Continuous infusion of meropenem in critically ill patients: practical considerations

In a recent study, Chytra et al. demonstrated that continuous infusion of meropenem provided better clinical outcome and bacteriological efficacy in a large cohort of septic patients. Additional considerations on the drug regimen and administration as well as the potential target population are discussed in this letter.

I read with interest the article from Chytra and colleagues, who investigated the eff ectiveness and safety of continuous infusion (CI) of meropenem compared with intermittent infusion (II) in a large cohort (n = 240) of critically ill patients [1]. Th ey found that although clinical cure at the end of therapy was similar between the two strategies, micro bio logical success was higher in the CI group and was independently associated with continuous drug adminis tration. CI was also associated with a shorter ICU stay, as well as shorter duration of therapy and a lower total dose of meropenem. Th is paper highlights the potential benefi ts of CI of β-lactams compared with standard adminis tration in critically ill patients, which has already been suggested in previous retrospective studies [2]. Nevertheless, some points need to be discussed.
First, the doses of meropenem used by Chytra and colleagues could be largely criticized. Th e authors have already under lined how the CI strategy received a lower daily regimen than the bolus strategy (4 g/day vs. 6 g/day) and the use of such an approach showed only clinical equivalence with but not superiority to II in clinical trials [3]. More importantly, the II group was treated with higher than recommended daily regimens (2 g every 8 hours rather than 1 g every 8 hours). In severe sepsis and septic shock, a 1 g loading dose of meropenem resulted in optimal serum concentrations to treat pathogen with a minimal inhibitory concentration (MIC) of 2 μg/ml in 75% of patients, while it provided adequate drug levels for lower MICs in all patients [4]. Th e same results were shown for both loading and steady-state doses when serum and subcutaneous drug levels were measured [5]. Calculating the doses of meropenem on popu lation pharmacokinetic models from patients without critically illness may thus under esti mate antibiotic concentrations measured in real popu lations and result in unnecessarily high drug regimens. Future research should therefore consider standard drug regimens (1 g every 8 hours) as a valuable control for CI strategies in septic patients.
Second, the CI group received 4 g meropenem over 24 hours, aiming to reach 100% of the time that drug concentrations would be above the MIC (T>MIC) for most Gram-negative pathogens. Nevertheless, carba pen ems need only 40% T>MIC to have bactericidal eff ects, because of the signifi cant post-antibiotic eff ect and enhanced leucocyte activity shown in in vitro models [6]. As such, prolonging the infusion of meropenem over 3 hours between two administrations would be suffi cient to maximize its antibacterial activity [3]. Clearly, further clinical investigations are needed to better identify the optimal T>MIC to use when CI of β-lactams is given during life-threatening infections.
Th ird, because the median MIC of the pathogens was approximately 0.125 μg/ml, it is diffi cult to understand how CI could result in higher clinical cure and bacteriological response rates when compared with II. In one study, CI of cefepime resulted in similar clinical outcome and bacterial eradication when compared with II in critically ill patients [7]; however, the eff ectiveness of drug concentrations at steady state was also similar between the two strategies because most of the isolated pathogens were highly susceptible to the study drug. On the contrary, CI of ceftazidime was associated with a greater clinical cure rate than II in patients with ventilatorassociated pneumonia, particularly for those infections caused by organisms with MIC 8 μg/ml [2]. A CI strategy may evidently result in better clinical outcome only when treating less susceptible strains, in which II is unable to achieve adequate T>MIC, and would not necessarily be more advantageous for all critically ill patients.

Ivan Chytra, Martin Stepan, Jan Benes, Petr Pelnar, Alexandra Zidkova, Tamara Bergerova, Richard Pradl and Eduard Kasal
We thank Dr Taccone for his interest in our article [1] and for his remarks. In general, we agree with most of them. We actually tried to address similar comments in the discussion of our article. Nevertheless, we would like to add a few remarks and clarifi cations.
First, when we designed and started the study (2007), the dose of meropenem (2 g every 8 hours) for intermittent administration was calculated according to the suggestion for achievement of the antibiotic's optimal probability of target attainment and cumulative fraction of response in critically ill patients with serious infections [8,9]. In view of the later published results from Taccone and colleagues [4] and owing to the low MIC of pathogens in our study, however, we retrospectively fi nd the dose used (2 g every 8 hours) unnecessarily high.
Second, although in carbapenems the recommended minimum percentage of the dosing interval for T>MIC is only 40%, in patients with serious bacterial infections the achievement of 100% T>MIC displayed a signifi cantly greater clinical cure (82% vs. 33%, P = 0.002) and bacterio logical eradication (97% vs. 44%, P <0.001) [10,11]. Maintaining antibiotic concentrations above the MIC for 100% of the dosing interval was thus used in our study.
Th ird, we agree with the statement that the effi cacy of CI of β-lactams should be investigated in a population suff ering from infections caused by less susceptible strains with elevated MICs (which we also pointed out in the conclusion to our article [1]).
To conclude, we concur with the comments of Dr Taccone and we originally strove to elucidate them in the discussion of our article [1]. Bearing in mind these new facts and information, we would respect them if designing the study in the present day.
Abbreviations CI, continuous infusion; II, intermittent infusion; MIC, minimum inhibitory concentration; T>MIC, time above the minimum inhibitory concentration.