Ill Adult Patients Receiving Continuous Renal Replacement Therapy

Background:Patients admitted to Intensive Care Units (ICUs) are at very high risk of developing severe nosocomial infections, with incidence rates ca. five-to ten-fold higher than in general medical wards, with high use of antimicrobials. The widespread use of antimicrobials has been identified as an important factor in the emergence of resistance, together with the crowding of patients with complexmedical problems into small areas of the hospital and the presence of more chronically and acutely ill patients who require prolonged hospitalisation. Inappropriate use of antimicrobialsmay be responsible for higher therapeutic failure, mortality rates, costs and patient toxicity as well as emergence of resistance.Antibiotic treatment of critically ill patients remains a significant challenge to intensivists world-wide with persisting high mortality and morbidity rates. Compelling evidence suggests that in infected critically ill patients, source control of the pathogen and early and appropriate antibiotic therapy remains the most important intervention that the clinician can implement for such patients. Therefore, optimizing antibiotic therapy should be a priority in the management of critically ill patients.Meropenem is a new carbapenem antibiotic with a broad spectrum of antibacterial activity against gram-positive as well as gram-negative pathogens, including beta-lactamase producers and Pseudomonas aeruginosa. The drug is therefore frequently employed in critically ill patients with severe infections or sepsis when the causative organism is unknown and beta-lactamase-mediated resistance has to be considered. Continuous renal replacement therapy (CRRT) is now commonly used as a means of support for critically ill patients with renal failure, and is likely to alter the pharmacokinetics of meropenem in these patients. Pharmacokinetic studies of meropenem in critically ill patients being treated with CVVH, however, are scarce. Because a routine dosing regimen cannot be applied, clinicians risk missing bactericidal plasma drug levels or causing severe side effects.Purpose:Give the single-dose meropenem of 1g to the critically ill patients with continuous renal replacement therapy (CRRT), to collect the blood samples, the concentrations of meropenem at different times were measured by high performance liquid chromatography (HPLC). Calculate the pharmacokinetic parameters, and study the pharmacokinetic characteristics of meropenem in critically ill patients with CRRT. then provide the data basis for the rational drug development program of meropenem in critically ill patients with CRRT.Materiala and methods:Seven critically ill patients (two females and four males) with acute renal failure receiving Continuous Renal Replacement Therapy and suspected or proven gram-positive or gram-negative infections were included in the study. The mean age and body weight were 69.1±20.7 years and 65±7.5 kg, respectively. All patients were anuric. All patients received parenteral nutrition and required mechanical ventilation. None of the patients had a known hypersensitivity to meropenem, imipenem-cilastatin or other beta-lactam antibiotics. Patients with bleeding disorders or a history of convulsions were excluded. All concomitant drugs were administered as clinically indicated.CRRT was performed as CVVH. The standard blood flow rate was 150-200mL/min. The ultrafiltrate pump rate was adjusted to 3000 ml/h. All patients received a single dose of 1.0 g of meropenem dissolved in 100 ml of physiological saline solution intravenously, which was infused over exactly 30 min. Blood samples (2mL)were drawn from the vein at 0,0.5,0.75,1.0,1.5,2,3,4,5,6,7,8 h after the start of the infusion, respectively. All blood samples were immediately centrifuged at 4000r/min for 5 min. Aliquots of plasma were instantly frozen and stored at-80℃. Establish an HPLC method to determinate the drug concentrations and calculate the pharmacokinetic parameters.Results:After intravenous drip with meropenem (1.0g) to the 7 critically ill patients with CRRT in ICU, The drug concentration-time datas are in line with a two-compartment pharmacokinetic model, The distribution half-life (t1/2a) were (0.15±0.09) h; The eliminate half-life (t1/2β) were (3.94±1.44) h; Area under the concentration-time curve (AUC) were (115.09±34.72) mg·h·L-1, The apparent volume of distribution (V) were (38.37±9.19) L, The clearance (CLs) were (8.22±7.15) L/h。Peak plasma drug concentrations measured 30 min postinfusion were 46.06±9.35 mg/mL, and trough levels after 8h of CVVH were 6.68±3.37 mg/mL.Conclusions:In conclusion, the elimination of meropenem by CVVH in patients with acute renal failure is comparable to the elimination characteristics in patients without renal failure. No dose reduction or additional dosing is required in patients with acute renal failure during CVVH, and dosing recommendations for patients with normal renal function can be applied. Trough levels of 6.68±3.37 mg/ml after 1 g doses of meropenem are above the MIC90s for gram-negative bacteria and for the most important gram-positive bacteria. In other words, 1g of meropenem every 8 h during CVVH will result in sufficient plasma antibiotic levels to cover the vast majority of pathogens in critically ill patients with ARE Because the consequences of underdosing are much more dangerous than the adverse effects of overdosing, a dose of 1.0 g meropenem every 8 h is recommended. However, the exact dose should be tailored according to weight and severity of illness as well as to the current minimal inhibitory concentration against the incriminated bacteria.