DISCUSSION
This study has shown that ARC was associated with lower concentrations and a higher risk of not achieving PD targets in critically ill patients even when administering meropenem by intermittent infusion (infused over 4- hr) since that, 77.7% and 16.6% of all samples not attained to 100%ft> MIC and 50%ft>MIC, respectively. In group 1(3g daily), 83.3% and 16.6 % of patients do not achieved 100%ft> MIC and 50%ft>MIC, respectively. In accordance with this consequence, previous studies with Carlier et al ., have demonstrated that 76% and 37% of critically ill patients with ARC, who received meropenem 1g every 8 hours as a 3-hr infusion, did not achieve 100%ft> MIC and 50%ft>MIC, respectively [21].
In the prospective observational study, Ehmann and colleagues mentioned that target attained, 50%ft>MIC and 100%ft> MIC, for Gram-negative pathogens with MIC 2 µg/mL, was zero percent in critically ill patients with ARC with the administration of meropenem 1g every 8 hours infused over 30 minutes and concluded that increasing dose or increasing infusion time could increase the number of patients who achieve to therapeutic targets [22]. A comparison of our findings with the mentioned study confirmed prolonged infusion (4-hr vs. 30 minutes) and higher doses (6g daily vs. 3g daily) increase the likelihood of achieving the target plasma concentrations.
Studies have shown that 40% to 70% ft>MIC is necessary for time-dependent antibiotics such as meropenem to treat infections [23]. However, many studies in critically ill patients demonstrated that to maximize the effect of β-lactam antibiotics, it is better to increase the ft to 100% (100%ft>MIC) or to maintain the concentration four times the MIC for the entire dosing interval (100%ft>4MIC) [24, 25]. In our study, we did not achieve 100%ft>4MIC in all samples, even in group 2 (6g daily), with 4-hr infusion in critically ill patients with ARC. Vd of meropenem in critically ill patients with ARC increased in comparison with healthy volunteers (reported Vd in our study and healthy volunteers were 77.15-118.02 L vs. 15-20 L, respectively) [26]. This result is in accordance with other studies in critically ill patients [27, 28].
Also, clearance of meropenem obtained from healthy volunteers was 7.82 L/hr [16], but, in our study clearance increased due to augmented renal perfusion in patients with ARC (41.25-42.85 L/hr), this is higher than those reported by other studies in critically ill patients (4.7 to 15.4 L/hour) [27, 28].
Another finding of our study was increased Vd in our subjects, which could reduce the concentration of time-dependent antibiotics such as meropenem. Due to the relationship between Vd and the loading dose (LD), the use of aggressive LD suggested in critically ill patients with ARC to overwhelm increased Vd [29]. The correlation between the clearance of meropenem and renal clearance has been proven [28]. Therefore, increases in renal clearance can lead to a decrease in concentrations. Low serum concentrations of meropenem in our study confirms these results [21, 30], so, because of the relationship between maintenance dose (MD) and clearance, MD can be initiated higher than the recommended doses of meropenem in critically ill patients with ARC [21, 31].
In coclusion, ARC is an essential cause of sub-therapeutic concentrations of meropenem in critically ill patients, and higher than the recommended doses of meropenem administered as an intermittent infusion may be necessary to achieve the PD targets and improve efficacy.